Applications of Pyridine Derivatives

#### **Chapter 4**

## Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications

*Edayadulla Naushad and Shankar Thangaraj*

#### **Abstract**

Heterocyclic moieties form important constituents of biologically active natural products and synthetic compounds of medicinal interest. Nitrogen heterocycles constitute important pharmacophores in drug design, especially pyridine derivatives, which are among the most frequently cited heterocyclic compounds. The isolated as well as synthesized pyridine compounds exhibited various pharmacological properties due to their diverse physiochemical properties like water solubility, weak basicity, chemical stability, hydrogen bond-forming ability, protein-binding capacity, cell permeability, and size of the molecules attracted the attention of medicinal chemists for the past few years. Their interesting molecular architecture seeks attention to isolate derivatives of medicinal interest from natural source. In this chapter, we plan to describe the isolated natural products having pyridine moiety and their pharmacological importance.

**Keywords:** pyridine, naturally isolated, nitrogen heterocyclic compounds, pharmaceutical applications

#### **1. Introduction**

Heterocyclic moieties form important constituents of biologically active natural products and synthetic compounds of medicinal interest. Thus, it is not surprising that the chemistry of heterocyclic compounds continue to receive special attention in drug discovery efforts. For more than decades, heterocycles have established one of the largest areas of exploration in organic chemistry. They contributed to the expansion of humanity from biological and industrial point of view as well as to the understanding of bioprocesses and to the efforts to advance the excellence of life [1]. Due to their diverse physiological potential, pharmacists have recently become pinched toward scaffolds with the intention of synthesizing an extensive range of novel bioactive molecules particularly natural product compounds.

Pyridine (C6H5N), an isostere of benzene, was initially isolated from the picoline by Anderson in 1846. Later, the structure of pyridine was elucidated by Wilhelm Korner (1869) and James Dewar (1871). Pyridine is one of the nuclear reactants of more than 7000 existing drug molecules of pharmaceutical importance. Pyridinebased natural products consist of a variety of interesting compounds with diverse

**Figure 1.** *Nicotine, niacin, and pyridoxine.*

structures that originate from the five kingdoms of life. Nicotine, niacin (vitamin B3 or nicotinic acid), and pyridoxine (vitamin B6) are extreme recognized compounds with an aromatic π electron pyridine moiety (**Figure 1**). The structures having other oxidation states of pyridine, such as tetrahydropyridine, dihydropyridine, piperidine, or pyridone moieties, are fewer existed than the pyridine-based natural products [2].

#### **2. Characteristic features of pyridine**

In plants, pyridine compounds are mostly originated as alkaloids. In biological systems, a redox reaction of nicotinamide adenine dinucleotide (NAD) reduces

**Figure 2.** *Effect of pyridine on physiochemical parameters.*

*Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.106663*

its pyridine moiety into dihydropyridine compounds, rendering NADH. Related redox reactions also exist in anabolic reactions involving NAD phosphate (NADP+/ NADPH) interconversion. According to the Food and Drug Administration of the United States (FDA), pyridine-and dihydropyridine-containing drugs constitute nearly 14% and 4% of all Nitrogen containing heterocyclic drugs approved by the agency [3]. Among the 18%, the most important therapeutic areas of attention are communicable infections, swelling, the nervous system, and cancer treatment.

In pharmaceuticals, a pyridine-based synthesized compound enhances its biological potency, enhances penetrability and metabolic solidity, and fixes protein-binding issues [4]. The incorporation of pyridine ring is an important strategy in the drug discovery. Vanotti et al demonstrated the effective promotion of DNA replication in eukaryotic organisms **5** by replacing the benzene group of 4 with pyridine [5]. Likewise, metabolic steadiness of sulfone-based nicotinamide phosphoribosyltransferase inhibitor **6** is enriched 160-fold when its benzene ring is replaced with pyridine

**Figure 3.** *Some commercially available drugs which contain pyridine rings.*

in **7** [6]. A pyridine ring in a compound is also adept of increasing its cell permeability. Hong et al observed that a pyridine-containing positive allosteric modulator **9** with 190-fold the cellular penetrability of **8** (**Figure 2**). It is thus valid to say that incorporation of nitrogen-containing heterocyclic moiety greatly disturbs the physicochemical parameters of the bioactive molecule [7].

Some drugs available in the market which contain pyridine rings (**Figure 3**), such as enpiroline for malaria [8], abiraterone for prostate cancer [9], nicotinamide for vitamin B deficiency [10], nikethamide for a respiratory stimulant [11], piroxicam for inflammatory [12], isoniazid to treat active TB infections [13], pyridostigmine to improve muscle strength in patients with a certain muscle disease [14], tropicamide to dilate the pupil and help with examination of the eye [15], doxylamine for the short-term treatment of insomnia [16], omeprazole to treat gastric and duodenal ulcers [17], delavirdine for an antiviral against HIV/ AIDS [18], enisamium iodide for influenza [19], and tacrine for an oral acetylcholinesterase inhibitor previously used for the prevention of Alzheimer's disease [20].

#### **3. Some pyridine scaffolds isolated from natural sources and their pharmacological importance**

Trigonelline **10** was first isolated from the fenugreek seeds, which is used as a spice in South Asian regions. Trigonelline, a plant harmone that is extensively spread in plants and also exists in many animal species, such as bryozoans, arthropods, coelenterates, cnidarians, mollusks, crustaceans, echinoderms, marine poriferans, marine fishes, and mammals. The constituents of trigonelline presents in the pods of various fabaceae species and coffee. It also presents in mammalian urine after administration of nicotinic acid. The pharmacological activities of trigonelline have been more thoroughly screened than fenugreek's other components, particularly for diabetes and central nervous system disease [21]. Trigonelline has neuroprotective, hypoglycemic, memory-improving, hypolipidemic, antimigraine, antibacterial, sedative, antitumor, and antiviral activities, and it has been shown to decrease diabetic auditory neuropathy and platelet formation. It acts by affecting β-cell regeneration, insulin secretion, activities related to glucose metabolism, free radical scavenging, axonal extension, and neuron impulsiveness.

The dried leaves of *Nicotiana tabacum* are named as tobacco. The tobacco was used by native American Indians about 8000 years, where the dried leaves were smoked in tube rituals for healing and ritualistic purposes [22, 23]. The compound Nicotine **1** was identified from dried leaves of *N. tabacum* leaves by Posselt and

#### *Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.106663*

Reimann [24]. Pictet and Cr´epieux established the structure through total synthesis in 1895 [25]. Nicotine is also present (albeit in lower amounts) in other species of the Solanaceae plant family, such as tomatoes, green peppers, and potatoes. At present, tobacco is cultivated in over many countries worldwide, where it is used to make cigars and as the source of nicotine for replacement therapy (NRT). The physiological studies of nicotine in a variety of cell systems and in animals have been evaluated by many researchers.

Nicotine stimulates the ion exchange channels to activate the discharge of neurotransmitters including serotonin (5-HT), dopamine, acetylcholine (ACh), norepinephrine, β-endorphins, γ-aminobutyric acid (GABA), and glutamate into the mesolimbic area, the corpus striatum, and the frontal cortex.

Picciotto and Zoli have explained that knocking out the α4β2 subunit gene in rats abolished the effects of nicotine and the discharge of dopamine. In associated studies, the α3β4-nAChR is occupied in the cardiovascular effects of nicotine and the α7-nAChR is tangled in memory, learning, and sensory gating [26]. Some other studies revealed that consumption of nicotine decreases the risk of Parkinson's disease (e.g. neurodegenerative disease) and anxiety and depression. In recent times, preliminary evaluations have described lower rates of SARS-CoV-2 contamination among smokers [27–30]. Various structurally related natural products to nicotine have also been identified from a variety of sources; many reviews on their biological activities are available.

Nicotinic acid **2** offers alkaloids with the pyridine moiety in the laboratory preparation. This nucleus presents in such alkaloids as nicotine, nornicotine, anabasine, ricine, anatabine, and arecoline. Furthermore, many alkaloids contain the pyridine ring as part of their total skeleton [31]. For example, anabasine is isolated from nicotinic acid and lysine [32]. Alkaloids with the pyridine ring occur in plants such as tobacco (*N. tabacum*), castor (*Ricinus communis*), and betel nuts (*Areca catechu*). The sesquiterpene-derived nucleus isolates partly from nicotinic acid and partly from the acetate biochemical pathway. There are more than 200 alkaloids identified in this group as potential compounds.

Demole & Demole isolated two terpenoid-based alkaloids from Burley tobacco (*Nicotiana tabacum*), 1,3,6,6-tetramethyl-5,6,7,8-tetrahydroisoquinolin-8-one **11** and 3,6,6-trimethyl-5,6-dihydro-7H-pyrindan-7-one **12** (**Figure 4**). Remarkably, **11** may be obtained from the glands of the *Castor fiber*, or by a synthetic method. Compound **11** has also been used to improve the flavor of tobacco [33].

Ricinine **13** is a familiar 2-pyridone derivative that occurs in the castor bean *Ricinus communis*. Nowadays, interest of the researchers has been focused on the relationship between the ricinine biogenesis and the pyridine nucleotide cycle [34]. The isomeric mixtures of pyridones ricinidine (**14**) and nudifluorine (**15**) have been isolated from the leaves of *Trewia nudiflora* (**Figure 5**) [35, 36].

**Figure 4.** *Terpenoid-based alkaloids.*

**Figure 5.**

*2-Pyridone derivatives isolated from the different plant species.*

**Figure 6.** *Fusaric acids from the mycelium species.*

Fusaric acid (**16**) a systemic wilt toxin present especially in cotton plants [37, 38], was formed by various species of Fursaria and other fungi [39]. Dehydrofusaric acid (**17**) and (+)-S-fusarinolic acid (**18**) (**Figure 6**), metabolites of fusaric acid, have been attained from the mycelium of different *Fusaria, S. cerevisiae,* and *Gibberella fujikurvi* [39–41].

*Ceropegia Juncea* is described to be an important orgin of traditional ayurvedic practices [42]. The ethanolic extract of the plant was found to show significant biological activities in animal study, such as analgesic, antipyretic, antiulcer, hepatoprotective, local anesthetic, mast-cell stabilizing, hypotensive, and tranquilizing activities. In 1991, Thirugnanasambantham et. al. reported Cerpegin **19** , a pyridine alkaloid, from the stem of the plant *Ceropegia Juncea* [43, 44]

#### *Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.106663*

(-)-Cytisine **20** and its derivatives are of great attention as pharmacological outfits and as vital drugs for the ailments of an extensive variety of conditions, from eating disorders, nicotine and alcohol dependence, stress, schizophrenia and Parkinson's diseases. (-)-Cytisine itself is used as a support to give up tobacco smoking, even though it is not very effective and proper physical alteration might well make it more so. The only linked compound in current medicinal use from cytosine, though not firmly a cytisine derivatives, is the anti-smoking drug varenicline [45]. Several researchers recommend that some cytisinoids display assured as hunger reducers, stress relief medicine, or drugs to treat neurodegenerative diseases [46].

Actinomytes from soil and marine are a potent source for diverse compounds in the drug discovery. Wataru Aida et al isolated pyridine-containing natural compounds, such as fuzanins A (**21**), B (**22**), C (**23**), and D (**24**). The compounds were isolated from the Kitasatospora sp. IFM10917. The structure of each compound was proven by the source of spectroscopic and chemical analysis. Out of these, Fuzanin D (**24**) demonstrated cytotoxicity against human colon carcinoma DLD-1 cells (IC50, 41.2 mM) (**Figure 7**) and adequate inhibition of Wnt signal transcription besides with low cytotoxicity at 25 mM when it was screened for its Wnt signal inhibitory activity using a luciferase reporter gene assay in SuperTOP-Flash transfected cells [47].

Germana Esposito and the co-workers [48] isolated 13 novel nitrogen compounds from the Indonesian sponge *Acanthostrongylophora ingens*, and their chemical structures were established using NMR spectroscopy and HR-ESI-mass spectroscopy. All isolated compounds were evaluated in standard bioactivity assays, including antibacterial, antikinases, and amyloid β-42 assays. The most fascinating bioactivity outcome was acquired with the compound acanthocyclamine A (**25**), which shown

**Figure 7.** *Isolated from the culture extract of Kitasatospora sp. IFM10917.*

for the exact *Escherichia coli* antibacterial action and as a result on amyloid β-42 assembly stimulated by aftin-5 and zero toxicity at the dose of 26 μM. These outcomes focus the potentiality of a bipiperidine skeleton as a favorable scaffold for inhibiting or decreasing the creation of amyloid β-42, a significant competitor in the beginning of Alzheimer's disease.

Xin Wei et al reported three pyridine-type alkaloids, (-)-vincapyridines A–C (**26-28**), besides with two known alkaloids namely nauclefine **29** and vincamajoreine **30 (Figure 8)** have been isolated from the stem of *Vinca major* grown in Pakistan. All the isolated compounds were assessed for their cytotoxicity against glioma initiating cell lines (GITC-3# and GITC-18#), glioblastoma cell lines (U-87MG and T98G), and lung cancer cell line A-549, but anyone entities was active at 20 μg/mL concentration [49].

Recently, Dumaa Mishig et al have isolated seven pyridine alkaloids (**31–37**), from the plants of *Caryopteris mongolica* Bunge. According to SciFinder and Reaxys

**Figure 8.** *Pyridine-type alkaloids isolated from Vinca major.*

*Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.106663*

**Figure 9.** *New compounds obtained from the aerial parts of C. mongolica.*

database search, the compounds **32**, **34**, **35**, **36**, and **37** (**Figure 9**) represent new chemical structures. The chemical structures of these compounds were elucidated by 1H NMR, 13C NMR, and 2D NMR (COSY, HSQC, HMBC, and NOESY) and mass spectroscopic methods [50].

Noranabasamine (**38**) is an alkaloid that has been isolated from the Dendrobatidae amphibian—*Phyllobates terribilis* [51]. Noranabasamine is basically related to the analogous plant alkaloid anabasamine, which is known to inhibit acetylcholine esterase and exhibits anti-inflammatory activity. (S)-Anabasamine (**39**) was found in the poisonous semi-shrub *Anabasis aphylla* of Central Asia [52]. After administration of anabasamine to rats, hepatic alcohol dehydrogenase was improved and levels of ethanol were decreased in the blood stream [53]. In addition, the adrenal-regulated production of tryptophan pyrrolase was induced in the liver of those rats that were administered anabasamine.

All the earlier investigation with (S)-noranabasamine (**38**) and (S)-anabasamine (**39**) generally focused on the isolation of this alkaloid from other related alkaloids

**Figure 10.**

*Poisonous compounds isolated from the skin of amphibians.*

**Figure 11.** *Isolated and semisynthetic compounds of camptothecin.*

found in amphibian skin and plants specimen (**Figure 10**). The mild concentrations in plants and amphibians, the difficulty in extraction, and the less existence in nature make these compounds smart goals for synthesis.

Camptothecin **40**, identified from the Chinese horticulture tree *Camptotheca acuminate* Decne , that belongs to Nyssaceae family was subjected to further clinical trials by National Cancer Institute in the 1970s but was stopped because of severe bladder toxicity [54]. Topotecan **41** and irinotecan **42** are semi-synthetic compounds of camptothecin for the healing of ovarian cancers and colorectal cancers, respectively (**Figure 11**).

Ageladine-A (**43**) is the first example of this family which contains 2-amino-imidazolopyridine. Ageladine-A was isolated from the combined extract of the sponge and purified by ODS flash chromatography, gel filtration, and ODS HPLC. Ageladine-A showed antiangiogenic activity [55].

Aaptamine (**44**) from Aaptos aaptos [56] possesses α-adrenoceptor blocking activity in the isolated rabbit aorta. Amphimedine (**45**), a fused pentacyclic yellow aromatic alkaloid from a Pacific sponge Amphimedon spp. [57], is a cytotoxic agent.

*Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.106663*

Berberine **46** is a comparatively nontoxic alkaloid found in several plants, including goldenseal (*Hydrastis canadensis*), barberry (*Berberis vulgaris*), Oregon grape (*Berberis aquifolium*), and goldthread (*Coptis trifolia*). It has a long past and is most commonly used as an antibacterial agent [58, 59]. Papaverine **47** is used as a vasodilator under the trade name Para-Time® SR and is used as oral medicine to treat erectile dysfunction (**Figure 12**) [60]. Ellipticine **48** is used in cancer treatment, as it is alleged to act through DNA intercalation and inhibition of topoisomerase II [61].

#### **4. Conclusion**

The nitrogen containing heterocyclic compounds, especially pyridine scaffolds tangled into the various natural product compounds. The isolated as well as synthesized pyridine compounds exhibited various pharmacological properties due to their diverse physiochemical properties like water solubility, weak basicity, chemical stability, hydrogen bond-forming ability, protein-binding capacity, cell permeability, and size of the molecules attracted the attention of medicinal chemists for the past few years. In this chapter, we addressed some important pyridine-based compounds and their pharmacological applications. Natural product research is a mandatory tool for exploring bioactive compounds with unique properties and mode of action to face the future challenges.

### **Acknowledgements**

We dedicate this chapter to our respectful Prof. (Late). P. Ramesh, Department of Natural Products Chemistry, Madurai Kamaraj University, Madurai. India.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Edayadulla Naushad1 \* and Shankar Thangaraj2

1 Department of Chemistry, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai, India

2 Department of Environmental Science, Sri Paramakalyani Centre for Environmental Science, Manonmaniam Sundaranar University, Tamilnadu, India

\*Address all correspondence to: edayam2004@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.106663*

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*Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications DOI: http://dx.doi.org/10.5772/intechopen.106663*

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#### **Chapter 5**

## Pyridine Heterocycles in the Therapy of Oncological Diseases

*Lozan T. Todorov and Irena P. Kostova*

#### **Abstract**

Oncological diseases pose a major challenge for modern medicine. Heterocyclic compounds play a vital role in modern medical and pharmaceutical science as most medicinal substances incorporate them. Nitrogen-containing heterocycles serve as the basis of numerous drugs and, therefore, are deeply involved in the design and synthesis of promising new therapeutic agents. Pyridine or pyrimidine scaffolds, with a number of substituents attached, comprise a large portion of FDA-approved drugs. They are chemically stable in the human body, manifest an affinity for DNA via hydrogen bonding, and present an opportunity for the development of novel anticancer agents. A large number of pyridine-based molecules are synthesized and tested for anticancer activity each year. The present chapter aims to introduce the most current synthetic approaches, published in scientific literature, and would also elaborate on structure-activity relationships described therein.

**Keywords:** pyridine, anticancer, biological activity, synthetic approaches, structure-activity relationship

#### **1. Introduction**

Oncological diseases pose a major problem worldwide in terms of societal, healthcare, financial, and economic impact with the number of cancer cases continually rising. The research for novel anticancer drugs comprises a significant portion of contemporary research and development in the field of medicine and pharmacy. Nitrogen heterocycles are a component of 59% of FDA-registered drugs [1] as of 2014. Among them, pyridine is the second most commonly incorporated nitrogen heterocycle. Pyridine-containing drugs are quite heterogeneous in terms of chemical structure, pharmacokinetics and pharmacodynamics – antihistamines (chlorpheniramine, brompheniramine), antiarrhythmic (disopyramide), antihypercholesterolaemic (cerivastatin), antitubercular (isoniazid, ethionamide), antibiotic (telithromycin), antiretroviral for AIDS treatment (indinavir), and anticancer (crizotinib, abiraterone) to name a few.

A multitude of natural substances contains pyridine. They tend to be involved in a number of physiological processes, among which is cancer pathogenesis. The pyridine ring is a chemically stable heterocyclic structure. Its nitrogen atom is able to participate in hydrogen bonding, which allows pyridines to bind to DNA and exhibit anticancer effects [2]. Pyridine can play the role of pharmacophore and can also serve as a stable basis for the synthesis of novel anticancer drugs. The present chapter aims to inform the reader in a brief and concise manner on the latest developments in the search for pyridine-based anticancer drugs, their mechanisms of action, and the most utilized synthetic approaches. Herein are included the most common types of novel, pyridine-based compounds, found in the scientific literature that do not involve fused ring structures. They are represented by molecular hybrids that the authors have classified into the following groups in terms of structure:


Additionally, the authors are also presenting data on biological activity, types of cancer cell lines being suppressed, and pharmacodynamic action of the molecules discussed, should such information be available.

#### **2. Pyridine derivatives recently approved for anticancer treatment**

A number of pyridines have recently been registered for anticancer treatment [3]. The list predominantly includes kinase inhibitors (apalutamide, pexidartinib, lorlatinib, acalabrutinib, abemaciclib, neratinib, and alpelisib) – drugs that inhibit cellular kinases. Kinases are a family of enzymes that participate in cellular metabolism, signaling, replication, and survival. Inhibiting them suppresses vital cellular functions, therefore, targeting cancer-specific kinases suppresses tumor growth. Ivosidenib and enasidenib serve as isocitrate dehydrogenase (IDH) inhibitors. IDH is involved in energy production and includes two subtypes (IDH1 and IDH2). Mutations in IDH1 and IDH2 can cause changes in DNA gene expression including expression of oncogenes [4]. Inhibition of these enzymes could impair cancer growth. Benetoclax is a Bcl-2 inhibitor. Bcl-2 is a protein that suppresses cell death (apoptosis) [4]. Overexpression of Bcl-2 can prevent or significantly delay cell death – a typical characteristic of cancer. These drugs have been approved by FDA within the period 2017–2019. Considering the extremely stringent approval process of novel medicinal molecules, such a large number of newly-approved anticancer agents underscores both the extreme intensity of scientific exploration for novel anticancer treatments as well as the important role of the pyridine structure plays in drug research.

#### **3. Coumarin-pyridine hybrids**

The coumarin (benzopyran-2-on) structure (**Figure 1**) is considered an important bioactive scaffold, included in numerous drugs currently in use [5].

Coumarins are derived both naturally and synthetically. The specific structure of the coumarin scaffold allows coumarin derivatives to interact with a large variety of receptors and enzymes. They are currently being clinically utilized as anticoagulants and antithrombotic agents with relatively low toxicity. Naturally occurring

*Pyridine Heterocycles in the Therapy of Oncological Diseases DOI: http://dx.doi.org/10.5772/intechopen.106406*

**Figure 1.** *Chemical structure of coumarin.*

**Figure 2.** *Structure of the 4-arylcoumarin isosteres.*

and synthetic derivatives have shown promise as antimicrobial, anti-inflammatory, anticancer, antioxidant, and MAO-B inhibitory agents [6]. They can exhibit cytostatic and cytotoxic activities against a significant number of cancer cell lines [7]. Adding a variety of functional groups and creating molecular hybrids is a promising direction for the development of novel medicinal molecules, aimed at alleviating a wide variety of maladies. Hybridization of coumarin derivatives with pyridines is a field of intense study in anticancer drug research [8–10].

4-Arylcoumarins are known for their cytotoxic and antiproliferative properties [11]. They can be viewed as structural analogs of the promising antiproliferative molecule combretastatin A-4 (CA-4), yielding very similar effects. For more information on CA-4 and its characteristics, please see Section 5. Pyridine isosteres of that class of compounds have been synthesized and tested for antiproliferative activity (**Figure 2**).

Pyridine derivatives manifest moderate activity against the A549 lung adenocarcinoma cell line [12]. Variants a and b significantly disrupt microtubule formation. Adding an electron-donating group in 6th place of ring A increases antiproliferative activity (**Figure 2**). Substituting with an electron-withdrawing group, such as a fluorine atom, in that same place decreases biological activity. Substituting the parasituated methoxy group in ring B only decreases the effect (**Figure 2**). The basics of the synthetic approach to yield 4-arylcoumarins are schematically presented in **Figure 3**.

Research and development of novel anticancer drugs are most often targeted toward a specific mechanism of action. A number of potential PI3K lipid kinase inhibitors have been synthesized by hybridization of coumarins and pyridines.

PI3K are enzymes, involved in the regulation of cellular growth, replication, and survival, as well as the mediation of protein kinase B (universally known as Akt). Upregulation of PI3K and Akt signaling is associated with tumor growth and tumor cell migration. The aforementioned substances have been tested for PI3K and Akt

**Figure 3.**

*Brief representation of the synthesis of 4-arylcoumarines.*

#### **Figure 4.**

*Synthetic approach for generating some PI3K kinase inhibitors.*

inhibition as well as antiproliferative activity against K562 (myelogenous leukemia), HeLa (cervical carcinoma), A549, and MCF-7 (adenocarcinoma) cancer strains [13]. A brief schematic of the synthesis is presented in **Figure 4**.

The member with difluoro-substituted phenyl ring (**Figure 5**) has the strongest effect on all observed cell lines.

All 3,4-disubstituted members exhibit a similar degree of antiproliferative effect. Another member, with monochloro substituted phenyl ring (**Figure 5**) has been found to significantly inhibit both PI3K and Akt and to initiate apoptosis in the K562 cell line.

A number of hybrid molecules have been synthesized using a novel approach [14]. The final step of the synthesis is conducted in two different media – in refluxing ethanol or under microwave heating. Microwave heating proves to be more energyefficient, quicker, and produces significantly higher yields. **Figure 6** represents the basic synthesis of the most potent substance which exhibits promising activity against HCT-116 (colorectal carcinoma) and MCF-7 cell lines.

**Figure 5.** *The most active PI3K inhibitors against various cancer cell lines.* *Pyridine Heterocycles in the Therapy of Oncological Diseases DOI: http://dx.doi.org/10.5772/intechopen.106406*

**Figure 6.** *Novel synthesis of coumarin-pyridine hybrid compounds.*

#### **4. Chalcone-pyridine hybrids**

Chalcones are natural products from the flavonoid family, found in abundance in plants. Chalcone (**Figure 7**) is a molecular scaffold, characterized by uncomplicated chemistry, easy synthesis, and a large number of hydrogen atoms that, when substituted, can yield a huge selection of derivatives, exhibiting multiple physiological effects – antioxidant [15], antidiabetic [16], antihypertensive [17], anticancer [18], and many others.

They are known to inhibit cell proliferation, acting as antitumor agents both in vitro and in vivo. The antiproliferative properties of chalcones have been known for more than two decades [19]. Chalcones tend to bind to the so-called colchicine binding site in tubulin – a building block of microtubules. Microtubules are essential structures in all eukaryotic cells, responsible for keeping the structural integrity of cells, cell division, and many others [20]. Disrupting their synthesis is the mechanism of action of a number of antineoplastic drugs [21]. Attaching a pyridine moiety to the chalcone skeleton would be a way to complement the observed anticancer activity.

A promising design approach for the synthesis of chalcone-pyridine derivatives would be replacing one of the benzene rings with pyridine. A number of such molecules have been generated and then tested for antiproliferative activities and tubulin polymerization suppression [22]. α-(4-pyridyl) ketones and the necessary aldehydes undergo an aldol reaction to yield a number of chalcone-pyridine hybrids. The aforementioned step in the synthesis of the most potent member is presented in **Figure 8**.

**Figure 7.** *The chalcone molecular scaffold.*

**Figure 8.** *Chalcone synthesis via aldol condensation.*

All generated substances prove to be effective against K652 cells. The most potent one (**Figure 8**) is almost as effective as combretastatin A-4. It acts as a microtubuledestabilizing agent with an IC50 lower than that of CA-4. It connects with the colchicine binding site with 88% potency at 5 μM concentration, arresting the cell cycle of K562 at the G2/M phase and inducing apoptosis in a concentration-dependent manner.

The α-positioned methyl moiety to the carbonyl group tends to improve activity. The exposed hydroxyl at the meta-position of ring B (R3 ) is important for the biological activity – changing it to methoxy decreases the observed effect. Adding electrondonating groups to ring A increases the effect, while adding electron-withdrawing groups (such as chlorine atoms) decreases the activity.

Aldol condensation has also been applied to generate a number of pyridinium bromide salts that have manifested promising antiproliferative activity against MCF-7, HeLa, U-87MG (malignant glioblastoma), and HEK293 (kidney) cell lines [23]. A brief summary of the synthesis of the two most active members is presented in **Figure 9**.

In terms of the structure-activity relationship, adding a strongly electron-donating functional group at the para-position of the phenyl radical R increases biological activity. Interestingly, adding the strongly electron-withdrawing nitro group also improves the antiproliferative properties. Replacing the radical R with a coumarin substituent (potentially anticancer-bearing) nullifies the anticancer effect.

Another class of substances that have been synthesized incorporates pyridine nucleus not as a substitute of one of the chalcone phenyl rings, but as a substituent [24]. They have been tested for their antiproliferative effect and colchicine-binding ability. The synthesis of the most active compounds is shown in **Figure 10**.

**Figure 9.** *Pyridinium bromide salts' synthesis.*

*Pyridine Heterocycles in the Therapy of Oncological Diseases DOI: http://dx.doi.org/10.5772/intechopen.106406*

**Figure 10.** *Synthesis of pyridine substituted chalcones.*

As in the previous case, adding electron-withdrawing groups, particularly in paraposition, to the chalcone phenyl ring increases biological activity. Adding electrondonating groups (methoxy) to the same position has the same effect on ACHN (renal adenocarcinoma), MCF-7, and A549 cancer cell lines. The novel compounds have been docked in silico to the tubulin receptor, yielding promising results in terms of microtubule disruption.

#### **5. Combretastatin: Pyridine hybrids**

Combretastatins are a family of stilbenes, derived from the bark of the African Willow tree [25]. Combretastatin A-4 (**Figure 11**) in particular is an effective, selective inhibitor of tubulin polymerization by binding to the colchicine binding site. Thus it inhibits microtubule growth and acts as an antivascular and antimitotic agent, preventing cellular multiplication, changing endothelial cell structure, and resulting in tumor necrosis [26].

The cis-orientation of rings A and B is crucial for combretastatin A-4's cytotoxicity [27]. CA-4's application has been limited by its low solubility in aqueous media.

**Figure 11.** *Structure of combretastatin A4.*

**Figure 12.**

*CA-4 analogs − 2,4-diphenyl-substituted pyridines.*

Modification of its molecular structure (changing the aromatic rings and replacing the stilbene bridge) to increase its bioavailability, while maintaining its physiological effect has been a source of numerous investigations [28–30].

A number of combretastatin A-4 analogs with pyridine aromatic rings as a linker have been synthesized [31]. Two examples are presented in **Figure 12**.

Compound 1 manifests moderate cytotoxicity against MCF-7 cancer cells. Replacing the methyl group in its pyridine cycle with a hydroxyl group causes negation of the observed effect (compound 2). The antiproliferative effect associated with these 2,4-diphenyl-substituted pyridine structures is not very clearly manifested.

Interesting observations have been made with similar compounds, utilizing a pyridine linker between the two phenyl rings [32]. Among dozens of substances, three exhibit notable anticancer activity (**Figure 13**).

In terms of the structure-activity relationship, when the phenyl rings are at a para position from each other in the pyridine linker, cytotoxicity is low. Meta-position improves biological activity. The best results are observed with a 2,6-diphenyl substituted pyridine linker. 3,4,5-trimetoxy substituted ring A does not contribute significantly to biological activity. Compound 3 is the only one from a multitude of members, bearing such substituent, that yields promising results. It is an almost full analog of CA-4 − the stilbene linker is replaced with a 2,6-disubstituted pyridine. On the other hand, a 2,4-dimethoxy substituted ring A causes significant suppression against several cell lines − MDA-MB-231 (breast cancer), A549, and HeLa. Any other

**Figure 13.** *CA-4 analogs - 2,6-diphenylsubstitited pyridines.*

type of dimethoxy substitution (e.g., 3,4-; 2,5-, etc.) decreases the antiproliferative effect. 3,4,5-trimethoxy substitution in ring B also weakens the biological effect. With 2,4-dimethoxysusbtituted ring A, 3-monomethoxy and 4-monomethoxy substituted ring B offer high antiproliferative effect, while 2-monomethoxy offers lesser activity. Thus, compounds 1, 2, and 3 potently inhibit cell survival and growth, arrest the cell division cycle and bind to the colchicine site to a degree, similar to combretastatin A4.

#### **6. Terpyridine derivatives**

Terpyridine is a known ligand in a variety of complexes [33]. Its structural analogs tend to bind to and intercalate in nucleic acids [34, 35]. α-Terpyridine (**Figure 14**) and its isosteres have manifested significant topoisomerase I and II inhibitory activity as well as notable cytotoxicity against a variety of cancer cell lines [36, 37]. Topoisomerases are a family of enzymes that catalyze changes in the topological state of the DNA double helix. They are involved in DNA replication and transcription, hence impairment of their function inhibits cellular replication – a way to suppress rapid tumor growth.

Terpyridines can be derived by way of the Kröhnke pyridine synthesis [38], represented in **Figure 15**.

Two families of terpyridine isosteres have been synthesized and tested for topoisomerase inhibitory activity and cytotoxicity – molecules with four aryl groups (furyl, thienyl, and pyridyl) and molecules with three aryl groups (**Figure 16**).

Three-ringed terpyridine members manifest low topoisomerase inhibitory activity and cytotoxicity. Some 2,4,6-trisubstituted members exhibit significant biological activity (listed in **Table 1**).

Notably, topoisomerase I inhibiting substances do not suppress topoisomerase II and topoisomerase II inhibiting substances do not suppress topoisomerase I. Interestingly, topoisomerase inhibitors manifest low toxicity toward a variety of cancer cell lines – MCF-7, HeLa, DU145 (prostate cancer), and HCT15 (colorectal

**Figure 14.** *Chemical structure of α-terpyridine.*

**Figure 15.** *Schematic representation of the synthesis of terpyridines and their isosteres.*

**Moiety: R1 R2 R3 Biological activity** = a a g c Topoisomerase I inhibitor = b a g d Topoisomerase I inhibitor = c c e d Topoisomerase I inhibitor = d c g d Topoisomerase I inhibitor = e a g d Topoisomerase II inhibitor = f c g f Topoisomerase II inhibitor = g a g b Topoisomerase II inhibitor c g c High cytotoxicity c g a High cytotoxicity c f d High cytotoxicity c f a High cytotoxicity d g c High cytotoxicity d g d High cytotoxicity

**Figure 16.** *Structures of the investigated terpyridines.*

**Table 1.**

*Biological effect of various terpyridine isosteres with four aryl groups.*

cancer). At the same time, some trisubstituted terpyridines did not behave as enzyme inhibitors but despite that are highly cytotoxic. In terms of molecular structure 2-furyl and 2-thienyl moieties in 2nd place, 4-pyridyl in 6th place, and 2/3-thienyl in 4th place seem to have the greatest impact on biological activity.

*Pyridine Heterocycles in the Therapy of Oncological Diseases DOI: http://dx.doi.org/10.5772/intechopen.106406*

#### **Figure 17.**

*An example of terpyridine-platinum complex. The ligand incorporates a "nitrogen mustard" moiety (in red), linked to the central pyridine ring. That molecular "tail" increases antiproliferative activity and DNA-binding of both the ligand itself and its platinum complex.*

Terpyridines are being intensely studied in the field of oncology not so much for their intrinsic antiproliferative properties but for their ability to chelate metal ions. Recent data show that chelating copper ions with terpyridine ligands produce coordination compounds with high cytotoxicity and G0/G1 cell cycle phase inhibitory activity [39]. Experiments have demonstrated that complexes of terpyridines manifest antiproliferative activity in the nanomolar range against a large variety of cancer cell lines – MCF-7, A549, HCT-116, U-251 (glioblastoma), and PANC-1 (pancreatic carcinoma). At the same time, the observed IC50 doses against normal human fibroblasts (NHDF) are about 10−15 times higher, demonstrating good selectivity and potentially lower toxicity toward healthy human tissues. Numerous terpyridine complexes with platinum (**Figure 17**), palladium, and lanthanides have also recently been synthesized [40–43], bearing promising protein-binding, DNA-binding, and antiproliferative activities.

#### **7. Conclusions**

The pyridine heterocycle is an important chemical structure, ubiquitously utilized within the field of modern pharmaceutical science, research, and development. Its characteristic physicochemical properties (chemical stability, participation in hydrogen bonding, and numerous hydrogen atoms that can be substituted) make it an attractive molecular basis for synthesis of medicinal substances. Its nitrogen atom makes it a useful pharmacophore, imbuing potential drug molecules with novel pharmacological effects. Attaching it to extant compounds can modify their pharmacokinetics, pharmacodynamics, and physiological effect. The authors' aim is that the present chapter reveals to the reader the important role pyridine chemistry plays in the field of oncology. Pyridine-based compounds are being intensely researched in the hope of inventing novel oncological drugs that combine significant anticancer cytotoxicity with an improved safety profile and a targeted mechanism of action. Within the past several years a large number of novel pyridine anticancer molecules have been synthesized, yielding some very promising results. Substances of both natural and synthetic origin have been generated and/or modified, synthetic approaches have been refined and interesting and potentially important structureactivity relationships have been revealed. Hopefully, the authors have been able to present the subject of pyridines in oncology to the reader's satisfaction, both informing them as well as sparking an interest in this rapidly evolving area of research.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Lozan T. Todorov\* and Irena P. Kostova Department of Chemistry, Medical University – Sofia, Faculty of Pharmacy, Sofia, Bulgaria

\*Address all correspondence to: ltodorov@pharmfac.mu-sofia.bg

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Pyridine Heterocycles in the Therapy of Oncological Diseases DOI: http://dx.doi.org/10.5772/intechopen.106406*

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[37] Basnet A, Thapa P, Karki R, Na Y, Jahng Y, Jeong B-S, et al. 2, 4, 6-Trisubstituted pyridines: Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship. Bioorganic & Medicinal Chemistry. 2007;**15**(13):4351-4359

[38] Adib M, Tahermansouri H, Koloogani SA, Mohammadi B, Bijanzadeh HR. Kröhnke pyridines: An efficient solvent-free synthesis of 2, 4, 6-triarylpyridines. Tetrahedron Letters. 2006;**47**(33):5957-5960

[39] Malarz K, Zych D, Kuczak M, Musioł R, Mrozek-Wilczkiewicz A. Anticancer activity of 4′-phenyl-2, 2′: 6′, 2 ″-terpyridines–behind the metal complexation. European Journal of Medicinal Chemistry. 2020;**189**:112039

[40] Adams M, Sullivan MP, Tong KK, Goldstone DC, Hanif M, Jamieson SM, et al. Mustards-derived Terpyridine–platinum complexes as anticancer agents: DNA alkylation vs coordination. Inorganic Chemistry. 2021;**60**(4):2414-2424

[41] Kacar O, Adiguzel Z, Yilmaz VT, Cetin Y, Cevatemre B, Arda N, et al. Evaluation of the molecular mechanisms of a palladium (II) saccharinate complex with terpyridine as an anticancer agent. Anti-Cancer Drugs. 2014;**25**(1):17-29

[42] Li C, Xu F, Zhao Y, Zheng W, Zeng W, Luo Q, et al. Platinum (II) terpyridine anticancer complexes possessing multiple mode of DNA interaction and EGFR inhibiting activity. Frontiers in Chemistry. 2020;**8**:210

*Exploring Chemistry with Pyridine Derivatives*

[43] Hussain A, Gadadhar S, Goswami TK, Karande AA, Chakravarty AR. Photoactivated DNA cleavage and anticancer activity of pyrenyl-terpyridine lanthanide complexes. European Journal of Medicinal Chemistry. 2012;**50**:319

#### **Chapter 6**

## The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels

*Yasodha Krishna Janapati, Sunithasree Cheweti, Bojjibabu Chidipi, Medidi Srinivas and Sunil Junapudi*

#### **Abstract**

Pyridine-based ring systems are heterocycle-structured subunits that are being abundantly employed in drug design, primarily because of their tremendous effect on pharmacological activity, which has resulted in the discovery of various broad-spectrum medicinal compounds. Pyridine derivatives are employed to treat multiple medical illnesses, including prostate cancer, AIDS, tuberculosis, angina, ulcer, arthritis, urinary tract analgesic, Alzheimer's disease, and cardiovascular diseases. This chapter emphasized the currently available synthetic pyridine derivatives, including nimodipine, ciclopirox, efonidipine, nifedipine, milrinone, and amrinone, effects on cardiac ionic channels and their mechanisms of action for the cure. Pyridine derivatives regulate several voltage-gated ion channel behaviors, including sodium (Nav), calcium (Cav), and potassium (Kv) channels, and are set as a therapeutic approach. Particularly, calcium-channel blockers are the most common action of medicines with a dihydropyridine ring and are often used to treat hypertension and heart-related problems. Finally, this chapter gives the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. This chapter discusses pyridine derivatives acting on cardiac ionic channels to combat CVS diseases. The book chapter describes the importance of pyridine derivatives as a novel class of medications for treating cardiovascular disorders.

**Keywords:** pyridine derivatives, privileged, scaffolds, cardiac ions

#### **1. Introduction**

#### **1.1 The physiological role of Pyridine derivatives**

Heterocycles are vital in the pharmaceutical sectors, which are an integral part of the essential roof of life processes, that is, DNA and RNA [1–3]. Recently, 90% of newly produced and commercialized medicines integrate heterocyclic compounds [4]. Pyridine and dihydropyridine are 6-membered heterocyclic rings with a wide variety of therapeutic potential in cardiovascular diseases, ulcers, HIV, antibacterial activity, etc. [5–9]. Pyridines are typically found in plants with the alkaloids, such as nicotine, anabasine, and trigonelline [10]. In the biochemical process, nicotinamide adenine dinucleotide (NAD) redox reactions are reduced to NADH, and a dihydropyridine ring is present in NAHD. We can also notice dihydropyridine ring in NADPH structure which reduced from the NADP<sup>+</sup> [11]. The food and drug administration (FDA) has approved 14% of drugs containing pyridine and dihydropyridine scaffolds [10].

#### **1.2 Natural and commercial drugs with pyridine and dihydropyridine scaffolds**

Pyridine and dihydropyridine are versatile chemicals used to make libraries with various functional groups and therapeutic objectives. The existence of pyridine or dihydropyridine heterocycles significantly impacts pharmacological properties. For instance, the pyridine ring in a medication boosts physiological properties, potency, metabolic stability, permeability, and binding to the protein [12]. There is a myriad of commercially accessible medications that include pyridine rings on the market which we listed in the below table.


*The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels DOI: http://dx.doi.org/10.5772/intechopen.106759*



#### **2. Pyridine and dihydropyridine scaffolds with cardiovascular action**

Torsemide with pyridine is an approved medicine that stimulates diuresis and reduces the patient's blood pressure [90]. Most dihydropyridine rings act as calciumchannel blockers, most commonly used to treat high blood pressure and cardiovascular disorders [91, 92]. The dihydropyridine ring-containing drugs are nilvadipine, nifedipine, amlodipine, azelnidipine, clevidipine, and felodipine [10]. Nimodipine helps cure vasospasm and subarachnoid hemorrhage [93, 94]. Levamlodipine, isradipine, nicardipine, benidipine, felodipine, nisoldipine, nitrendipine, and clevidipine are used to treat hypertension [95–102]. Efonidipine is specially used to treat hypertension and angina [103]. Torasemide is also a cure for renal and liver diseases other than heart failure and hypertension [104]. Quinidine is used to treat atrial fibrillation and flutter [105]. Papaverine used as vasodilator [106].

The nifedipine drug is also used to treat diseases premature birth and Raynaud's syndrome [87]. Milrinone and amrinone are FDA-approved vasodilators containing pyridine and dihydropyridine ring systems [88, 89].

Examples of a few pyridines and dihydropyridine derivatives of cardiovascular action drugs are shown in **Figure 1**.

#### **3. Pyridine derivatives regulation of cardiac ion channel behaviors is established as a therapeutic strategy**

#### **3.1 Cardiac ion channels**

Ion channels are pore-forming membrane proteins that permit ions to pass through the channels. The selective permeability of ion channels on the cell membrane causes the heart to produce an action potential. The ion channels reduce the activation energy required for ion movement across the lipophilic cell membrane. Ion channels are established within the membrane of all excitable cells and various intracellular organelles. In search for new drugs, ion channels are a recurrent target [107].

All elements of cardiac function, including rhythmicity and contractility, rely on ion channels. Ion channels are unavoidably important therapeutic targets for heart pathology, such as atrial fibrillation or angina [108].

#### **3.2 Cardiac action potential and ion channels**

The cardiac action potential is characterized by a rapid shift in membrane potential (voltage) across the cell membrane of heart cells. The passage of ions between the interior and exterior of cells via proteins known as ion channels generates the cardiac

*The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels DOI: http://dx.doi.org/10.5772/intechopen.106759*

**Figure 1.**

*Pyridine and dihydropyridine derivatives of cardiovascular action drugs.*

action potential [109]. Ion channels have unique structures and are composed of numerous proteins situated in the cell membrane [107]. Identifying the ion channels that create the action potential is accomplished by examining the molecular basis of hereditary cardiac arrhythmias.

Normal atrioventricular and ventricle contraction requires the fast stimulation or activation of cardiac cell clusters. An activation mechanism must authorize rapid heart rate variations and respond to changes in autonomic tone. These responsibilities are executed by generating the cardiac action potential [107]. The five phases of the cardiac action potential are depicted in **Figure 2** [107]:

1.In healthy functioning cardiac cells, phase 4 (resting potential) is around −90 mV.

**Figure 2.** *Membrane currents that provide a standard action potential.*


*The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels DOI: http://dx.doi.org/10.5772/intechopen.106759*


The five phases of the action potential are resting (4), upstroke (0), early repolarization (1), plateau (2), and final repolarization. A broken line represents a fall in potential toward the end of phase 3 in pacemaker cells, such as the sinus node. The inward currents INa, ICa, and the sodium-calcium exchanger are illustrated in yellow boxes (NCX). It is electrogenic and can produce both inward and outward currents. Gray boxes represent IKAch, IK1, Ito, IKur, IKr, and IKs. The action potential duration (APD) is typically between 200 and 400 milliseconds [111].

The start of the action potential and the variances observed throughout the heart show that ion channels dispersed on the cell membrane have selective permeability. Ion channels minimize the activation energy required for ion transport across the lipophilic cell membrane [107].

Ion channels have two primary characteristics: ion permeation and gating [112]. The passage of ions via an open channel is described by ion permeation. The classification of ion channels is based on the selective permeability of ion channels to specific ions (e.g., Na<sup>+</sup> , K<sup>+</sup> , and Ca2+ channels). Size, valency, and hydration energy are essential factors of selectivity. Ion channels do not function as simple fluid-filled pores but provide multiple binding sites for ions as they traverse the membrane. Most ion channels are singly occupied during permeation; specific K<sup>+</sup> channels may be multiply occupied. The bulk of ion channels has a nonlinear current–voltage relationship. The size of the current depends on the direction of ion migration into or out of the cells for the same absolute degree of change in voltage. This is known as rectification, an essential trait of K<sup>+</sup> channels; they carry minimal outward current at positive (depolarized) potentials. The fundamental mechanism of rectification differs depending on the kind of ion channel. The mechanism of significant inward rectification displayed by many K<sup>+</sup> channels is blocked by the internal Mg<sup>+</sup> and polyvalent cations [113].

Ion channel gating, which explains how they open and close, is their second characteristic. Ion channels can also be categorized into categories based on their gating mechanisms, including voltage-dependent, ligand-dependent, and mechanosensitive gating. Voltage-gated ion channels modify their conductance in response to variations in membrane potential. The gating mechanism used by ion channels is typically voltage-dependent [109].

Changes in the electrical membrane potential close to the channel cause a set of transmembrane proteins called voltage-gated ion channels to open and close. The channel proteins' shape is altered by the membrane potential, which also regulates how they open and close. Ions must diffuse through the membrane through transmembrane protein channels because they are unable to generally flow through cell membranes. They are essential for enabling an immediate and coordinated depolarization in response to triggering voltage changes in excitable tissues, such as neurons and muscle cells [114]. The opening and closing of the channels are activated by changing ion concentration, and hence charge gradient between the sides of the cell membrane [115].

#### **3.3 Voltage-gated sodium (Nav)**

Nav channels are integral membrane proteins that change conformation in response to membrane potential depolarization, open a transmembrane pore, and convey sodium ions inward to initiate and propagate action potentials. Nav is responsible for the rising phase of action potentials in excitable cells, such as neurons, myocytes, and certain types of glia. These channels cycle through three states: resting, active, and inactive. Even though the ions would not be able to move through the channels in their resting or inactive states, there is a variation in their structural conformation. When the membrane potential of a cell change, a modest but noteworthy number of Na<sup>+</sup> ions migrate into the cell down their electrochemical gradient, further depolarizing the cell. Therefore, the more the Na+ channels get localized in a section of a cell's membrane, the more excitable and quickly propagating the action potential of that portion of the cell will be [116].

#### **3.4 Voltage-gated calcium (Cav)**

There are two voltage-gated Cav channels within the cardiac muscle: L-type calcium channels ("L" for Long-lasting) and T-type calcium channels ("T" for Transient, i.e., short). L-type channels are more numerous and densely populated within ventricular cell t-tubule membranes. On the other hand, T-type channels are located primarily within atrial and pacemaker cells but to a smaller extent than L-type channels. Higher positive membrane potentials activate L-type channels, take longer to open, and remain open for a longer time than T-type channels. This implies that T-type channels contribute more to depolarization (phase 0), whereas L-type channels contribute more to plateauing (phase 2) [117].

#### **3.5 Voltage-gated potassium (Kv)**

Kv is the most widely distributed ion channel type found in all living organisms. They are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting stage. Potassium channels are found in most cell types and control various cell functions [112].

The two main K<sup>+</sup> channels in cardiac cells are inward rectifiers and voltage-gated potassium channels.

Potassium channels that internally correct (Kir) encourage the entry of K+ into cells. However, the significance of this potassium influx increases when the membrane potential is lower than the equilibrium potential for K+ (~ − 90 mV). The amount of potassium entering the cell through the Kir reduces as the membrane potential moves in a more positive direction, as it does when an adjacent cell stimulates the current flow. Kir is therefore in charge of preserving the resting membrane potential and starting the depolarization phase. However, the channel starts to let K+ leave the cell when the membrane potential continues to move in a more positive direction. The Kir can also help with the last phases of the repolarization because of this outward influx of potassium ions at the more positive membrane potentials [118].

Depolarization activates voltage-gated Kv channels. These channels generate currents, such as the transient out potassium current *I*to1. This current is made up of two parts. Both components activate quickly. However, *I*to, fast deactivates faster than *I*to, slow. These currents contribute to the action potential's early repolarization phase (phase 1) [118].

*The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels DOI: http://dx.doi.org/10.5772/intechopen.106759*

The delayed rectifier potassium channels are yet another variety of voltage-gated potassium channels. These channels transport potassium currents that cause the action potential's plateau phase. They are named according to how quickly they activate: *I*Ks that activate slowly, *I*Kr that activate quickly, and *I*Kur that activate extremely quickly [119].

#### **4. Pyridine derivatives an ion channels modulator**

The pyridine ring system can be found in a variety of natural products and pharmaceutically relevant molecules. Many of these compounds have fascinating and distinctive pharmacological characteristics that have often encouraged their production and reactivity. This chapter highlights recent advances in the regulation of several ion channel behaviors, such as voltage-gated sodium (Nav), calcium (Cav), and potassium (Kv) channels by the Pyridine derivatives [120].

#### **4.1 Regulation of voltage-gated calcium (Cav) ion channel by pyridine derivatives**

Calcium channel blockers (CCBs) are unique drugs that prevent calcium from moving through calcium channels. They all have a similar mode of action, but are not interchangeable and can have diverse physiologic consequences. Calcium channel blockers are divided into dihydropyridines [DHPs] such as nifedipine and non-DHPs such as verapamil and diltiazem. These families bind to calcium channels at various binding locations, which could explain the clinical discrepancies. Non-dihydropyridines are more myocardial selective and tend to lower the heart rate, while dihydropyridines are more vascular selective [121]. Calcium channel blockers all relax atrial smooth muscle and cause peripheral vasodilation, decreasing blood pressure.

Furthermore, because calcium is directly implicated in cardiac contraction, lowering intracellular calcium concentrations via calcium channel blocking can reduce ventricular contractility. However, DHP CCBs do not exhibit this negative ionotropic effect, since they are more effective peripheral vasodilators than verapamil and diltiazem [122]. Because of their cardiac inotropic and vasomotor properties, DHPs are frequently employed as medicines. Many members of this class are commercially important cardio protectants, vasodilators, and calcium antagonists [123]. This possible peripheral vasodilation causes a baroreceptor-mediated increase in sympathetic tone, which mitigates the DHPs' negative inotropic action. In patients with heart failure and systolic dysfunction, it is recommended to avoid and use calcium channel blockers [non-dihydropyridines] with negative inotropic effects with caution [124]. Verapamil and diltiazem, unlike DHPs, lower the sinoatrial (SA) node conduction rate (negative chronotropes) and slow atrioventricular (AV) conduction (negative chromotropes) [125]**.** The rationale for employing non-DHPS (verapamil and diltiazem) for the treatment of supraventricular tachyarrhythmias (SVTS) and atrial fibrillation is to slow the rate of conduction via the AV node [126]. The DHP CCBs do not slow conduction across the AV node and are thus ineffective in treating SVT.

Furthermore, they do not disable the SA node's automaticity. Indeed, DHP CCBs may cause a rise in heart rate due to reflex tachycardia induced by powerful peripheral vasodilation. This effect is particularly noticeable with nifedipine quick release [127]. To emphasize immediate release, when used for acute blood pressure lowering, nifedipine has been linked to increased morbidity (myocardial ischemia and infarction), particularly in individuals with coronary artery disease (CAD) [125]. When taken for acute blood pressure reduction, immediate-release nifedipine has been linked to

higher morbidity (myocardial ischemia and infarction), particularly in individuals with CAD [128]. Nifedipine was the chosen drug for hypertension crises because of its quick onset of action.

On the other hand, immediate-release nifedipine is no longer considered safe or efficacious for this indication. Sustained-release nifedipine formulations are less dangerous and do not cause strong reflex reactions to tachycardia. It is also worth noting that reflex tachycardia is not concerned with DHP CCBs with a delayed onset of action, such as amlodipine and felodipine.

To summarize, there are numerous distinctions between DHP and non-DHP CCBs. The non-DHPs are notable for being negative chronotropes, inotropes, and dromotropes. They should be taken with caution in individuals with heart failure and with drugs that have comparable hemodynamic effects. DHP CCBs are the most commonly used medications in individuals with hypertension and angina because they affect cardiac conduction [129].

#### **4.2 Regulation of voltage-gated sodium (Nav) ion channel behaviors by pyridine derivatives**

Action potentials are initiated by voltage-gated sodium channels in neurons, cardiac muscle, and other electrically excitable cells. Sodium channel blockers are utilized in local anesthetic and in treating epilepsy, bipolar disorder, chronic pain, and cardiac arrhythmia. Pyridine, having the chemical formula C5H5N, is an essential heterocyclic organic molecule. The presence of a pyridine derivative, such as nicotinamide, as a nitrogen base distinguishes pyridine nucleotides (PNs). In addition to their role as soluble electron carriers, pyridine nucleotides [NAD(P) (H)] influence ion transport mechanisms. According to new research, pyridine nucleotides [NAD(P)(H)] influence ion transport processes in addition to their role as soluble electron carriers. PNs are vital in various physiological responses, including stress, energy metabolism, and cell survival/death in cardiovascular cells. The development of congestive heart failure may be influenced by oxidative stress in the myocardium (HF) [130]. Cells include an antioxidant system comprising GSH and thioredoxin (Trx) and reducing enzymes, such as superoxide dismutase and catalase, to protect against excessive ROS [131]. PNs function in regulating cellular redox status by acting as electron donors for both negative and positive oxidative stress regulators. Pyridine nucleotide regulation of ion channels may be essential for integrating cell ion transport to energetics and sensing oxygen levels or metabolite availability. Aside from these regulatory activities, current research has demonstrated that pyridine nucleotides also influence the activity of ion channels by acting as ligands or substrates of accessory subunits that modify channel gating. The modulation of KNa/SLO2 channels by NAD(P)<sup>+</sup> shows that their activity may be linked to the cell's metabolic condition. This form of control may be especially relevant during ischemia–reperfusion, and other circumstances in which NAD(P)<sup>+</sup> buildup may promote K<sup>+</sup> efflux through these channels. High intracellular NAD(P)<sup>+</sup> levels would also increase the sensitivity of these channels to intracellular sodium [132].

Moreover, it has been proposed that in ischemic cardiac myocytes, increased [Na<sup>+</sup> ]i levels activate KNa, and an increase in this current shortens ADP and promotes calcium overload [133, 134]. As a result, regulating these channels with pyridine nucleotides would allow them to adapt to both the metabolic and ionic circumstances present in the ischemic heart. Interestingly, despite the lack of direct proof, it has

#### *The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels DOI: http://dx.doi.org/10.5772/intechopen.106759*

been claimed that SLO2 channels exist in the cardiac mitochondria [135]. Pyridine nucleotide control of these channels could present the preservation of the relationship between metabolism and ion transport in modern mitochondria and their prokaryotic progenitors. Although these findings are exciting, more research is needed to understand how intracellular changes in pyridine nucleotides influence SLO channels' activity and physiological relevance.

#### **4.3 Regulation of voltage-gated potassium (Kv) ion channel activity by pyridine derivatives**

Potassium channels are a diverse and widespread type of ion channel. They primarily regulate the cell's resting membrane potential and reduce the level of excitement. The current invention relates to novel pyridine and quinoline derivatives, pharmaceutical compositions incorporating them, and their use in treating ion channel disorders, such as potassium channel dysfunction. Potassium (Kv) channels also interact with pyridine nucleotide-binding proteins. These channels are essential in numerous physiological functions. They regulate the membrane potential of excitable cells and affect the shape and frequency of the action potential. These channels are also involved in the regulation of neurotransmitter release and cell volume [136, 137], proliferation, [138] and apoptosis [139]. They are also important in T-cell differentiation, activation, and cytokine generation [140]. These channels' activity affects baseline and agonist-stimulated vasomotor tone, and the membrane hyperpolarization generated by Kv channel activation governs the vasodilation [141]. Oxygen-sensitive variations in Kv channel activity drive hypoxic pulmonary vasoconstriction in small resistance arteries (HPV) [142, 143]. As a result, aberrant Kv channel activity has been linked to cardiac arrhythmias, pulmonary hypertension, epilepsy, and aberrant immunological responses [141, 144, 145]. The many functions of Kv channels are related to their various structures. The ion-conducting pore of Kv channels is produced by four membrane spanning subunits, assembled in a homotetrameric or heterotetrameric fashion. Twelve distinct Kv channel proteins have been reported so far [146, 146]. Several Kv families' pore-forming subunits interact in situ with accessory subunits that help channel construction and influence channel function, such as Kv family proteins, that interact with the cytosolic domains of Kv1 and Kv4 channel proteins [148]. Pyridine nucleotide function at the binding location N-type inactivation by NADPH, removal of inactivation by NADP+ , and membrane trafficking are the functions of voltage-gated potassium (Kv) ion channels' ancillary subunit-Kv [149]. Changes in the amount of cofactor binding, which passively replicates the physiological levels of these nucleotides, could modulate the gating of the Kv-Kv assembly. Thus, increased intracellular NAD(P)H levels would promote inactivation, but increased NAD(P) + levels would eliminate inactivation. Membrane voltage may influence catalysis via Kv contact with the cytosolic T1 domain or the C-terminus of Kv channels. The C-terminus of the shaker channel linked to Kv2 is in intimate contact with the Kv active site, according to the electron microscopic single particle analysis [150]. This analysis demonstrates that the Kv channel's inner helices, which are anticipated to move considerably during gate opening and closing, are directly connected to the channel's C-terminus. This suggests that the conformation and orientation of the Kv C-terminus relative to the subunits may change as a function of membrane voltage. Kv1.5's C-terminal peptide interacts more avidly with NADPH than NADP+ bound Kv2, and its deletion prevents differential regulation of Kv1.5 + Kv2 and Kv1.5 + Kv3 currents by reduced and oxidized nucleotides, despite the fact that the role of the Kv C-terminus in enhancing voltage sensitivity to Kv catalysis has not been

studied [151]. Despite these observations, the general physiological function of the Kv C-terminus is unknown. The C-terminus of Kv1.1, unlike the C-terminus of Kv1.5, does not affect channel control by Kv1 coupled to pyridine nucleotides [152]. Although pyridine nucleotides have been shown to regulate Kv currents in heterologous systems, the physiological importance of this regulatory axis has yet to be determined. Even though Kv channels are involved in numerous physiological processes, their function is heavily influenced by posttranslational modification and subunit assembly. Pyridine nucleotide regulation may give additional control by linking the activity of these channels to changes in metabolic activity of the cell's redox state. For example, hypoxic depolarization of pulmonary artery smooth muscle cells (PASMCs), which underpins the HPV phenomenon, has been linked to the Kv1.5 inhibition [153]. The fact that Kv1.5 is oxygen sensitive when produced in PASMCs but not in other cell types suggest that factors other than the pore-forming subunits of the channels may be necessary for the channel's oxygen sensitivity [154]. The ability of pyridine nucleotide-binding Kv proteins to modulate Kv current might theoretically confer oxygen sensitivity to Kv1.5 channels. Kiβ is abundantly expressed in PASMCs, and its expression is substantially higher in the distal than the proximal bovine pulmonary artery, indicating a potential function in oxygen sensing and HPV infection [155]. Furthermore, the Kv1.5-Kv1.3 channels are the primary components of IKv in PASMC, and these channels are variably controlled by oxidized and reduced pyridine nucleotides in COS-7 cells [153, 155]. As a result, an increase in the NADPH:NADP+ ratio during hypoxia may activate Kv1.5-Kv1.3 currents at more negative membrane potentials, whereas the current is blocked at higher positive membrane potentials, where inactivation becomes more pronounced. This activity has only been observed in hypoxic canine PASMC and not in other species [156]. This species difference could be attributed to variations in Kv expression. While inhibition may be related to Kv2, which does not impact Kv inactivation but shifts the voltage dependence of activation, hypoxia may increase Kv currents, whilst inhibition may be related to Kv2. However, it would be anticipated that a rise in the NADPH:NADP+ ratio would result in a shift in the activation threshold, that is, more hyperpolarizing than depolarizing [147]. Therefore, more research is needed to implicate Kv in HPV and to determine the role of distinct Kv subunits in regulating the oxygen sensitivity of Kv channels.

#### **5. Clinical approaches of Pyridine derivatives**

A glance at the US FDA database reveals that pyridine and dihydropyridine drugs constitute nearly 14% and 4% of N-heterocyclic drugs are approved for the treatment of various diseases.

#### **5.1 Pioglitazone**

Pilot research was conducted to compare the effects of pioglitazone on cardiac function and oxidative stress in patients with type II diabetes and insulin resistance undergoing elective percutaneous coronary intervention to placebo [157]. In cardiac insulin resistance, pioglitazone corrects mitochondrial dysfunction [158], PPARgamma activation which is associated with improving cardiovascular risk were observed in many clinical investigations. The change in cardiovascular or metabolic markers and mRNA will be isolated from circulating mononuclear cells to investigate the degree of activation of the immune system, which is another measurement of the atherosclerosis risk [159]. It also have myocardial protection in atherosclerosis and coronary heart

*The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels DOI: http://dx.doi.org/10.5772/intechopen.106759*

disease [160]. Pioglitazone reduces left ventricular mass in people with type II diabetes who have ischemic heart disease [161]. Pioglitazone treatment or physical training alone enhance the hearts in HIV patients with metabolic syndrome. The combination of physical training and pioglitazone treatment results on in reducing insulin resistance and subsequently improving cardiac metabolism, and enhancing heart function in the type II diabetes population with cardiovascular risk [162].

### **5.2 Niacin**

Niacin plays a key role in regulating atherosclerotic plaque inflammation. It has a protective effect on endothelial progenitor cells and microparticles, and it is vigorously used in chronic statin therapy to treat atherosclerotic disease on chronic statin therapy. The effects of niacin on vascular health were assessed using fluorodeoxyglucose-PET/CT and circulating endothelial progenitor cells and microparticles [163]. Niacin reduces the elevation of triglycerides and HDL [164]. Extended-release niacin/laropiprant has a significant effect in patients with the atherosclerotic disease compared to placebo. Dilatation of arterial walls improved in statin therapy assessed by the brachial vasoreactivity [165].

#### **5.3 Nicorandil**

Nicorandil is recommended as a second-line treatment for the angina treatment [166]. Still, randomized-controlled trials going on to evaluate the benefit of nicorandil for patients with chronic total occlusion [167]. The treatment of oral nicorandil to reduced cardiac death after coronary revascularization in hemodialysis patients [168].

Nicorandil, a combination of nitrates, is an ATP-sensitive K+ channel activator that reduces infarct size in animal models. Moreover, a prospective and randomized, multicenter study was conducted by the Japan-working groups of acute myocardial infarction for the reduction of necrotic damage by activating K-ATP channel to determine potential use of nicorandil. The treatment of Nicorandil for acute myocardial infarction, reduces myocardial infarct size and improves regional wall motion [169]. The infarct size in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention treated by nicorandil before and after the reperfusion with those standard therapy treated by percutaneous coronary intervention [170].

#### **5.4 Riociguat**

Riociguat has been shown pharmacodynamics affects in patients with pulmonary hypertension and heart failure with remodeled ejection fraction [171].

#### **5.5 Vericiguat**

Vericiguat (BAY1021189) is currently being developed to treat heart failure, which is a condition where the heart has unable to pump blood throughout the body. Patients with heart failure frequently also have renal impairment, which prevents the kidneys from properly filtering the blood [172]. Many investigators found the pharmacodynamic drug-drug interaction and the safety and tolerability of Isosorbide Mononitrate and Vericiguat in patients with stable coronary artery disease [173]. In Phase III clinical trials, the optimal dose of soluble guanylate cyclase stimulator BAY1021189 per day by orally preserved ejection fraction in the heart failure [174].

*The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels DOI: http://dx.doi.org/10.5772/intechopen.106759*

#### **5.6 Mangafodipir**

Mangafodipir is also known as manganese dipyridoxyl diphosphate, and its lipophile metabolite manganese dipyridoxyl diethylene diamide has a catalytic antioxidants and iron chelators properties. In preclinical studies, these agents reduce injuries induced by oxidative stress in cancer chemotherapy and reperfusion/reoxygenation of ischemic/hypoxic myocardium. The treatment of Mangafodipir, decreased the size of the myocardial infarct by 55% in a in vivo myocardial infarct pig model. Most likely, mangafodipir promotes recovery of downregulated pathways and guards against fatal reperfusion damage [175].

#### **5.7 Tezosentan**

Tezosentan has shown efficacy, and safety profile in patients with acute heart failure [176, 177].

Estrogens, dextrothyroxine, nicotinic acid, and clofibrate are used to treat coronary artery disease. These drugs cause more toxicity [178].

#### **6. Conclusion**

The book chapter describes the importance of pyridine derivatives as a novel class of medications for treating cardiovascular disorders. Pyridine derivatives are known to be ion channel modulators and change the action potential by changing voltage-gated potassium, sodium, and calcium ion channel activity. This chapter presents a critical study of many medications and research on designing and developing various pyridine and dihydropyridine-based derivatives. They have been classified based on their pharmacological activity. Every specific structural aspect relevant to exclusive activities has also been considered. The central pyridine core is more significantly tractable for producing anti-infectious and anticancer medicines. Dihydropyridine derivatives primarily regulate the dihydropyridine protein, also known as calcium channels. Dihydropyridine ring-containing drugs, including nimodipine, ciclopirox, efonidipine, nifedipine, milrinone, and amrinone, primarily function as calcium channel blockers, and are used to treat hypertension and heart issues.

The structure, application, and diversity of pyridine- and dihydropyridine-containing compounds will expand in the future decade, with tremendous potential for new cardiovascular, anti-inflammatory, anti-infectious, neurogenic, and anticancer therapies incorporating the two heterocycles. Because of the enormous structural diversity of pyridine- and dihydropyridine-containing compounds, the present literature just scratches the surface of potential therapeutic applications. In conclusion, paired with a broader chemical space, pyridine and dihydropyridine-containing compounds will aid medicinal chemists in designing bioactive molecules for specific targets.

*The Expanding Role of Pyridine Derivatives as Privileged Scaffolds in Cardiac Ionic Channels DOI: http://dx.doi.org/10.5772/intechopen.106759*

#### **Author details**

Yasodha Krishna Janapati1 , Sunithasree Cheweti2 , Bojjibabu Chidipi3 , Medidi Srinivas4 and Sunil Junapudi4 \*

1 School of Pharmacy and Health Sciences, United States International University – Africa, Nairobi, Kenya

2 Hindu College of Pharmacy, Nagarjuna University, Guntur, Andhra Pradesh, India

3 Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

4 Department of Pharmaceutical Chemistry, Geethanjali College of Pharmacy, Medchalmalkajgiri, Telanga, India

\*Address all correspondence to: suniljunapudi@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 7**

## Fused Pyridine Derivatives: Synthesis and Biological Activities

*Huseyin Istanbullu, Gulsah Bayraktar and Merve Saylam*

#### **Abstract**

Five-membered heteroaromatic ring fused pyridine derivatives are of increasing interest in drug design and medicinal chemistry. The structural similarity of many drugs (especially antiviral and anticancer ones) with DNA bases such as adenine and guanine is a key factor to explain their effectiveness. Apart from these, it is also found in the structures of substances with antituberculosis, antibacterial, antifungal, anti-inflammatory, and antimalarial activities. Another advantage of this group of compounds is their positive contribution to solubility, polarity, lipophilicity, and hydrogen bonding capacity properties of the compounds they are incorporated into. In this chapter, various bioactivities of fused pyridine derivatives will be categorized and summarized.

**Keywords:** fused pyridine, medicinal chemistry, furopyridines, thiazolopyridine, triazolopyridine, oxadiazolopyridine

#### **1. Introduction**

Fused pyridine heterocyclic ring derivatives are frequently used structures in drug research. Due to the vastness of the chemical space of fused pyridine derivatives, the most common fused pyridine derivatives, namely furopyridines, thienopyridines, pyrrolopyridines, oxazolopyridines, isoxazolopyridines, oxadiazolopyridines, imidazopyridines, pyrazolopyridines, thiazolopyridines, isothiazolopyridines, triazolopyridines, thiadiazolopyridines, tetrazolopyridines, selenazolopyridines, and dithiolopyridines, with their bioactivities were selected to cover in this chapter.

#### **2. Fused pyridine derivatives**

#### **2.1 Furopyridines**

Furopyridine synthesis was firstly reported almost a century ago. Since furopyridines are isosteres of benzofuran and indole cores, they are frequently encountered in the chemical structure of compounds possessing various bioactivities such as antihypertensive and antimicrobial.

**Figure 1.**

*Furopyridine isomeric structures and example drug molecule bearing furopyridine ring.*

One of the first studies on furopyridine derivatives focused on anti-inflammatory, anti-aggregation, and anticoagulant activities [1, 2]. Sato et al. reported tetrahydrofuro[3,4-b]pyridine derivatives with coronary vasodilating activity [3]. Garay et al. examined the effect of furopyridines on the stimulation of K+ movement across human red cells membrane [4].

On the other hand, cicletanine, a diuretic drug bearing furopyridine scaffold, used in the treatment of hypertension, also is a competitive histamine antagonist (**Figure 1**) [5, 6]. Clinical trial on its usage in hypertension with diabetes is ongoing (NCT02709031).

In addition to the activities mentioned before, there are several studies on furopyridine containing compounds with antimicrobial, anti-infective, and antiproliferative activities [7–14]. Also, furopyridine scaffold is present in a HIV protease inhibitor, L-754394 [15, 16]. Interestingly, it is also found in the structure of the antibiotic isolated from the fungus, *Cladobotryum varium* [17].

Compounds bearing furopyridine scaffold were reported in many studies as both core structure and substituent with kinase inhibitor properties, namely selective inhibitors of cdc-like kinases (CLKs), cyclin-dependent kinase (CDK2) inhibitors, and dk1, cdk2, Fyn, JNK3 kinase inhibitors [18–21].

On the other hand, furopyridine derivatives were reported possessing melaninconcentrating hormone (MCH1) receptor modulator activity and melatoninergic MT1 and MT2 receptor activity [22, 23].

In addition to these, inhibitor effect against angiogenetic targets on VEGFR2, Tie-2, and EphB4, mGluR5 noncompetitive antagonist activity, cannabinoid-1 receptor inverse agonist activity, σ receptor affinity, 5-HT1A agonists/5-HT3 antagonist activity, and 5-HT1F receptor agonist activity of various compounds bearing furopyridine fused ring were also reported [24–29].

#### **2.2 Thienopyridines**

The first report on bioactivity of thieno[3,2-b]pyridines focused on chemotherapy of parasites (*Entamoeba histolytica*) [30].

Thienopyridine ring system is an important structural element of anti-aggregation drugs (**Figure 2**). Ticlopidine, tetrahydrothieno[3,2-c]pyridine derivative, is the first reported drug with in vitro anti-inflammatory (carrageenan-induced edema) and inhibition of ADP-induced platelet aggregation activity in 1974 [2]. Then clopidogrel, having the same ring was reported in 1987 and is still on the market for antiplatelet

*Fused Pyridine Derivatives: Synthesis and Biological Activities DOI: http://dx.doi.org/10.5772/intechopen.107537*

**Figure 2.**

*Thienopyridine isomeric structures and example drug molecules bearing thienopyridine ring.*

therapy [31]. Third drug of this class, prasugrel, was reported to the literature in 2000 [32]. Lastly, vicagrel was reported in 2011 to literature and is still undergoing clinical trials (NCT05162053) (**Figure 2**) [33].

On the other hand, compounds containing thienopyridine ring were reported having antimicrobial, anti-infective, antiviral, and antiproliferative effects [34–45].

Also, thienopyrimidine ring occurs either as core scaffold or a substituent in a group of kinase inhibitors such as VEGFR, EGFR, Src, Aurora, KDR, B-Raf, Pim kinases, check point 1 kinase (CHK1) IκB kinase-β (IKKβ), COT, and JAK2 inhibitors [46–56].

In addition to these, thienopyridine bearing structures are also associated with HMG-CoA reductase inhibitors, agonists for the luteinizing hormone receptor, histone lysine demethylase KDM5A Inhibitors, ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors, alkaline phosphatase (ALPase) activity, 5-HT1A agonists/5-HT3 antagonists, allosteric modulators of metabotropic Glu5 (mGlu5) and mGlu2 receptors, urotensin-II receptor antagonists, positive allosteric modulator targeting the M4 muscarinic acetylcholine receptor (M4 mAChR), selective inhibitors of *Plasmodium falciparum* glycogen synthase-3 (PfGSK-3), urea transporter inhibitors, and uridine diphosphate-galactose glycosyltransferase 8 (UGT8) inhibitor in the literature [28, 57–69].

#### **2.3 Pyrrolopyridines**

There are six isomeric structures of pyrrolopyridine ring, and azaindole term is also commonly used in the literature.

First reported bioactivity of pyrrolopyridine-bearing compound had been synthesized by Hooper et al. and had pyrrolo[3,2-b]pyridine scaffold with moderate antibacterial effect [70].

The first pyrrolo[2,3-b]pyridine-derived drug in literature is vemurafenib, a B-Raf enzyme inhibitor for the treatment of melanoma [71, 72]. On the other hand,

**Figure 3.**

*Pyrrolopyridine isomeric structures and example drug molecules bearing pyrrolopyridine ring.*

ceralasertib, a pyrrolo[2,3-b]pyridine-bearing compound, is under phase II trials as ATR kinase inhibitor for antineoplastic therapy (NCT04417062) (**Figure 3**) [73].

On the other hand, several studies were reported on pyrrolopyridine ring-derived compounds with antimicrobial, anti-infective, and antiviral activities [74–79].

Da Settimo et al. reported that pyrrolo[3,4-c]pyridine derivatives with local anesthetic activity and aldose reductase inhibitory properties [80].

Additionally, Kulagowski et al. found out that pyrrolo[2,3-b]pyridine derivatives showed selective D4 receptor antagonist activity [81].

As mentioned before, similar to thienopyridine ring, platelet aggregation inhibitor activity of pyrrolo[3,2-*c*]pyridine-derived scaffold was reported by Altomare et al. [82].

Moreover, antiproliferative activity of several pyrrolopyridine derivatives was investigated in many studies [83–91].

Apart from these, compounds bearing pyrrolopyridine moiety were found in various kinase inhibitors such as Met, insulin-like growth factor-1 receptor (IGF-1R), tyrosine, Aurora, Fes and Flt3 tyrosine kinases, Traf2 and Nck-interacting kinase (TNIK), Tau Tubulin Kinase 1 (TTBK1), JAK1 selective, BTK, DYRK1A, and RAF-1 dual inhibitor [92–103].

Lastly, many compounds containing fused pyrrolopyridine anologs were reported in the literature having several different bioactivities such as allosteric mGluR5 antagonist activity, diacylglycerol acyltransferase-2 inhibitors, antagonists of the G-protein-coupled chemoattractant receptor (CRTh2), in vivo TNF-a inhibitory activity, preventing protein phosphatase 2A (PP2A) inhibition, human neutrophil elastase (HNE) inhibitors, retinoic acid receptor-related orphan C2 (RORC2) inverse agonist, selective GluN2B negative allosteric modulators, 5-HT1F receptor agonist, agonist of ORL-1(Opioid receptor-like) receptor, and cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonist activity [104–116].

#### **2.4 Oxazolopyridines, isoxazolopyridines, and oxadiazolopyridines**

Oxazolopyridine derivatives, an aza analog of benzoxazole, have been studied extensively since the first report of their synthesis by Fraser and Tittensor in 1956 (**Figure 4**) [117]. Yet, the first bioactivity (anthelmintic and acaricidal activity) of compounds with oxazolopyridine moiety, namely oxazolo[4,5-b]pyridine, was reported nearly 20 years later by Rüfenacht et al., and then, oxazolo[5,4-b]

*Fused Pyridine Derivatives: Synthesis and Biological Activities DOI: http://dx.doi.org/10.5772/intechopen.107537*

#### **Figure 4.**

*Oxazolopyridine, isoxazolopyridine, and oxadiazolopyridine isomeric structures.*

pyridine-bearing compounds were reported having carrageenan rat foot edema assay activity by Clark et al. [118, 119]. Later, antimicrobial, anti-infective, antiviral, and antiproliferative activities of several compounds having oxazololopyridine moiety were reported [120–124].

Additionally, various bioactivities such as fatty acid amide hydrolase (FAAH), topoisomerase II, monoamine oxidase B, GSK-3beta-, sphingomyelin synthase 2 inhibitory, SIRT1 activation, and histamine H3-receptor antagonistic activity of oxazololopyridine moiety-bearing compounds were reported in the literature [125–133].

Although the synthesis of isoxazolo[5,4-b]pyridines was reported in 1968 by Markillie, there has been a few bioactivity studies on isoxazolopyridine derivatives including GABAergic activity, HMG-CoA reductase inhibitory activity, anticancer activity, polo-like kinase inhibitor activity, and gamma-secretase modulator activity (**Figure 4**) [57, 134–138].

The synthesis of oxadiazolopyridine core was firstly reported by Bailey et al. in 1971 (**Figure 4**) [139]. Only antitumor activity and fluorescent properties of oxadiazolopyridine containing compounds were reported [140, 141].

#### **2.5 Imidazopyridines**

Imidazo[4,5-b]pyridine, the first synthesized imidazopyridine isomer, was synthesized by Takahashi and Yajima in 1946, and then analeptic activity of imidazopyridine was reported in 1965 [142, 143].

Imidazopyridines are one of the most studied fused pyridine ring systems; therefore, it is found in many drugs' structures (**Figure 5**). The various bioactivity profiles of these groups of compounds might be associated with the fact that imidazopyridines, also known as 3-deazapurines, are isosteres of purine ring.

Miroprofen, an imidazo[1,2-a]pyridine derived NSAID, has analgesic, antipyretic, and anti-inflammatory activity. Another imidazo[1,2-a]pyridine derivative, Zolpidem, is a hypnotic drug and positive GABA-A receptor modulator. Similarly, Alpidem, Necopidem, and Saripidem are other imidazo[1,2-a]pyridine containing anxiolytic drugs. Olprinone acts as a cardiotonic agent and is used in Japan. Zolimidine is a marketed anti-ulcerative drug. Minodronic acid, a bone resorption inhibitor and Sch 28080, gastric antisecretic compound, and H<sup>+</sup> K+ -ATPase inhibitior are other imidazo[1,2-a]pyridine-bearing compounds [144–152].

**Figure 5.** *Imidazopyridine isomeric structures and example drug molecules bearing imidazopyridine ring.*

Imidazo[4,5-b]pyridine ring is occurred in various drugs including Vardax (sulmazole), a cardiotonic drug with positive inotropic activity, phosphodiesterase inhibition and adenosine receptor antagonist activity, and Rimegepant and Telcagepant, antimigraine drugs possessing CGRP receptor antagonists activity. Additionally, imidazo[4,5-b]pyridine-derived Tenatoprazole is reported with proton pump inhibitory activity and gastric acid secretion inhibitory properties in rats [153–158].

On the other hand, Tegobuvir, imidazo[4,5-c]pyridine-bearing compound, is used in prophylaxis and treatment of HCV infection, and Fadrozole, a Tetrahydroimidazo[1,5-a]pyridine derivative, is a nonsteroidal aromatase inhibitor for breast cancer treatment [159–162].

Moreover, there are several reports on imidazopyridine-bearing compounds possessing antibacterial, antiviral (HIV, etc.), and antiparasitic (anti-leishmanial and anti-trypanosomal) properties [163–174]. Also, imidazopyridine derivatives are often studied as anticancer agents [175–181].

The imidazopyridine scaffold has been reported in the structures of various kinase inhibitors, such as KDR kinase, calmodulin-dependent kinase II (CaMKII), Glycogen Synthase Kinase-3, cyclin-dependent kinase (CDK), Bruton's tyrosine kinase, AKT Kinase, c-Met kinase, VEGFR2 kinase, FLT3 kinase, Pan-JAK, Aurora-A kinase, phosphatidylinositol-3-kinase (PI3K) and apoptosis signal-regulating kinase 1 (ASK1) [182–195].

In addition to these bioactivities, imidazopyridine ring isomers expressed several including positive modulation of GABA-A receptor, positive allosteric modulation of metabotropic glutamate receptor 2 (mGluR2), angiotensin II receptor antagonist,

receptor-related orphan receptor gamma (RORc) inverse agonist, melanin-concentrating hormone receptor 1 (MCHR1) antagonist, anti-inflammatory, anticonvulsant, phosphodiesterase (PDE) inhibitory, platelet-activating factor antagonist, TNF-α suppressing, mammalian target of rapamycin (mTOR) inhibitory, autotaxin inhibitory, cholinesterase inhibitory, and PARP-1 inhibitory activities in the literature [196–209].

#### **2.6 Pyrazolopyridines**

The synthesis of pyrazolopyridines was reported firstly by Englert and McElvain (**Figure 6**) [210]. Shortly after the synthesis, compounds containing pyrazolopyridine moiety with anti-inflammatory, antipyretic, and analgesic activity were reported [211]. Additionally, antibacterial (against both gram-positive and gram-negative bacteria), antiviral (anti-enterovirus), and antifungal and antiparasitic (antimalarial) activity reports of pyrazolopyridine-bearing compounds were reported in the literature [212–217]. Moreover, anticancer activity of various pyrazolopyridine derivatives was investigated in many studies [218–222].

Apart from these, many kinase inhibitors, namely CDK1/CDK2, glycogen synthase kinase-3, protein kinase Cθ (PKCθ), phosphatidylinositol-3-kinases (PI3K), aurora-A kinase, pim-kinase, TYK2, ALK5 (activin receptor-like kinase 5), anaplastic lymphoma kinase (ALK), and mitogen-activated protein kinase kinase 4 (MKK4) inhibitors, have pyrazolopyridine ring in their scaffold [223–232].

Lastly, in addition to activities mentioned before, anxiolytic, adenosine A1 receptor antagonist, PDE4, PDE5, PDE9 inhibitory, mTOR inhibitory, guanylate cyclase agonist, B-RafV600E inhibitory, dopamine D3 receptor agonist, and tubulin polymerization inhibitory and cholinesterase inhibitory activity of pyrazolopyridine derivatives were reported [233–244].

#### **2.7 Thiazolopyridines and isothiazolopyridines**

Thiazolo[4,5-b]pyridine ring was synthesized by Saikachi in 1944 [245]. The first reported bioactivity of thiazolopyridine was antituberculous activity of thiazolo[4,5 c]pyridine derivatives (**Figure 7**) [246].

Antibacterial (against both gram-positive and gram-negative bacteria), antiviral, antifungal, antituberculose, and antiparasitic activity of compounds containing thiazolopyridine structure were reported [247–251]. Additionally, cytotoxic and anticancer activity of thiazolopyridine derivatives were investigated in many studies [252–255].

**Figure 6.** *Pyrazolopyridine isomeric structures.*

#### **Figure 7.**

*Thiazolopyridine and isothiazolopyridine isomeric structures.*

Moreover, there are many thiazolopyridine-bearing compounds with various bioactivity profile, such as histamine H3-receptor antagonistic activity, mGluR5 metabotropic glutamate receptor subtype 5-antagonist, sphingosine-1-phosphate (S1P) agonist, DNA Gyrase B (GyrB) ATPase inhibitor, anti-inflammatory activity, phosphoinositide 3-kinase inhibitor, and allosteric inhibitor of MALT1 [129, 256–261].

On the other hand, synthesis of isothiazolopyridines was firstly reported by Taurins and Khouw in 1997 [262]. Later, in vivo anorectic action activity of isothiazolo[5, 4-b]pyridine derivatives was reported by Malinka and Rutkowska [263]. There have been a few reports on bioactivity of isothiazolopyridine derivatives such as antitumor and radioprotective activities, in vitro antibacterial activity, analgesic activity, cyclin G-associated kinase inhibition, antiviral activity, and COX-1/2 inhibitory activity [264–269].

#### **2.8 Triazolopyridines**

Triazolopyridine scaffold is an isostere of purine ring; therefore, there are several bioactivity reports on compounds containing triazolopyridine ring.

The first report on the synthesis of (3*H*)1,2,3-triazolo[4,5-*c*]pyridine derivatives and their analeptic activity was published by Reitmann in 1936 [270].

1,2,3-Triazolo[4,5-*b*]pyridine and 1,2,3-triazolo[4,5-*c*]pyridine derivatives were reported possessing depressant, tranquilizing, anticonvulsant, and cardiovascular activities [143].

An antidepressant drug Trazodone, 1,2,4-triazolo[4,3-*a*]pyridine derivative, was first reported in 1968 and has been used commonly for the treatment of depression (**Figure 8**) [271]. In addition to its antidepressant effect, it was recently reported that trazodone inhibits tau amyloidogenesis [272].

On the other hand, several triazolopyridine-containing compounds were reported having antibacterial, antiviral, antifungal, antituberculose, and antiparasitic activity [273–278]. Additionally, triazolopyridine derivatives were investigated in many studies for their anticancer activity [279–281].

*Fused Pyridine Derivatives: Synthesis and Biological Activities DOI: http://dx.doi.org/10.5772/intechopen.107537*

#### **Figure 8.**

*Triazolopyridine isomeric structures and example drug molecule-bearing pyrrolopyridine ring.*

Similar to other fused pyridine derivatives, triazolopyridine scaffold has been reported in many papers as kinase inhibitors, such as PIM kinase, JAK1, JAK2, PI3Kgama-delta, ALK-5, VEGFR2 kinase, spleen tyrosine kinase (Syk), c-met kinase, and monopolar spindle 1 (MPS1) kinase inhibitors [282–290].

Lastly, compounds containing triazolopyridine ring were evaluated for their bioactivities, such as anti-inflammatory, p38R, 11beta-hydroxysteroid dehydrogenase-type 1 (11beta-HSD-1), prolylhydroxylase domain-1 (PHD-1), myeloperoxidase, tubulin polymerization, polycomb repressive complex 2 (PRC2) inhibitory, HIV-1 allosteric inhibitor activity, mGlu receptor 2 (mGluR2) PAM, muscarinic acetylcholine receptor subtype 1 (M1) PAM, and retinoic acid receptor-related orphan nuclear receptor gama-t (RORγt) inverse agonist [174, 291–303].

#### **2.9 The other five-membered heteroaromatic ring fused pyridine derivatives**

Apart from fused pyridine derivatives mentioned before, there are several reports on five-membered heteroaromatic fused pyridine ring derivatives possessing bioactivity (**Figure 9**).

#### **Figure 9.**

*Five-membered heteroaromatic ring fused pyridine derivatives.*

For instance, 1,3,4-thiadiazolo[3,2-a]pyridine derivatives were reported having antimicrobial effects [304]. On the other hand, tetrahydrotetrazolopyridine scaffold was found in bovine liver-D-glucuronidase and human-alfa-L-iduronidase inhibitors [305]. Interestingly, an unusual fused pyridine derivative selenazolo[5,4-b]pyridine scaffold can highly induce apoptosis in human breast carcinoma MCF-7 cells [306]. Lastly, dithiolo[4,5-b]pyridine derivatives were reported possessing antimicrobial activity [307].

#### **2.10 Conclusion**

In conclusion, fused five-membered pyridine heteroaromatic rings are privileged scaffolds in medicinal chemistry. Therefore, selected ring systems and their bioactivities are covered in this chapter.

There are several drugs containing these heteroaromatic rings on the market, and several phase trials are ongoing on various compounds. Considering the chemical similarity between fused pyridine rings and nucleobases and amino acids, the wide variety of the bioactivity is unsurprising. The most commonly reported bioactivities of these kinds of derivatives are antimicrobial, anticancer, and kinase inhibition.

### **Author details**

Huseyin Istanbullu1 \*, Gulsah Bayraktar2 and Merve Saylam1

1 Faculty of Pharmacy, Izmir Katip Celebi University, Department of Pharmaceutical Chemistry, Izmir, Turkey

2 Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ege University, Izmir, Turkey

\*Address all correspondence to: huseyin.istanbullu@ikc.edu.tr

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 8**

## Advances in Pyridyl-Based Fluorophores for Sensing Applications

*Andreia Leite, Carla Queirós and Ana M.G. Silva*

#### **Abstract**

Fluorescence sensing plays an important role in high sensitivity, selectivity, and real-time monitoring of biological and environmentally relevant species. Several classes of fluorescent dyes (fluorophores) including rhodamine, BODIPY, 1,8-naphthalimide, and coumarin-among others−when conveniently functionalized with reactive pyridyl receptors, have emerged as effective sensors to detect and quantify chemical species with high accuracy through fluorescent imaging and spectroscopy. Among the sensing targets, monitoring of harmful chemical species, e.g., metal ions (zinc, copper, iron, mercury, cadmium, lead, etc.) and anions (chloride, fluoride, sulfide, thiocyanate, etc.) can be used to understand their physiological and pathological role in live-cells and tissues, as well as to protect human health. This chapter focuses on recent advances in the molecular design of pyridyl-substituted fluorophores, their photophysical properties, and sensing applications.

**Keywords:** molecular design, fluorescent dyes, pyridyl receptors, photophysical properties, sensing behavior

#### **1. Introduction**

Fluorescence detection techniques have become of paramount importance for monitoring biochemical and biological processes, allowing the detection and quantification of levels of chemical species in the human body and in the surrounding environment. Indeed, fluorescence sensing is a highly sensitive technique having numerous parameters that can serve as analytical information, including decay time, energy transfer, and quenching efficiency, in addition to the more conventional measurement of fluorescence intensity or polarization. Through the design of fluorescent dyes (fluorophores), it is possible to obtain molecules and materials that respond to the presence of a target analyte through changes in its physicochemical properties, presenting typically high sensibility and selectivity, quick response time and simplicity of measurement, and quantification of the analyte [1].

When combined with specific receptor units, fluorescent dyes can be extremely useful in several applications such as detection and quantification of chemical species, as well as in understanding their physiological and pathological role in cells and tissues. Receptors based on the pyridyl group are of major importance in ligand design for many of the above applications. The pyridine ring possesses a dipole moment found to be 2.22 D; therefore, it exhibits greater electronegativity as compared with the phenyl ring [2]. The pyridyl groups, such as di-(2-picolyl)amine (DPA), are excellent metal ion binding sites for the construction of fluorescent probes and can be attached to specific fluorophores or integrated into the fluorophore as part of the metal binding group, as found in quinolines. The principal fluorescence mechanisms involved in the design of the chemosensors are schematized in **Figure 1** and include:

i.Photoinduced electron transfer (PET, **Figure 1a**): Originally proposed by A. Prasanna de Silva and coworkers [3], PET involves the use of fluorophorespacer-receptor-type structures. The spacer is used to separate the fluorophore

**Figure 1.** *Schematic representation of the main fluorescence mechanisms.*

from the receptor at a certain distance while allowing the intramolecular electron transfer causes the interruption of the fluorophore's fluorescence. The interaction of the analyte with the receptor causes a change in the redox potential of the receptor and the electron transfer became energetically unfavorable, which leads to the re-establishment of fluorophore's fluorescence;


Such fluorescence mechanisms have inspired the development of new fluorescent structures and materials for the preparation of optical sensors for analyte detection in real scenarios. This chapter will focus precisely on recent advances in the molecular design of pyridyl substituted fluorophores, their photophysical properties, and sensing applications.

### **2. Pyridyl groups in fluorescent dyes**

#### **2.1 Rhodamine dyes**

#### *2.1.1 Molecular design*

Xanthene is a heterocyclic organic compound with yellow coloration that contains two benzene rings connected through an oxygen atom and a methylene group (**Figure 2**). This class of dyes comprises fluorescein, rhodamine, and rhodol derivatives. Rhodamines were first produced in the late nineteenth century. They can be distinguished from other dyes by the presence of *N-*atoms at positions 3 and 6 of the xanthene core and they are one of the most widely used organic dyes with application in areas such as bioimaging, chemosensing, cosmetics, inks, and textiles. Rhodamine's photophysical properties are highly dependent on the structural features and substituent groups. The periphery of the xanthene ring can be modified using several strategies and it affects the selectivity in their metal ion-induced signaling pattern. The most common derivatizations are:


**Figure 2.**

*Representative examples of rhodamine dyes functionalized with pyridyl groups.*

iii.Modifications in the periphery of the phenyl ring at positions 4′ and/or 5′ are difficult to perform, especially when aiming to prepare isomerically pure derivatives from the sequential Friedel–Crafts reaction of an aminophenol with an asymmetric anhydride. This reaction usually led to a mixture of two isomers often difficult to separate and purify. Some of these derivatives are used for labeling molecules of interest [5];

iv.Modifications at position 9 are used for the synthesis of dihydro derivatives;

v.Substitution of the xanthene heteroatom (O), for example, by Si can potentiate the absorption and emission capacity in the near-infrared region, fluorescence quantum yield, or fluorescence intensity [6].

Some studies also focus on the influence of the positional isomers of the pyridine's nitrogen (*ortho*-, *meta*-, and *para*-) in the sensitivity and selectivity toward analytes, such as metal ions.

#### *2.1.2 Photophysical properties*

The excellence of the photophysical properties of rhodamines is one of the main reasons for their success and wide application in several areas. Rhodamines possess high molar absorptivity coefficient (ε), long absorption and emission wavelengths (>500 nm), high fluorescence quantum yield, photostability, and good water solubility [7]. These properties are directly associated with the extensive π-conjugated systems, molecular rigidity, and presence of functional groups.

One of the most interesting features of rhodamine derivatives is the existence of two isomeric forms-spirolactone (closed form) and quinoid (opened form) (**Figure 2**)-with very different optical properties. The spirolactone form is colorless and nonfluorescent, while the open form is highly fluorescent and has a pink coloration. The open form owes its properties to its extended π-conjugation and the interconversion from the closed to open form allows the rhodamine derivatives to possess an *off–on* (*turn-on*) characteristic fluorescence, usually promoted by acid or specific metal ions interactions [8].

#### *2.1.3 Sensing applications*

Rhodamines are frequently used in the preparation of highly selective, fast response, and sensitive sensing tools, employed in the detection of contaminants and environmental parameters in air, water, and waste [9]. **Figure 2** shows a series of selected examples of rhodamine derivatives/probes, those structural and photophysical features and sensing behaviors will be discussed in the next paragraphs.

One of the most explored rhodamine-based dyes for conjugation with pyridyl derivatives is rhodamine B hydrazide (**RhoHyd**, **Figure 2**), being the condensation product between the two moieties involving the terminal NH2 of **RhoHyd**. This condensation can be achieved by attaching directly the pyridyl derivatives, through single or double bonds, or by using spacers. Uvdal and co-workers have reported probe **1,** which is prepared by appending a hydroxymethyl-pyridine group to **RhoHyd** [10]. This probe presented specific Hg2+-induced color change and fluorescent enhancement in aqueous systems based on a metal binding induced ring-opening process of the spirolactam form. Probe **1** presented a limit of detection (LOD) of 15.7 × 10−9 mol dm−3, and the **1**-Hg complex, with 1:1 stoichiometry, was formed by the coordinating atoms •O–N–N–O• from hydroxymethyl-pyridine and **RhoHyd** - with an association constant of 0.70 × 105 mol−1 dm3 . The results also revealed good cell-membrane permeability and applicability of probe **1** for the detection of intracellular Hg2+ in living cells with almost no cytotoxicity. The simple change of linking the -NH group of **RhoHyd** to the hydroxyl-pyridyl derivative using a double bond, allowed the

synthesis of probe **2** with even a higher association constant (1.27 × 107 mol−1 dm3 ), suitable for a pH range from 5 to 9 and capable to detect basal levels of Fe3+, as well as the metal ion dynamic changes in live cells at subcellular resolution [11]. The confocal laser scanning microscopy experiments showed two Fe3+ pools in mitochondria and endosomes/lysosomes for the first time.

In 2012, a study related to the influence of the number, nature, and size of coordinating entities was reported [12]. The synthesized probe **3** has been reported several times in literature and can be prepared from a condensation reaction between **RhoHyd** and 2-pyridinecarboxaldehyde [12–14]. In all cases, the probe was isolated in the ring-closed spirolactam form. Chereddy and co-workers [12] reported that in the presence of 50 × 10−3 mol dm−3 concentration of Cu2+ or Fe3+, a clear pink color solution (0.01 mol dm−3 Tris HCl:CH3CN solvent mixture, pH 7.4) was observed with the concomitant appearance of a new peak at 555 nm in the absorption spectra-ring opening mechanism: 57-fold for Fe3+ and 53-fold for Cu2+. This lack of selectivity of probe **3** was overcome by using a CH3CN/H2O binary solution (7:3 v/v) [13]. A 1:1 stoichiometry of the **3**-Cu complex was estimated with a binding constant of 2.5 × 104 mol−1 dm3 . The UV–vis and fluorescence spectra showed an increase in the absorption maximum band and the depletion of fluorescence intensity, respectively. Besides, this complex proved to be reversible in the presence of KI. In 2017, Stalin and co-workers selected a solvent mixture of CH3CN/H2O (2,8, v/v) buffered with 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), pH = 7.2, to perform their studies [14]. In this case, the probe revealed sensitivity (binding constant of 4.25 × 104 mol−1 dm3 and LOD of 0.10 mol dm−3) and selectivity toward Cd2+ by an intramolecular FRET process induced by the binding to Cd2+ ion and significant spectral overlap between the absorption spectrum of **3** with the emission spectrum of the pyridine fragment. Using a hand-held UV lamp, naked-eye detection of Cd2+ presence was possible by observing the color change from deep magenta to bright orange. On the other hand, the *in situ* generated **3**–Cd2+ complex was able to selectively sense S2−, with the remarkable recovery of fluorescence and UV-vis absorption spectra, by means of a displacement approach-formation of a CdS complex. This same chemosensor was later explored by our research group as a probe that could allow discrimination of light-up effects induced by metal ion chelation and variation of pH [15]. The probe synthesis was optimized using a solvent-free approach under microwave irradiation and a crystal suitable for single-crystal X-ray diffraction (SCXRD) proved the isolation of the probe in the expected spirolactam form. The fluorescence properties of the probe were studied and determined that: i) the probe was fluorescent in the pH range 2−4 (max. Value at pH 3; pKa1 = 2.98 and pKa2 = 2.89); ii) the presence of Fe3+ triggered the opening of the spirolactam ring with the formation of a new and intense fluorescence band at 586 nm (dimethylsulfoxide (DMSO) and DMSO:H2O (9,1, v/v); and iii) the determined 1:2 (metal: dye) was consistent with the formation of the Fe3+ complex with the tridentate probe.

A similar dye with a longer spacer (**4**) was synthesized via one-pot Schiff base reaction of rhodamine B, ethylenediamine, and isonicotinaldehyde and was characterized by SCXRD, where suitable orange-brown crystals were obtained by slow solvent evaporation methods [16]. The Fe3+ recognition mechanism, established by density-functional theory (DFT), involved a PET mechanism between the rhodamine core and pyridine and proved to be reversible by UV/Photoluminescence (PL) and time-resolved photoluminescence (TRPL) in the presence of EDTA (ethylenediaminetetraacetic acid tetrasodium salt). A LOD estimated value of 102.3 × 10−9 mol dm−3 was reported as well as the probe sensitivity in the pH range from 3 to 10 and cellular

#### *Advances in Pyridyl-Based Fluorophores for Sensing Applications DOI: http://dx.doi.org/10.5772/intechopen.107912*

imaging studies revealed real applicability of the probe in Fe3+ detection. Another work showed its selectivity toward SCN− in human embryonic kidney cells, including fluorescence and "naked-eye" detection of nanomolar concentration of the analyte [17]. DFT calculations suggested the existence of non-covalent interactions and longrange electrostatic forces between the analyte and the probe, and a comparison using a fluorescein derivative as a model compound allowed to establish a "lock" and "key" mechanism for the analyte sensing. The probe was used successfully in the quantification of SCN− in real samples such as sheep blood serum and cow milk.

Kan and co-workers reported two probes (**5** and **6**) prepared by a two-step approach: i) reaction of rhodamine B with ethylenediamine followed by ii) reaction with 2-picolinic acid and pyridine-2,6-dicarbonyl dichloride, respectively [18]. Both probes exhibited excellent selectivity and sensitivity for Fe3+ in EtOH/H2O solution (3:1, v/v, HEPES, 0.5 × 10−3 mol dm−3, pH = 7.33) and living human breast adenocarcinoma (MCF-7) cells. Probe **5** presented a 1:1 binding stoichiometry and a lower LOD (0.067 × 10−6 mol dm−3) than probe **6**, which presented a 1:2 binding stoichiometry. Both were successfully applied in the detection of trace amounts of Fe3+ up to 200 × 10−6 mol dm−3- in tap water and real mud water with good recovery efficiency, and once again the *turn-on* mechanism was observed. Probe **6,** reported by Li and co-workers [19], operates under two different Fe3+ recognition mechanisms based on the solvent used: i) in acetonitrile (CH3CN), a Fe3+ complex is formed causing the quenching of fluorescence, and ii) in phosphate-buffered saline (PBS), hydrolysis occurred leading to the ring opening and a 75-fold increase in fluorescence intensity, with the formation of dipicolinic acid - a result supported by mass spectrometry (MS). The fluorescent imaging of living cell revealed low cytotoxicity, cell viability, and that the probe could penetrate cell membranes.

Some probes are designed to incorporate selected receptor groups, such as sulfur derivatives-thiourea, sulfonyl, or thiol groups. Sarkar and co-workers [20] prepared a rhodamine-linked pyridyl thiourea probe (**7**) with distinct cation and anion binding sites. The probe was capable of selectively detecting different analytes: i) in CH3CN, fluoride was detected by changes in the emission at 518 nm; ii) Al3+ detection occurred at concentrations of approximately 10−5 mol dm−3 by colorimetric and ratiometric responses; iii) in aqueous CH3CN mixture, the probe was capable to distinguish between Al3+ and Cu2+-possessing higher sensitivity and selectivity toward Al3+ at the emission wavelength 558 nm; and iv) the probe could also detect Ag<sup>+</sup> through an increase in the emission intensity at 416 nm, with a LOD of 2.09 × 10−4 mol dm−3. In 2020, probe **8** based on the linkage of rhodamine B and pyridine-3-sulfonyl chloride was reported [21]. This dye resulted from the combination of an electron-donor group (amino group) for fluorescence and sensitivity enhancement and a recognition group with good ion coordination ability (pyridine-3-sulfonyl chloride). **8** presented fast (280 s) and dual response-absorption and fluorescence-upon addition of Al3+, with a LOD of 14.23 × 10−9 mol dm−3. The **8**-Al complex could further be used as a sensor for fluoride by fluorescence intensity decrease. The probe was used successfully in the detection of low Al3+ concentrations in natural water, living cells, zebrafish, and plant tissues. Other derivatizations can also be used, for example, Duan and co-workers reported a rhodamine-thiospirolactam probe prepared from the reaction of thiooxorhodamine B hydrazide and 2-pyridinecarboxaldehyde (**9**) [22]. In this case, the *N*-atom of the spirolactam was replaced by an S-atom, while the carbonyl was converted into a hydrazone linked to the pyridine derivative. The probe presented a color change from colorless to pink and a fluorescence intensity enhancement in the presence of Hg2+ even at the ppb level. The thioether probe was compared to its

thioamide congener and revealed higher selectivity for Hg2+, which was related to its poorer coordination affinity for other interference metal ions.

In 2015, Fu and co-workers prepared three novel rhodamine-triazine aminopyridine derivatives, in which the *N*-atom of the aminopyridine ring was placed in *ortho*-, *meta*-, or *para*- position [23]. These probes' design took into account the aminopyridine water solubility and the excellent reactivity properties of cyanuric chloride as the connecting bridge. The *ortho*-derivative (**10**) presented higher selectivity for Fe3+ in water-over other metal ions and amino acids-due to its more suitable space coordination sphere. In the presence of Fe3+, a new absorption band appeared (562 nm) and the emission intensity at 582 nm increased up to 35-fold, along with the change in color from colorless to pink. This probe possessed a LOD for Fe3+ of 4.1 × 10−8 mol dm−3 and an association constant of 1.49 × 106 mol−1 dm3 , being a 1:1 stoichiometric structure supported by Job's plot and MS. Furthermore, the probe revealed to be: i) capable to detect Fe3+ in environmental samples using paper-made test kits impregnated with the probe; ii) capable to detect up to 0.3 mol dm−3 Fe3+ in tap water, and iii) suitable for imaging intracellular Fe3+ in HL-7702 cells. Another example was the report from Bhattacharya and co-workers where the three isomers of the pyridine's nitrogen were compared toward Cu2+ and Hg2+ sensitivity using probe **11a** as the common point [24]. The dye with the pyridine nitrogen at *ortho*-position was the only isomer that presented selective colorimetric detection of Cu2+-in water (pH 7.4), in a medium containing bovine serum albumin and blood serum. The detection mechanism was based on the formation of the Cu2+ complex (2:1 stoichiometry) involving the carbonyl oxygen, amido nitrogen, and pyridine nitrogen (see **Figure 2**). The analytes were detected in different water sources at the ppb level, and the probes could be used for rapid *on-site* detection by the preparation of portable test strips. A very similar probe to the *ortho*-derivative **11a**, with a methyl substituent in the *N*-atom attached to the pyridine (**11b**) was prepared through the condensation of **RhoHyd** and 2-acetylpyridine and applied in the selective detection of Cu2+, again by a *turn-on* process due to spirolactam ring opening [25]. The probe was suitable for Cu2+ detection within a concentration range from 2.0 to 20.0 × 10−6 mol dm−3 and presented a LOD of 0.21 × 10−6 mol dm−3 - a value lower than the maximum concentration established by the World Health Organization (WHO).

In 2014, a study based on the influence of different substituents attached to the *N-*atom of the xanthene at positions 3 and 6 was reported [26]. The probes were prepared from the condensation of rhodamine 6G with 2-aminoethylpyridine (**12**), followed by a subsequent nucleophilic substitution (*SN*2) reaction with 9-bromomethyl anthracene (**13**) or with 1-bromo-octane (**14**). All the probes revealed chromogenic and fluorogenic *turn-on* spectral responses in the presence of Pb(II) ions and **13** also presented the lowest LOD and reversibility due to the perturbation of the combined PET inhibition and FRET processes associated with its bifluorophoric nature. In the same report, a derivative with two ethyl-substituents at both *N*-atoms attached to the xanthene core is presented as a selective sensor of Hg2+ with a dual mode spectral amplification. The authors have concluded that changes in selectivity and signaling pattern are associated with induced amine rigidity in xanthene. Other positions of the rhodamine dye can also be used for structural modifications. For example*,* probe **15** based on the modification of the 3′*-*position of the benzolate in the rhodamine with an amino pyridine substituent was prepared [27]. This probe exhibited high selectivity and sensitivity toward Ni2+, possessed a LOD down to 4.6 ppb, and the chelation of the metal ion involved the carboxylate group of the rhodamine moiety and the *N*-atom of the pyridine moiety.

#### *Advances in Pyridyl-Based Fluorophores for Sensing Applications DOI: http://dx.doi.org/10.5772/intechopen.107912*

Another strategy for the design of rhodamine-pyridine probes is by conjugation with other dyes or aromatic rings. In 2016, a rhodamine derivative incorporating a 2-[(1H-pyrrol-2-ylmethyl)-(2-pyridinyl-methyl) amino]- tripodal receptor was reported (**16**) and used as a sensor for the detection of accumulated Co(II) in *Hybanthus enneaspermus* plant [28]. The addition of Co(II) to a solution of **16** in THF/H2O (8:2 v/v, 0.01 mol dm−3 HEPES, pH 7.4) promoted the spirolactam ring opening with the formation of a 2:1 complex (probe:Co) with LOD of 4.3 × 10−9 mol dm−3. The complex was reversible in the presence of EDTA and the probe proved to be suitable for *in-situ* detection of Co(II) in a pH range from 5 to 10. Xu and co-workers designed a multidentate dye **17** with rhodamine-triazole-pyridine units for the detection of Sn2+ [29]. In the presence of Sn2+ the probe, in CH3CN:H2O (99:1, v/v), showed changes in color, from colorless to orange, and in the absorption and fluorescence spectra—appearance of a new band at 560 nm and intensity enhancement at 587 nm, respectively. The recognition mechanism was studied by several techniques and confirmed the formation of stable 5-member or 6-member rings between Sn2+ and **17** (1:1 complex).

In 2019, our work group designed a series of pyridyl analogs of rosamines (rhodamine derivatives lacking the carboxylic group at position 2′ of the benzenic ring) and studied the influence of solvent and charge on their photophysical properties [30]. It was found that the structural variation involving the position of the *N*-atom in the pyridine did not influence the absorption and fluorescence properties of dyes, the same could not be said about the charge - the introduction of a positive charge at the *N*-atom (**18**) in the pyridinium analog promoted a significant bathochromic shift in the absorption and fluorescence quenching, both effects associated to *d*-PET mechanism. Probe **18** showed extinction of color and fluorescence in the presence of EtOH, the same being true for the uncharged derivative. The detection of EtOH was more pronounced for **18** and resulted from the nucleophilic addition of the ethoxide ion to the central 9-position of the xanthene core, the process was reversible with the addition of a weak acid (trifluoroacetic acid, TFA). Two years later, Xie and co-workers reported a pyridine-Si-rhodamine-based probe (**19**) that could be used as a lysosomaltargeted near-infrared (NIR) fluorescent probe for reactive oxygen species (ROS) [31]. Probe **19** possessed a pyridine-Si-rhodamine moiety as a fluorescent reporter and a borophenylic acid moiety as a reacting group. The probe exhibited good water solubility and, in the presence of hydrogen peroxide (H2O2), revealed a significant enhancement in the fluorescence intensity at 680 nm, which could be attributed to the solvent effect and ICT. The response toward other ROS was also evaluated and revealed that the fluorescence enhancement would occur in the order: hypochlorous acid (HClO, 5-fold) < H2O2 (14-fold) < hydroxyl radical (•OH, 16-fold). The recognition mechanism, proved by high-resolution MS, indicated the oxidation of phenylboronic acid and was similar with that of phenylboronic acid-based ROS probes. **19** revealed sensitivity to detect ROS in cancer cells and in tumor-bearing mouse xenograft models, being indicative of the probe's applicability to the study of lysosomal cell death.

Many other examples of rhodamine-pyridyl derivatives can be found in literature for selectively sensing several analytes, such as picric acid [32].

#### **2.2 BODIPY dyes**

#### *2.2.1 Molecular design*

The 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene, also known as boron dipyrrin or boron dipyrromethene (BODIPY), is one of the most popular families of organic fluorophores that have found numerous practical applications as fluorescence probes for bioimaging and sensing, laser dyes, and as bright pigments in various fields of technology, *e.g.* in solar fuel generation, in photovoltaic devices, in lightharvesting arrays for antenna systems, and in photocatalysis, among others. Their main credits are due to the excellent photophysical and spectral properties they possess, including insensitivity to solvent polarity and pH, high photostability with high absorption coefficients, and high fluorescence quantum yield, allowing them to be excited at rather long wavelength (~500 nm) [33, 34]. When compared with rhodamine and fluorescein dyes, the BODIPY fluorophore is smaller and more insensitive to environmental conditions, while Förster radius *R*o has about the same value [35].

From the molecular design point of view, the BODIPY dye (**Figure 3**) can be functionalized at the pyrrolic ring, at the central *meso*-position, and at the boron atom [36]. By introducing substituent groups into the different positions of the BODIPY scaffold, as well as by varying the conjugation length with appropriate spacer or *π*-linker, the spectroscopic, (photo)physical, and chemical characteristics of the final molecule can be fine-tuned according to the intended application.

#### *2.2.2 Photophysical properties*

The BODIPY typically exhibits a weak absorption band in 350–450 nm region and a strong absorption band in the 450–580 nm, corresponding to *π* → *π*\* transitions. It shows a strong fluorescence spectrum in the visible region and the fluorescence quantum yields are typically higher than 0.8. The BODIPY dye shows fluorescence lifetime (s) on nanosecond scale, which is independent of the excitation and emission wavelengths, suggesting simple emission from the locally excited state [35].

#### *2.2.3 Sensing applications*

Several BODIPY derivatives having very attractive photophysical properties and photochemical stability have found very useful applications as fluorescent platforms for sensing applications. The introduction of the pyridyl or polypyridyl groups at the periphery of the BODIPY core can lead to a large variety of chemosensors for detecting anions, cations, amino acids, etc. **Figure 3** shows a series of selected examples of these BOPIDY derivatives with different sensing behaviors.

Y. Wu and co-workers [37] reported one of the most notable examples of *meso*functionalized BODIPY for detection of Zn2+ by preparing the probe (**20**) through the combination of 1,3,5,7-tetramethyl-boron dipyrromethene with the DPA receptor. This probe works in an aqueous solution, it exhibits λabs/λem = 491/509 nm with ФF = 0.077 and has the advantage of being very selective for Zn2+, with the fluorescence emission of zinc-binding being pH independent in the range of pH 3−10.

Another example of a *meso*-functionalized BODIPY comes from the X. You's group [38], through the preparation of the BODIPY derivative (**21**) containing a tridentate 2-*N*-(2-pyridylmethyl)amino-phenol ligand. The probe, which is almost nonfluorescent because of the PET quenching process from the *meso*-electron-donating substituent to the excited BODIPY unit, upon addition of Hg2+, the fluorescence intensity increased remarkably, showing a very high sensitivity (detection limit ≤2 ppb), a rapid response time (≤5 seconds), and high selectivity for Hg2+ over other metal cations.

Developed by G. T. Sfrazzetto and co-workers [39], probe **22** contains a tetratiaaza-crown receptor and an alkyl-pyridinium moiety to get water solubility and selectivity for target mitochondria. The probe was found to be highly selective to detect Cu<sup>+</sup> in solution and in living cells through an emission quenching response, which is attributed to the PET process between the BODIPY core and the Cu+ chelated tetrathia-aza crown receptor.

Through a benzyl pyridinium cleavable unit at *meso* position of BODIPY, probe **23** was developed for detection of HOCl. Upon addition of HOCl, it exhibits a fastresponsive rate and a dramatic red fluorescence increase (λem = 614 nm, 170-fold) with high selectivity and sensitivity (LOD = 60 × 10−9 mol dm−3) [40].

The dyad **24** featuring two BODIPY fluorophores linked by a *N,N*′*-(*pyridine-2,6-diylbis(methylene))-dianiline substituent showed a highly selective fluorescent *turn-on* response in the presence of Hg2+ [41]. Through theoretical calculations, it was possible to predict the photophysical properties of the **24**-Hg2+ complex, both the reductive and oxidative PETs are prohibited, thus justifying its strong fluorescence emission observed experimentally.

In a similar approach, dyad **25** consisting of a 2,2′-(ethane-1,2-diylbis(oxy)) bis(*N,N*-bis(pyridine-2-ylmethyl)-aniline receptor, which was covalently connected through aromatic amides with two BODIPY fluorophores, was found to selectively

detect both Hg2+ and Cd2+ ions [42]. In this case, the receptor has been designed to effectively wrap around a metal ion and, at the same time, make the dye watersoluble for its operation in aqueous environment. This probe exhibited LOD values of 38 × 10−9 mol dm−3 for aqueous Hg2+ and a 77 × 10−9 mol dm−3 for aqueous Cd2+.

The functionalization of the BODIPY dye at the δ-position has been also highly explored and one of the most representative examples is the distyryl-substituted BODIPY dye **26** developed by E. U. Akkaya's group [43]. This compound contains the DPA receptor combined with six triethylene glycol (TEG) groups to provide water solubility. It presents λabs /λem = 680/726 nm and the gradual addition of Zn2+ ions to this compound results in a blueshift to 625 nm with a concomitant increase in emission intensity, in aqueous solutions, resulting from the coordination of Zn(II) ions to the DPA receptor (see **Figure 3**). Other similar BODIPY probes for Zn2+ include: (i) the BODIPY functionalized with a *N,N*-di-(2-picolyl)ethylenediamine (DPEN) receptor [44], which can detect Zn2+ cation through fluorescence enhancement and also detect pyrophosphate anion through a fluorescence quenching and (ii) the BODIPY featuring a DPEN and a methyl acetate group for monitoring and quantifying levels of Zn2+ in living cells and detecting intracellular Zn2+ released from intracellular metalloproteins [45].

Probe **27** is another interesting example of a BODIPY functionalized at δ-position with a 1-(furan-2-yl)-*N*-((pyridin-2-yl)methyl)methanamine group [46]. The probe is almost nonfluorescent, but upon addition of Cu2+, a large bathochromic shift in the absorption and fluorescence spectra and induced fluorescence amplification at ∼600 nm was observed, showing great potential for imaging and sensing of Cu2+ in living cells. On the other hand, by modifying BODIPY with a 4-aminostyryl group [47], a probe for Cu2+ with a large Stokes shift, high photostability, and high quantum yield was obtained for monitoring *in vivo* Cu2+ imaging in live mice.

#### **2.3 1,8-Naphthalimide dyes**

#### *2.3.1 Molecular design*

1,8-Naphthalimide (**NI**) core is considered as one of the most versatile fluorophore units due to its synthetic versatility and unique photophysical properties. The aromatic **NI** core, an electron acceptor, along with the *N*-imide site can be easily modified (**Figure 4**), which allows the introduction of an enormous variety of structural units and functional groups in the main core. Regarding their photophysical properties, naphthalimide structures are strongly influenced by the nature of the substituent. The functionalization at C-4 with donor moieties, such as amine or hydroxyl groups, induces a red-shifted ICT band with marked solvatochromic effect. These characteristics encourage the use of **NI** as probes as the changes in spectroscopic properties, such as absorption, dichroism, and fluorescence can all be used to monitor their binding to different analytes. The **NI** and its derivatives have immense potential in the development of new fluorescent probes, laser dyes, optoelectronic materials, and bioimaging but also present high antitumor and antiviral activities [48].

#### *2.3.2 Photophysical properties*

The spectroscopic properties of 1,8-naphthalimides are strongly dependent on the C-4 substituent group. To increase the fluorescent quantum yield, the substituent

group at the 4-position should be an electron-donating group. Other features that contribute for 1,8-naphthalimides extensive use are related with their extraordinary thermal and chemical stability.

#### *2.3.3 Sensing applications*

Several **NI** derivatives have been used as fluorescent platforms in distinct sensing applications. The introduction of one or more pyridyl units in the periphery of the **NI** core led to a large variety of chemosensors for different analytes. In **Figure 4**, a series of **NI** derivatives having different structural characteristics and sensing behaviors are shown.

The first example, probe **28**, uses a 1,8-naphthalimide unit as a receptor, and 1-(2-pyridyl)piperazine as a receptor to design a *turn-on* fluorescent probe for Fe3+ [46]. In this example, the sensor was achieved by mild reaction and simple post process and found to have excellent selectivity and sensitivity to Fe3+. The chelation with Fe3+ over other cations caused a 15.8-fold fluorescence enhancement, which could be explained by the fact that the *N*-atoms in pyridine and piperazine moieties provided the binding sites for Fe3+ and enhancing the fluorescence by blocking the PET process. The maximal fluorescence intensity was linearly proportional to the Fe3+ concentration (60–140 × 10−6 mol dm−3), a LOD of 81 × 10−9 mol dm−3 and the probe worked in a pH range of 5.0–8.0. A 1:1 complex was formed reversibly between the probe and Fe3+. Moreover, tests were performed with other metal cations and it was verified a negligible influence on the fluorescence spectrum of probe **28**/Fe3+.

This result indicated that probe **28** had good anti-interference ability and was a reliable high sensitivity fluorescent probe for Fe3+.

In the next example, a fluorescent ion-imprinted probe (**FIIS**) for rapid and convenient detection of Cu2+ ions was fabricated. Probe **29** represents a fluorescent polymerizable ligand, 4-(2-aminomethyl)pyridine-*N*-allylnaphthalimide [49]. The design of this probe took into consideration to increase the fluorescence quantum yield of 1,8-naphthalimides and at the same time introduced a chelating unit, the substituent group at the 4-position should be an electron-donating group. Taking these considerations into account, 2-aminomethyl pyridine was chosen as the C-4 substituent group in the synthesis of this fluorescent functional monomer (F). The **FIIS** was prepared by surface functionalization of PVDF membrane with a thin layer of Cu2+ ion-imprinted polymer using the synthesized ligand as the fluorescent functional monomer. The intensity of fluorescence emission of **FIIS** decreased linearly with the increase of Cu2+ ions concentration in the range of 0-70.0 × 10−6 mol dm−3. The results of selectivity tests indicated that FIIS had a high specific recognition ability for Cu2+ and its application in the determination of Cu2+ in real water samples revealed a LOD for Cu2+ ions in the range of 0.11–0.14 × 10−6 mol dm−3.

The third example, probe **30**, was published by Wu and co-workers and presented the successful design and synthesis of a simple fluorescent and colorimetric probe [50]. The design involved the functionalization in the *N*-imide site but also in positions 3 and 4 of the **NI** core. This probe exhibited an excellent selective fluorescence response for the simultaneous detection of Zn2+ and Al3+ with a single excitation wavelength in the same solvent system. The LOD of probe **30** for Zn2+ and Al3+ were 14.4 × 10−6 and 74.0 × 10−6 mol dm−3, respectively. In addition, the solution of probe **30** with Zn2+ exhibited a dramatic color change from bright green to bright blue, light, and dark blue with Al3+*,* which could be easily detected by *naked eye* under UV.

The fourth example represents a ratiometric and selective fluorescent probe (**31**) for Cu2+. This probe was easily synthesized by conjugating 2-(aminomethyl)pyridine and *N*-butyl-4-bromo-5-nitro-1,8-naphthalimide [51]. The design and synthesis took into consideration was the mechanism of ICT since this mechanism had been widely exploited for cation sensing. Another aspect that was taken into consideration was the use of a tetradentate receptor site with nitrogen and pyridyl donors since there were strong pieces of evidence that these receptors were very useful for binding Cu2+ ions [52]. The capture of Cu2+ by the receptor resulted in the reduction of the electrondonating ability of the two amino groups of the naphthalene ring; thus, the receptor showed a 50 nm blue shift of fluorescence emission and provided high selectivity for Cu2+ over other heavy and first transition metal ions. The fluorescence of the probe at 525 nm remains unaffected between pH 4.7−13. This probe presents high sensitivity and selectivity toward Cu2+ ions, allows the detection of Cu2+ ratiometrically, and forms a 1:1 complex (see **Figure 4**) [51].

In the last example, Lee and co-workers designed a pyrene-appended naphthalimide, probe **32**, as a ratiometric fluorescence probe that can detect Zn2+ ion in physiological conditions [53]. In this approach, the pyrene unit acts as a reference fluorophore emitting an unaffected fluorescence intensity for Zn2+ and the naphthalimide-dipicolylamine moiety acts as a Zn2+ sensing unit providing a fluorescence change based on a PET mechanism. This probe displayed a ratiometric change in the fluorescent intensities at 385 and 530 nm, which corresponds to the emissions of pyrene and naphthalimide units, for Zn2+ allowing for a precise quantitative analysis. This ratiometric change could be also visualized by a fluorescent color change from blue to green. The probe presented a rapid detection of Zn2+ ions in a 1:1 ratio with

high sensitivity, even in the presence of other competitive metal ions, and with a LOD of 10.5 × 10−9 mol dm−3. Moreover, this probe was able to detect Zn2+ ions in the pH range of 4–11 and it could be efficiently recycled by treating it with EDTA.

#### **2.4 Coumarin dyes**

#### *2.4.1 Molecular design*

Coumarins are a large family of compounds containing the 2*H*-chromen-2-one motif. This platform has been widely used in the design of fluorescent chemosensors because of its small size, excellent biocompatibility, strong and stable fluorescence emission, and good structural flexibility. Hence, this scaffold is an important unit in the development of fluorescent chemosensors with different applications in different fields, such as molecular recognition, molecular imaging, bioorganic, analytical, and materials chemistry, as well as in biology and medical science. Most coumarins were synthesized or designed *de novo* rather than *via* post-functionalization of the coumarin skeleton. The synthetic transformation of coumarins into other heterocyclic compounds and larger fused heterocycles with a coumarin moiety has also been developed [54]. In addition, the benzene subunit of the coumarin ring system is not as reactive as the unsubstituted benzene ring, while the 3 and 4 positions are highly reactive.

#### *2.4.2 Photophysical properties*

Although the coumarin unit exhibits a very weak fluorescence, the introduction of proper substituents originates new coumarin derivatives with significant fluorescence in the visible light range. Hundreds of coumarin dyes have been developed as active components due to their improved quantum yields, tunable emission wavelengths, and the fact that they are very responsive to the polarity of their microenvironments. The previously published results on the photophysical properties of fluorescent coumarins have revealed important structure-property relationships, which have also been important to guide the design of fluorescent chemosensors.

#### *2.4.3 Sensing applications*

A vast variety of coumarin-derived fluorescent chemosensors were built by combining the coumarin moiety with other functional receptors. Herein we present a series of coumarin derivatives in which the receptor is a pyridyl moiety (**Figure 5**).

L. Wang and co-workers reported two ratiometric probes, **33a** and **33b**, to be employed in the quantitative determination of pH value in acidic pH zone. The development of such ratiometric probes, employing the ratio of two emissions at different wavelengths as the detecting signal, allows for more accurate analysis [55]. The reported probes were strategically designed with a 7-diethylamino-coumarin moiety as the fluorophore and pyridine as the receptor. Both probes exhibited a fluorescence ratiometric response to acidic pH. For probe **33a**, upon decreasing the pH from 8.35 to 2.36, the fluorescence emission spectra exhibited a large red shift from 529 to 616 nm, and the emission ratio changed dramatically from 8.58 to 0.09. The emission ratio also displayed good linearity with the pH in the range of 4.0 to 6.5, which is valuable for the quantitative determination of pH values in this acidic pH window. Similar behavior was observed for probe **33b**. By performing some NMR experiments and

#### **Figure 5.**

*Representative examples of coumarin dyes functionalized with pyridyl groups.*

theoretical calculations they conclude that the ratiometric response of the probes to acidic pH was due to H+ binding with the nitrogen of the pyridine receptor and the induced enhancement of the ICT process.

J. Portilla and co-workers reported the coumarin probe (**34**) bearing a 7-hydroxy −4-methylcoumarin unit for selective detection of Mg2+ [56]. The design also includes the 2-pyridylhydrazone substituent as a chelating unit as well as a phenolic hydroxyl group in the fluorophore unit. In addition, the 2-pyridylhydrazone substituent has the C=N donor system that can quench the fluorescence of the fluorophore by PET process and C=N isomerization. The coordination of probe **34** to Mg2+ probably disrupts these processes and increases its structural rigidity producing a fluorescence enhancement. The binding mode of the complex probe **34**- Mg2+ was studied by several spectroscopic methods and revealed the formation of a 1:1 complex (see **Figure 5**). The probe showed good binding ability toward Mg2+, low interference from Ca2+, and a LOD of 105 × 10−9 mol dm−3 in ethanol-water solution.

Another example of a simple coumarin-pyridyl probe was presented by K. Xu and co-workers. The study presents two probes, but we will focus on probe **35** [57]. This probe contains C=N bond to enhance the ability of binding metal ions and contribute to extending the system conjugation. As a result, free probe displays a weak fluorescence due to C=N isomerization, but when a metal ion binds to the chelating unit, the isomerization process is disrupted and there is a fluorescence enhancement. The probe was synthesized for the sequential detection of Zn2+ ion and phosphate anion (PA) in DMF (dimethylformamide)/HEPES buffer medium. The binding of Zn2+ resulted in a pronounced fluorescence enhancement, accompanied by a noticeable

color change in the *naked eye*. The detection limits of probe **35** toward Zn2+ was 1.03 × 10−7 mol dm−3. Probe **35**-Zn2+ complex was then used as a probe for detecting phosphate anion, showing an *off–on–off* fluorescence switching response with Zn2+ and phosphate anion.

Probe **36** was published by K. J. Wallace, with the intention of synthesizing a planar molecule with a high degree of conjugation, which could be easily perturbed to produce a spectroscopic response, taking advantage of intramolecular hydrogen bonding [58]. The design also took into consideration that electron-withdrawing functional groups attached to a carbonyl moiety will pull electron density away from the carbon atom, consequently making this region more electrophilic and susceptible to rapid nucleophilic attack. This probe can undergo the Michael addition of cyanide at the α,β-unsaturated carbonyl, and demonstrated its selectivity for CN− over 12 common anions with LOD of approximately 4 ppb [59].

The next examples were designed by F. Yu and co-workers and represent twophoton fluorescence probes, probes **37** and **38**, possessing coumarin derivatives, for selective and sensitive detection of Zn2+ [60]. Both probes exhibited excellent analytical properties for Zn2+ detection including rapid response, high sensitivity, and good selectivity. In each probe, the coumarin moiety acts as a fluorophore and 2-hydrazinopyridine unit as a metal ion coordination site. Upon addition of Zn2+, solutions of the weakly emissive probes **37** or **38** become strongly fluorescent with emission at 543 nm (probe **37** *ca.* seven times and probe **38** *ca.* four times) in HEPES buffer. In addition, the two-photon properties of these coumarin derivatives make them applicable to detect Zn2+ in biological systems.

#### **2.5 Other pyridyl-based fluorophores**

In quinoline dyes, for example, the pyridyl group is part of the fluorophore, as well as an integral part of the metal-binding group. This fluorophore can be conveniently functionalized with several substituent groups for sensing essentially Zn2+ including 6-methoxy-(8-*p*-toluenesulfonamido) group [61], DPA group [62], among others. Other pyridyl-based fluorophores include: (i) the triazole-pyridine system featuring two pyridine receptors, which behave as an interesting ICT chemosensor for cations and anions [63]; (ii) the 7-nitrobenzo-2-oxo-1,3-diazole dye comprising two pyridines for Zn(II) detection [64] and (iii) the carbazole derivative integrating pyridine units exhibiting fluorescence switching by acid/base exposing [65].

#### **3. Conclusions**

The optical properties of dyes as well as their sensitivity and selectivity toward analytes are highly dependent not only on the fluorophore backbone but also on its substituents and the solvent in which the detection occurs.

Throughout the chapter, several classes of fluorescent dyes-rhodamines, BODIPY's, 1,8-naphthalimides, and coumarins-functionalized with reactive pyridyl receptors were examined. The presented examples explored the strategies used for structural optimization to improve sensing abilities using the principal fluorescence sensing mechanisms. In coming years, new developments are expected toward better sensitivity and selectivity of the probes, to improve their application in the detection and quantification of important analytes in the fields of health and environment.

#### **Acknowledgements**

This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e a Tecnologia, and Ministério da Ciência, Tecnologia e Ensino Superior) through the project UIDB/50006/2020, UIDP/50006/2020, PTDC/ QUI-QIN/28142/2017, EXPL/QUI-OUT/1554/2021 and PARSUK for the Portugal-UK Bilateral Research Fund (BRF 2022). A. M. G. Silva and A. Leite thank FCT for funding through program DL 57/2016 - Norma transitória.

#### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Andreia Leite, Carla Queirós and Ana M.G. Silva\* LAQV/REQUIMTE, Chemistry and Biochemistry Department, Faculty of Sciences, University of Porto, Porto, Portugal

\*Address all correspondence to: ana.silva@fc.up.pt

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Exploring Chemistry with Pyridine Derivatives*

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#### **Chapter 9**

## Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands and Chemosensors

*Kaushal K. Joshi*

#### **Abstract**

Pyridine is a valuable nitrogen based heterocyclic compound which is present not only in large number of naturally occurring bioactive compounds, but widely used in drug designing and development in pharmaceuticals as well as a precursor to agrochemicals and chemical-based industries. Pyridine derivatives bearing either formyl or amino group undergo Schiff base condensation reaction with appropriate substrate and under optimum conditions resulting in Schiff base as product which behave as a flexible and multidentate bioactive ligand. These Schiff bases are of great interest in medicinal chemistry as they can exhibit physiological effects similar to pyridoxalamino acid systems which are considered to be very important in numerous metabolic reactions. They possess an interesting range of bioactivities including antibacterial, antiviral, antitubercular, antifungal, antioxidant, anticonvulsants, antidepressant, anti-inflammatory, antihypertensive, anticancer activity etc. and considered as a versatile pharmacophore group. Further, several pyridine-based Schiff bases show very strong binding abilities towards the various cations and anions with unique photophysical properties which can be used in ion recognition and they are extensively used in development of chemosensors for qualitative and quantitative detection of selective or specific ions in various kinds of environmental and biological media. These chapter insights the bioactivity and ion recognition ability of Schiff bases derived from pyridine derivatives.

**Keywords:** pyridine derivatives, Schiff bases, bioactive ligands, pharmacophore, chemosensors, ion recognition

#### **1. Introduction**

Nitrogen based heterocyclic compounds are well dispersed in nature and present in large number of alkaloids, vitamins, essential oils, amino acids, metabolites etc. all of them are essential for various biochemical processes and cellular life. Pyridine is considered among the most important nitrogen based heterocyclic compounds which is present in numerous bioactive compounds. Pyridine acts as a versatile solvent and

gives different types of reactions including nucleophilic substitution, electrophilic substitution, N-protonation easily. It also possesses some unique optical properties. Due to its important physical, chemical and biological properties, pyridine forms large number of derivatives which are found to be less toxic, but possess much enhanced chemical and biological activities as compared to parent compound. These pyridine derivatives are frequently used in various chemical-based industries like paints and adhesives, dyes and textiles, flavors and perfumes, disinfectants and explosives and so on. They are also used in large scale as a precursor for production of various agrochemicals like herbicides, insecticides, fungicides etc. Pyridine moieties or scaffold are also present in large number of lifesaving drugs and dietary supplements. Pyridine has capability to bind with number of transition metal ions and form innumerable metal complexes. Some of them are widely used as organometallic catalysts in chemical reactions whereas some others possess unique photophysical and luminescence properties and can be used as electrochemical or colorimetric sensors. The most important applications of pyridine and its derivatives are found in pharmaceutical field due to their significant biological activities. Pyridine nucleus is found to be basic skeleton of large number of bioactive molecules which ranges from Antitubercular, Antibacterial, Antiviral, Antianginal, Antihistaminic, Antiulcer, Antitumor drugs etc. Such bioactive pyridine derivatives bearing excellent coordination and strong binding ability can act as important bioactive ligand and can effectively bind with important biomolecules such as proteins, DNA, coenzymes, amino acids and other metabolites by reflecting their pharmacological potential. Thus, pyridine derivatives or scaffolds form the basis of a potent pharmacophore group having biological significance with important therapeutic applications.

Pyridine derivatives bearing either formyl or amino group readily undergo Schiff base condensation reaction with appropriate substrate and optimum conditions. Schiff bases are the condensation products of primary amines and carbonyl compounds and considered as sub-class of imines. They act as an effective organic ligand due to the presence of imine nitrogen which is basic in nature and exhibits π-acceptor properties. Further, if some other hetero atoms like nitrogen, oxygen or sulfur of a specific functional group is present in vicinity of azomethine group, the schiff base act as multidentate ligands with flexibility in structure. Thus, Schiff bases of pyridine can be regarded as much better ligand as compared to pyridine itself in terms of strong binding ability, flexibility in structure and greater bioactivity. Schiff bases derived from pyridine derivatives are of great interest in medicinal chemistry due to their role of bioactive ligand as these can exhibit physiological effects similar to pyridoxalamino acid systems which are considered to be very important in numerous metabolic reactions. They possess a wide variety of biological activities that include antibacterial, antiviral, antitubercular, antifungal, antioxidant, anti-inflammatory, anticonvulsants, antidepressant, antihypertensive, anticancer activity and so on. Due to their vast pharmacological activities, they are considered as a versatile pharmacophore. Further, pyridine-based Schiff bases also play important role in analytical chemistry. As Schiff bases show very strong binding abilities towards the various cations and anions, flexibility in their structure and unique photophysical properties, they can be used in ion recognition and therefore they are extensively used in development of different types of chemosensors for selective detection of specific ions in various kinds of environmental and biological media as well as in industrial and agricultural fields.

In the view of the versatile pharmacological properties as possessed by Schiff bases derived from pyridine derivatives, it is expected that they have high potential in the field of various biological activities that are still unexplored and can be used effectively in drug *Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

discovery. Further, the designing of specific sensor for the recognition of various ions is one of the most demanding areas of chemical research due to their significant contribution in analytical, industrial, agricultural, environmental and biological fields and there is an urgent need to explore the chemistry of pyridine-based Schiff bases to find out their applications as chemosensors for ions recognition studies. This chapter throws some light on chemistry and biological significance of pyridine derivatives, reviews the recent work done on Schiff bases derived from pyridine derivatives and their potential as effective bioactive ligands as well as efficient chemosensors.

#### **2. Pyridine derivatives: chemistry and biological significance**

#### **2.1 Pyridine**

#### *2.1.1 A valuable N-based heterocyclic compound*

Heterocyclic compounds are widely distributed in nature and they are found to be essential for various biochemical processes. They also play a vital role in the metabolism of all living cells as well as in the composition of genetic material of the cells. Many of them are pharmacologically active and are in clinical usage. Among these heterocyclic compounds, those based on nitrogen are of great importance as they are widely spread in nature, possess more therapeutic values and less toxicity as compared to other heterocycles based on oxygen or sulfur. Moreover, their structure can be subtly manipulated to achieve a required modification in function. Such nitrogen based heterocyclic compounds represent important building blocks in both natural and synthetic bioactive compounds. Among these, pyridine is the simplest monoazine compound but considered as one of the most valuable N-based heterocyclic. An important property of pyridine is that it's a polar solvent but aprotic in nature. Thus, it can be easily mixed with polar as well as with many non-polar organic solvents which makes it a versatile solvent. Further, the derivatives of pyridine are found to be less toxic, but possess much more important chemical and biological properties as compared to parent pyridine and therefore, they are frequently used as precursors for many important chemicals, agrochemicals and pharmaceuticals. Owing to their important chemical properties and biological significance, pyridine derivatives find applications in variety of fields as shown in **Figure 1**. These properties of

#### **Figure 1.**

*Applications of pyridine derivatives in variety of fields.*

**Figure 2.** *Naturally occurring compounds containing pyridine ring.*

pyridine and its derivatives make them useful in synthesis of innumerable products such as medicines, agrochemicals, catalysts, optical sensors, food flavorings, perfumes, dyestuffs, paints, adhesives, rubber products, textile fabrics etc. [1–5].

#### *2.1.2 Naturally occurring compounds*

Pyridine derivatives are the fundamentally important nitrogen-based heterocycles which are present in large number of naturally occurring compounds. They are often present as a partial structure in many plant-based alkaloids. For example: Nicotine and Anabasine are found in tobacco whereas Ricinine is present in castor oil and Arecoline is present in betelnut. Nicotinamide adenine dinucleotide phosphate is a cofactor used in anabolic reactions and nucleic acid syntheses which is used by all forms of cellular life (**Figure 2**) [6].

#### *2.1.3 Vitamins and dietary supplements*

Some essential B group vitamins such as Niacin (Vitamin B3) and Pyridoxine (Vitamin B6) are simply the derivatives of pyridine. Chromium picolinate and Zinc picolinate are used as dietary supplements (**Figure 3**) [6, 7].

#### *2.1.4 Pharmaceutical compounds*

Pyridine moieties are present in large number of bioactive compounds and form the basis of pharmacophore group. They can be used as prodrugs or drug molecules themselves which possess wide range of medicinal applications including Antitubercular, Antibacterial, Anticholinesterase, Antihistamine, Antiulcer, Antianginal etc. (**Figure 4**). Further detailed studies on bioactivity of pyridine derivatives are given in Section 2.2 [8, 9].

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

#### **Figure 3.**

*Vitamins and dietary supplements based on pyridine derivatives.*

#### **Figure 4.**

*Pharmaceutical compounds having pyridine moiety.*

#### *2.1.5 Agrochemicals*

Pyridine or its derivatives are used as starting materials for synthesis of many agrochemicals or pesticides. They act as the precursor or intermediates for many important herbicides, fungicides and insecticides (**Figure 5**) [10, 11].

#### *2.1.6 Catalysts*

Several pyridinium salts are used as catalyst in many organic reactions. For example: Collins reagent is used to convert primary alcohols into aldehydes; Cornforth reagent is used for oxidation of primary and secondary alcohols into carbonyls whereas PCC is used primarily for selective oxidation of alcohols into carbonyls. Pyridineborane is used as a reducing agent with improved stability and solubility over NaBH4 (**Figure 6**). Crabtree catalyst and Milstein catalyst are well known organometallic catalyst used for hydrogenation and dehydrocoupling of alcohols respectively [12, 13].

#### *2.1.7 Optical sensors*

Several bipyridine or terpyridine based metal complexes exhibit intense luminescence and can be used as fluorescent chemosensors. For example: [Ru(bipy)3] +2 is

used as a luminophore whereas [Fe(bipy)3] +2 is used in redox titrations and colorimetric analysis. The complex [Fe(phen)3] 2+ is widely used as Ferroin indicator in redox titrations and for the photometric determination of Fe (II) (**Figure 7**) [14, 15].

#### *2.1.8 Chemical based industries*

Pyridine derivatives are also used on large scale in many chemical-based industries. Pyridone based azo disperse dyes are widely used for making dyestuffs. Pyridine derivative ADP is applied to improve network capacity of cotton in textile industries. Polyvinyl pyridines are used as copolymer with styrene for making adhesives and install water proofing properties in paint industries. Several alkyl or acyl derivatives of pyridines are the main source of flavors and essential oils which are widely used in food industries and cosmetic industries (**Figure 8**) [16–19].

**Figure 8.**

*Pyridine derivatives used in chemical-based industries.*

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

#### *2.1.9 Speciality reagents*

Many specialty reagents used in chemical lab are based on pyridine. Pyridine is often used as a reaction solvent for many organic reactions because of its polar nature, low reactivity and miscibility with wide range of solvents. For example: pyridine is an important constitutes of Karl Fischer reagent for determining traces of water in pharmaceuticals, deuterated pyridine is used as common solvent in <sup>1</sup> H-NMR spectroscopy, and pyridine is also used as denaturant for making anti freezing mixtures of ethyl alcohol.

Hence, pyridine and its derivatives have significant applications in various fields, especially in the medicinal and agrochemicals. Due to such wide range of applications and extremely usage in industries, pyridine and its derivatives are considered among the most important and valuable N-based heterocyclic compounds which is also evident from the current annual worldwide production of pyridine which is approximately 20,000 ton per year.

#### **2.2 Biological importance of pyridine derivatives**

Pyridine is one of the most important nitrogen-based heterocyclic compounds which is present in large number of naturally occurring compounds. It is widely used as a precursor to agrochemicals and pharmaceuticals. Pyridine moieties are present in large number of drug molecules as well as in essential dietary supplements. This indicates that pyridine compounds can be used as precursor of drugs and with their proper structural modification or derivatization they can be led to important prodrugs or drugs itself of therapeutic value. Pyridine is an important heterocyclic organic compound. Pyridine and their heterocyclic annulated derivatives are of great interest due to the wide variety of biological activities as observed in these compounds. Pyridine nucleus is found to be basic skeleton of large number of bioactive molecules which ranges from Antitubercular, Antibacterial, Antiviral, Antiseptic, Antihistaminic, Antianginal, Anticholinesterase, Anti-inflammatory, Antiulcer, Anticancer etc.

#### *2.2.1 B-group vitamins*

Pyridine ring is present as basic nucleus in various B group vitamins such as Nicotinamide, Nicotinic Acid and Pyridoxine which are used as essential dietary supplements and for therapeutic effect (**Figure 9**).

**Figure 9.** *B-group vitamins based on pyridine derivatives.*

#### *2.2.2 Antituberculars*

These drugs are medications used to treat bacterial infection caused by *Mycobacterium tuberculosis*. Pyridine nucleus is found to be basic skeleton of major antitubercular drugs such as Isoniazid, Ethionamide and Prothionamide which are used in treatment of tuberculosis (**Figure 10**).

#### *2.2.3 Antibacterials*

These drugs are a principal type of antimicrobial agent or antibiotic which are used to either kill or inhibit the growth of certain bacteria. Sulfapyridine and Sulfasalazine are sulpha drugs containing pyridine nuclei which act as antibacterial agents used to inhibit bacterial infection (**Figure 11**).

#### *2.2.4 Antihistamines*

These drugs are used to oppose the activity of histamine receptors in human body so that to treat different allergic conditions like allergic rhinitis, common cold, influenza etc. Betahistine, Chlorpheniramine, Dexchlorpheniramine, Mepyramine, Pheniramine and Triprolidine are Histamine H1-receptor antagonist and used as antihistaminic drugs for allergic disorders. All of them contain the pyridine ring as an important part of their structure (**Figure 12**).

**Figure 10.** *Antitubercular drugs containing pyridine as basic skeleton.*

**Figure 11.** *Antibacterial drugs containing pyridine nuclei.*

*Antihistamine drugs having pyridine nucleus.*

**Figure 12.**

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

#### *2.2.5 Antianginals & antihypertensive drugs*

Antianginal drugs are used in treatment of angina pectoris, a type of heart disease. They are also classified as calcium channel blockers or beta blockers. Antihypertensive drugs are used to prevent conditions of high blood pressure, stroke and myocardial infarction. Amlodipine, Azelnidipine, Clinidipine, Felodipine, Lacidipine, Nicardipine and Nifedipine are some Antianginal/Antihypertensive drugs which contain the pyridine as core structure (**Figure 13**).

#### *2.2.6 Anticholinesterase drugs*

These drugs act as antidote for cholinesterase inhibitors and prevent the breakdown of neurotransmitter acetylcholine. Examples are Pralidoxime and Pyridostigmine which are simply the pyridinium salt derivatives (**Figure 14**).

#### *2.2.7 Analgesic and anti-inflammatory drugs*

These drugs are used to reduce pain, decreases inflammation and also reduce fever. Etoricoxib, Phenyramidol, and Piroxicam are used as analgesic and ant-inflammatory drugs that contain the pyridine scaffold (**Figure 15**).

**Figure 14.** *Anticholinestearase drugs based on pyridinium salts.*

**Figure 15.**

*Analgesic/anti-inflammatory drugs having pyridine scaffold.*

#### *2.2.8 Antiulcer drugs*

These are class of drugs used to treat peptic ulcer or gastrointestinal tract infections. They also include the class proton pump inhibitor that is used in reduction of gastric acid production. Lansoprazole, Omeprazole, Pantoprazole and Rabeprazole are proton pump inhibitor and used as antiulcer drugs. All of them contain pyridine nucleus as an important part of their structure (**Figure 16**).

#### *2.2.9 Anticancer drugs*

These drugs are effective in the treatment of malignant or cancerous disease by inhibiting the cell division and proliferation. Abiraterone, Imatinib and Sorafenib are used as anticancer drugs that consist of pyridine ring (**Figure 17**).

#### *2.2.10 Antivirals*

These drugs are used in treatment of viral infections. They do not destroy the target pathogen but inhibit its growth. Atazanavir and Indinavir are antiretroviral drugs that are used in treatment of HIV/AIDS. Both of them have pyridine nuclei as a part of their structure (**Figure 18**).

**Figure 16.** *Antiulcer drugs containing pyridine nuclei.*

**Figure 17.** *Anticancer drugs bearing pyridine ring as part of their structure.*

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

**Figure 18.** *Antiviral drugs containing pyridine moiety as part of their structure.*

#### *2.2.11 Antiseptics*

These are antimicrobial agents that can be applied on living tissues or skin in order to reduce the possibility of infection or putrefaction. Cetylpyridinium chloride and Laurylpyridinium chloride are used as antiseptic in oral and dental care products. Both of these are simply the derivatives of pyridinium chloride salt (**Figure 19**).

Additionally, there are many other important pyridine-based drugs like Bisacodyl as laxative, Disopyramide as antiarrhythmic, Nikhetamide as respiratory stimulant, Pioglitazone as antidiabetic, and Torsemide as diuretic and so on (**Figure 20**) [20–22].

**Figure 19.** *Antiseptics based on pyridinium salts.*

#### **Figure 20.**

*Miscellaneous drugs having pyridine ring as part of their structure.*

#### **3. Schiff bases of pyridine: the excellent bioactive ligands and efficient chemosensors**

#### **3.1 Schiff bases and their metal complexes**

#### *3.1.1 Schiff base*

Schiff bases are generally the condensation products of primary amines and carbonyl compounds. They are considered as a sub-class of imines which are the organic compounds containing carbon-nitrogen double bond. Structurally, Schiff base is an analogue of an aldehyde or ketone in which the carbonyl (C]O) group has been replaced by an imine or azomethine (>C]Nd) group. Schiff bases are generally synthesized by the condensation reaction between primary amines and aldehydes or less commonly ketones (**Figure 21**). Schiff bases are more readily formed with aldehydes as compared to ketones. Schiff bases derived from aliphatic aldehydes are unstable in nature and readily get polymerized whereas those derived from aromatic aldehydes are more stable especially due to their effective conjugation systems.

Schiff bases have an interesting range of applications in various field of science ranging from synthesis to catalysis, analysis and medicine to modern technologies. For example, they are widely used in organic synthesis especially as the precursor of heterocyclic compounds and as the catalysts in many catalytic reactions. Several Schiff bases can be used for the qualitative and quantitative detection of metal ions. Some Schiff bases can be used as optical, fluorescent as well as electrochemical sensors. The most important application of Schiff bases is in the field of medicinal chemistry. Some important drugs consist azomethine group of Schiff base in their structure e.g., Thiocetazone, Nitrofurazone, Nitrofurantoin etc. (**Figure 22**).

In recent years, various Schiff base containing derivatives have been synthesized and evaluated for their biological activities including antimicrobial, antitubercular, antifungal, antioxidant, anti-inflammatory, anticonvulsants, antidepressant, antihypertensive and anticancer activity. As they possess a wide variety of biological activities, they are considered as a versatile pharmacophore and emerged as a potent class of pharmaceuticals. Several studies showed that the presence of a lone pair of electrons in sp<sup>2</sup> hybridized orbital of nitrogen atom of the azomethine group is of considerable chemical and biological importance as it interferes in normal cell processes by the formation of hydrogen bond between the active centers of cell constituents and

$$\mathbf{g}^2 = \mathbf{g}^3$$

**Figure 21.** *Reaction scheme for Schiff base condensation.*

**Figure 22.** *Important drugs containing azomethine (*d*CH*]*N*d*) group.*

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

sp2 hybridized nitrogen atom. Thus, Schiff bases have key role in design and development of novel compounds which are more potent and have interested biological activities. Due to the vast pharmacological activities, they constitute a significant class of compounds for new drug development and continue to be an active area of research in medicinal chemistry [23–27].

#### *3.1.2 Schiff base metal complexes*

Schiff bases are widely used as ligands in coordination chemistry due to the presence of imine nitrogen which is basic in nature and exhibits π-acceptor properties. These act as Flexi-dentate ligands due to presence of nitrogen of azomethine group and other hetero atoms like nitrogen, oxygen or sulfur of specific functional group if present. The metal complexes of Schiff bases are also known as metallo-imines and they play a central role in coordination chemistry. Jacobsen's catalyst is a well-known example of Schiff base metal complex which is derived from chiral tetradentate Salen ligand (**Figure 23**).

Some metal complexes play a vital role in the bioactivity of life saving drugs especially anticancer drugs. Cisplatin, Carboplatin and Oxiplatin are anticancer drugs designed from binding of organic ligands with platinum metal ion (**Figure 24**).

In organic synthesis the Schiff base reactions are very useful in making carbonnitrogen bonds. Schiff base are considered as a very important class of organic ligands which can be used as building blocks and find extensive applications in organic synthesis as well as in organocatalysis. Thus, Schiff base appears to be an important intermediate in a number of enzymatic reactions that involves interaction of an enzyme with an amino or a carbonyl group of the substrate. It is a well-known fact that the binding of bioorganic molecules or drugs to the metal ions drastically change their biomimetic properties, therapeutic effects and pharmacological activities. Thus, both the Schiff base ligands and their metal complexes have further extensive applications ranging from material sciences to biological sciences. Due to their biological activities and clinical usage, they are of worth attention. Their successful application

**Figure 24.** *Metal complexes of platinum used as anticancer drugs.* can lead to the formation of series of novel compounds with wide range of physical, chemical and biological activities [28–33].

#### **3.2 Schiff bases of pyridine as bioactive ligands and versatile pharmacophore**

#### *3.2.1 Protein-ligand interactions*

Protein-ligand interactions are essential for all processes happening in living organisms as proteins are the fundamental units of all living cells that play a vital role in various cellular functions. It is a reversible non-covalent interaction comprises biological recognition at molecular level in which the molecules i.e. protein and ligand recognize each other by stereo specificity. The evolution of the protein functions depends on the development of specific sites which are designed to bind ligand molecules. Ligand binding capacity is important for the regulation of biological functions which occur through the molecular mechanics involving the conformational changes in proteins. This change initiates a sequence of events leading to different cellular functions. A detailed understanding of the protein–ligand interactions is therefore central to understand biology at the molecular level. Moreover, knowledge of the mechanisms responsible for the protein-ligand recognition and binding helps to understand the drug-receptor interaction in detail and facilitate the discovery, design, and development of drug molecules. A modern computational technique based on protein-ligand interactions is Molecular docking which is now routinely used for drug designing and development processes [34, 35].

#### *3.2.2 DNA-Metal complex interactions*

Many transition metal complexes are known to bind with DNA via both covalent and non-covalent interactions. Formation of a protein-ligand complex is based on molecular recognition between biological macromolecules and ligands which depends on affinity and specificity. The interaction between transition metal complexes and DNA has aroused the widespread interest because it helps not only to understand the life processes at the molecular level but also to promote the development of chemistry discipline itself. The interest in preparation of new metal complexes gained the tendency of studying on the interaction of metal complexes with DNA for their applications in biotechnology and medicine. Cisplatin, Carboplatin, Oxiplatin and their derivatives are widely used as anticancer drugs which are based on DNA-Metal complex interactions but they create several side effects such as anemia, diarrhea, alopecia, petechia, nephrotoxicity, emetogenesis, ototoxicity, neurotoxicity etc. Efforts are continuously made to prepare the chemotherapeutic drugs without side effects or fewer side effects. In recent times, the treatment of cancer with a chemotherapeutic approach is based on DNA-Metal complex interactions [36–38].

#### *3.2.3 Role of Schiff bases as bioactive ligand*

The Schiff bases display significant biological activities due to presence of imine (>C]Nd) functional group. Thus, Schiff base derived from aromatic aldehyde and aromatic amines have enormous applications in biological fields. Pyridine carboxaldehyde derivatives of Schiff bases are of great interest due to their role in natural and synthetic organic chemistry as these can exhibit physiological effects

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

similar to pyridoxal-amino acid systems which are considered to be very important in numerous metabolic reactions (**Figure 25**).

They show diverse biological activities in terms of antibacterial, antiviral, antitubercular, antipyretic, anti-inflammatory, antiulcer, antihistaminic, antitumor etc. (**Figure 26**). The bonding interaction between aromatic ring of Schiff base ligand and aromatic amino acid side chains of receptor has also been revealed in most of the X-ray crystal structures of protein complexes. This protein ligand interaction involves some non-covalent interactions and the evaluation of the structure-activity relationship of Schiff bases also demonstrates their desired biological activity. This ensures the application of Schiff bases in drug designing process and they are widely used as prodrugs as well as the drug molecules itself [39–41].

A series of Schiff bases have been synthesized using 2-vinylaniline and various aldehydes including pyridine-2-aldehyde (**Figure 27**). These Schiff bases were then complexed to transition metal ions like Mn+2, Co+2, Ni+2 and Cu+2. All of these compounds were evaluated for their antibacterial activity against bacterial species like *E. coli*, *Staphylococcus aureus* and *Pseudomonas aeruginosa* as well as for their antifungal activity against fungal species like *Candida albicans* and *Candida krusei*. It was concluded that different Schiff bases and their metal complexes had varying degree of antibacterial and antifungal activities. However, all the metal complexes had enhanced antimicrobial activity as compared to their ligand [42].

A combination of pyridine-2-aldehyde with S-methyl and S-benzyl dithiocarbazate resulted in synthesis of Schiff bases (**Figure 28**) which were allowed to form

**Figure 25.** *Pyridoxal amino acid system.*

**Figure 26.** *Bioactivities of Schiff bases derived from pyridine derivatives.*

complexes with Mn+2 and Zn+2 ions. These Schiff bases and metal complexes were evaluated for their biological activities against bacteria, fungi and K562 leukemia cell line. It was observed that Schiff base with S-methyl dithiocarbazate and its complex with Zn+2 had broad antimicrobial activity as compared to the Schiff base with Sbenzyl dithiocarbazate and its complex with Mn+2. Further only S-methyl dithiocarbazate and its complex with Mn+2 showed significant antitumor activity against K562 leukemia cell line [43].

Schiff bases have been derived from pyridine-4-carbaldehyde and various aromatic amino compounds such as 2, 3 and 4-aminobenzoic acids, 4-aminoantipyrene, 2-aminophenol, 2-aminothiophenol etc. (**Figure 29**). The synthesized compounds were evaluated for their antioxidant activities and DNA binding interaction studies. It was found that the Schiff base of pyridine-4-carboxaldehyde and aminophenol was an efficient antioxidant with 74% inhibition of free radicals generated by DPPH. Further most of the synthesized Schiff bases showed efficient binding with DNA which was in good agreement with molecular docking studies [44].

A Schiff base was derived from 2,6-diaminopyridine and salicylaldehyde by microwave irradiation (**Figure 30**) which form complexes with transition metal ions such as Co+2, Ni+2, Cu+2, Zn+2 and Cd+2. It was found that all the complexes were non electrolyte and possessed an octahedral geometry in which N donor sites of imine and O donor site of phenolic groups were coordinated to the metal ions [45].

A series of Schiff bases was derived from Isoniazid and various aromatic aldehydes like 2-benzyloxybenzaldehyde and its derivatives as well as with various ketones like n-hexanophenone, cyclohexanone etc. (**Figure 31**). All these novel Schiff bases were then evaluated for their antitubercular activities. It was found that these compounds

**Figure 27.** *Schiff base derived from pyridine-2-aldehyde and 2-vinylaniline.*

$$\bigotimes\_{\mathsf{R}\_{\mathsf{R}}\mathsf{C}^{\mathsf{H}\mathsf{O}}\mathsf{C}^{\mathsf{H}}\mathsf{C}^{\mathsf{H}}\mathsf{N}}\mathsf{N}\_{\mathsf{A}}\bigotimes\_{\mathsf{R}^{\mathsf{A}}\mathsf{C}^{\mathsf{H}}\mathsf{N}}\mathsf{N}\_{\mathsf{A}}\bigotimes\_{\mathsf{R}^{\mathsf{A}}\mathsf{C}^{\mathsf{H}}}\mathsf{N}\_{\mathsf{A}^{\mathsf{H}}}\mathsf{N}\_{\mathsf{A}^{\mathsf{H}}}\quad,\quad\bigotimes\_{\mathsf{O}\mathsf{st}\mathsf{C}^{\mathsf{H}}\mathsf{N}\_{\mathsf{A}}}\mathsf{N}\_{\mathsf{A}^{\mathsf{H}}}\bigotimes\_{\mathsf{O}\mathsf{st}^{\mathsf{A}}}\mathsf{N}\_{\mathsf{A}}$$

**Figure 28.**

*Schiff bases derived from pyridine-2-aldehyde with dithiocarbazate derivatives.*

**Figure 29.**

*Schiff bases derived from pyridine-4-aldehyde with different aromatic amino compounds.*

**Figure 30.**

*Schiff base derived from salicylaldehyde and 2,6-diaminopyridine.*

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

**Figure 31.** *Schiff base derived from 2-bezyloxybenzaldehyde and isoniazid.*

showed high level of activity against Mycobacterium tuberculosis in vitro and in vivo and they had also low toxicity [46].

Schiff bases were derived by the reaction of Isoniazid with 2-acetylfuran and 2 acetyl-5-methylfuran (**Figure 32**). Antibacterial and antifungal activity of the Schiff bases and their complexes were evaluated. It was observed that all these compounds were active against all the microbial strains and their metal complexes with Pd+2 and Pt+2 were far more active as compared to their parent Schiff base [47].

A Schiff base was derived from Isoniazid and 2-hydroxy-5-methoxybenzaldehyde (**Figure 33**). The metal complexes of this Schiff base were prepared using transition metal ions Mn+2, Ni+2, Cu+2 and Zn+2. It was observed that Mn+2, Ni+2 and Cu+2 complexes had moderate activity against gram positive *Staphylococcus aureus* and gram-negative *E. coli*. It was found that Zn+2 complexes showed the highest antifungal activity against the fungal species *Aspergillusflavus* [48].

A Schiff base synthesized from Isoniazid and 2-hydroxynaphthaldehyde (**Figure 34**) was complexed with various transition metal ions like Co+2, Ni+2, Cu+2 and Zn+2. The biological activity of Schiff base as ligand and its metal complexes were tested on gram-positive bacteria *E. coli* and gram-negative bacteria *Staphylococccus Aurous* as well as two fungi *Aspergillusflavus* and *Candida albicans*. It was observed that all the metal complexes possessed biological activity and some of them were more potent than their parent Schiff base [49].

**Figure 32.** *Schiff base derived from isoniazid and 2-acetylfuran.*

**Figure 33.** *Schiff base derived from isoniazid and 2-hydroxy-5-methoxybenzaldehyde.*

**Figure 34.** *Schiff base derived from isoniazid and 2-hydroxynaphthaldehyde.*

Schiff base derived from Nicotinic acid hydrazide and 2,5-dimethoxybenzaldehyde (**Figure 35**) were complexed with various transition metal ions. In-vitro antimycobacterial activities of these complexes were evaluated against *Mycobacterium tuberculosis* and *H37Rv*. It was found that some of the metal complexes showed higher activity than the Isoniazid and the Schiff base whereas some others showed moderate activity. However, all these metal complexes were found to be more toxic as compared to Isoniazid [50].

Schiff base synthesized from the reaction of Isoniazid and Ketoprofen (**Figure 36**) was found to be a bioactive compound due to large energy gap between HOMO and LUMO as observed from Frontier orbital theory analysis. It was also found to be a more potent against *Mycobacterium tuberculosis* infection as compared to Isoniazid with the help of Molecular docking studies [51].

Two schiff bases were developed by the condensation of 3,4-diaminopyridine with 3,5-difluorine-2-hydroxybenzaldehyde and 5-fluorine-2-hydroxybenzaldehyde (**Figure 37**). The antifungal activity of both the schiff bases were assessed against yeast among which the schiff base obtained from 3,5-difluorine-2-hydroxybenzaldehyde was found to give good results [52].

A schiff base was synthesized by the reaction between 2-benzoylpyridine and 2 aminopyrimidine (**Figure 38**). The binuclear complexes of the schiff base with transition metal ions V(IV), Co (II) and Cu (II) were obtained and examined for their antibacterial properties against three bacterial strains *Escherichia coli*, *Klebseilla pneumonia* and *Staphylococcus aureus*. The antifungal activity was also determined against three fungal strains *Candida albicans*, *Candida glabrata* and *Candida parapsilosis*. It


**Figure 37.** *Schiff bases derived from 3,4-diaminopyridine with 5-fluoro-2-hydroxy benzaldehyde derivatives.*

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

**Figure 38.** *Schiff base derived from 2-aminopyrimidine and 2-benzoylpyridine.*

was revealed that the schiff base showed good to moderate antibacterial and antifungal activities [53].

A novel methyl substituted pyridine Schiff base was obtained by reacting 2,4 dihydroxybenzaldehyde and 2-amino-4-methylpyridine (**Figure 39**). Its metal complexes were also designed with transition metal ions Fe(III), Co(III), Cu(II) and Ni (II). The schiff base and all of its metal complexes were examined for their antimicrobial and antioxidant properties which were found to be moderate to good against reference standards [54].

A series of schiff bases were synthesized from syringaldehyde by reaction with different aminopyridines (**Figure 40**) and their antibacterial properties were evaluated for different gram-positive and gram-negative bacteria. It was observed that compound3 was more effective against gram negative bacteria *P. aeruginosa* in comparison to standard ampicillin drug. The antioxidant potential was also determined and predicted [55].

A pyridine-based Schiff base (S)-N-benzylidene-2-(benzyloxy)-1-(5-(pyridine-2 yl)-1,3,4-thiadiazol-2-yl) ethanamine was synthesized (**Figure 41**). Its antioxidant and antimitotic activities were correlated with standards Ascorbic acid and Methotrexate respectively and both of these activities were found in good agreements to standards [56].

**Figure 39.** *Schiff base derived from 2,4-dihydroxybenzaldehyde and 2-amino-4-methylpyridine.*

**Figure 40.** *Schiff bases derived from syringaldehyde with different aminopyridines.*

#### **3.3 Schiff bases of pyridine as chemosensors for ion recognition studies**

#### *3.3.1 Chemosensors*

A chemosensor is a molecular structure i.e. an organic or inorganic complex that can be used for sensing of an analyte to produce a detectable change or a signal. In general, chemosensors are the chemical molecules that bind selectively with the guest moiety and produce a detectable or measurable change in physical, chemical or spectral properties of the system. As shown in **Figure 42**, the designing of a chemosensor is simply based on Host-Guest recognition.

These changes may be the color development or masking, modulation of emission intensity or redox potential which can be detected with the help of UV–visible absorption spectroscopy, fluorescence spectroscopy and voltammetry respectively. Thus, chemosensors are designed to contain a signaling moiety and a recognition moiety that gives rise to change in either UV–visible absorption or the emission properties. The color change or spectral change observed in either case is due to the formation of host-guest complex i.e., the complex formed between the receptor and ion. The visualization of color is based on the coordination between organic molecules having lone pair of electrons which act as donors and the metal ion or a specific anion which act as receptor [57–60].

#### **Figure 42.**

*Designing of chemosensor based on host-guest recognition.*

#### *3.3.2 Need for cation recognition*

There are several transition metal ions which are very crucial for the life of living organisms. Some of them are required in trace quantity but if their concentration

#### *Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

exceeds than the trace amount, they become toxic for the biological systems and may lead to various diseases and disorders. There are certain non-essential elements for living system which are widely used in industries and daily life. Their frequent and larger use can lead to overloading of such elements in the human body which may cause a large number of diseases like bone disorder, neurodegenerative diseases, sclerosis, dialysis encephalopathy etc. Their high concentration in water is harmful to growing plants and aquatic life. Transition metal ions as pollutants have some toxic impact on human health as well as on environment. The detection of these ions has gained extreme importance in recent years in the field of chemical, biological and environmental sciences. There is an urgent need to develop some efficient approaches to detect such metal ions with high selectivity and sensitivity so that to control the harmful effect on human health and environment [61, 62].

#### *3.3.3 Need for anion recognition*

Anion recognition plays a vital role in aqueous medium due to analysis of various anions in biological and environmental systems. Anion sensing continues to be a developing field in supramolecular chemistry because of its significance in industrial chemistry, environmental sciences as well as in biological fields. However, anion sensing in pure water is challenging job because they have large variation in size as compared to metal cations. Moreover, they have large solvation energy in aqueous medium and there is a strong competition occurs between solvent and anions for binding with the receptor. These problems can be overcome to certain extent by the use of chemosensors. A large number of chemosensors have also been reported for anion recognition and sensing with high selectivity as well as sensitivity. Literature review revealed that most of these sensors have complicated structure and hard synthetic routes. Moreover, some of them have poor yields and troublesome purification process. It can be expected that chemosensors derived from Schiff bases may solve these issues up to certain extent as they do not have much complex structure and can be synthesized easily with good yield and purity [63–65].

#### *3.3.4 Role of Schiff bases in ion recognition*

Schiff bases are organic molecules that contain azomethine group and are capable of donating lone pair of electrons, so that they can coordinate with large number of metal ions especially transition metal ions. Schiff bases of nitrogen-based heterocycles such as pyridine or their derivatives can act as excellent ligands due to presence of ring nitrogen atom with a localized pair of electrons leading to the formation of very stable complexes with transition metal ions. It has been demonstrated that the presence of nitrogen atom of azomethine group and oxygen atom of phenolic or carbonyl group in Schiff base has strong affinity towards metal ions which results in metal-oxygennitrogen cycle i.e. chelatogenic cycle. Due to this, the intramolecular charge transfer is improved between the π-conjugated rings which displays unique emission enhancement. Schiff bases have the strong binding abilities to the various ions and also have individual photophysical properties. This property of Schiff base can be used in ion recognition and their derivatives are extensively used in development of chemosensors for detection of metallic cations and anions in various kinds of environmental and biological media. **Figure 43** represents the different kind of chemosensors based on Schiff bases that can be derived from pyridine derivatives [66–70].

#### **Figure 43.**

*Chemosensors based on Schiff bases derived from pyridine derivatives.*

A pyridylazo compound (**Figure 44**) was designed which showed a very high affinity towards Al+3 ions. The turn on fluorescence behavior showed that the synthesized compound could be used for detection of Al+3 ions with high selectivity in qualitative as well as quantitative estimations [71].

A condensation reaction between 4<sup>0</sup> -amine-2,2<sup>0</sup> 60 <sup>2</sup>″-terpyridine with benzaldehyde derivatives resulted in the synthesis of Schiff bases (**Figure 45**) which were studied for its cation recognition properties for various ions. It was observed that the synthesized Schiff bases selectively recognized Al+3 ions due to enhancement in fluorescence [72].

A reversible fluorescent colorimetric imino-pyridyl bis Schiff base receptor was developed (**Figure 46**) for the detection of Al+3and HSO3 � in aqueous medium.

#### **Figure 44.** *Fluorescent chemosensor based on pyridylazo compound.*

**Figure 45.** *Schiff base derived from 4*<sup>0</sup> *-amine-2,2*<sup>0</sup> *,6*<sup>0</sup> *,2 -terpyridine with benzaldehyde derivatives.*

**Figure 46.** *Schiff base derived from pyridine-4-aldehyde and 4-aminoaniline.* *Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

The receptor exhibited excellent fluorescent colorimetric response towards Al+3 ions with high selectivity and also selective colorimetric response towards HSO3 ions [73].

A fluorescent chemosensor based on 2-(7,10-diphenylfluoranthen-8-yl)-pyridine (**Figure 47**) was designed and examined for its cation recognition ability. It was found to show excellent selectivity towards Fe+3 ions by exhibiting a great decrease in emission intensity [74].

A series of donor-acceptor systems was synthesized in which pyridine moiety acted as acceptor unit and carbazole moiety acted as donor unit (**Figure 48**). The synthesized compounds were then investigated for their sensing properties towards various metal cations. The compound showed a remarkable enhancement in fluorescence in presence of Cu+2 ions and could be used as sensor for Cu+2 ions with high selectivity over various other metal ions [75].

A chemosensor based on naphthalimide and pyridine moiety was designed (**Figure 49**) and found to show good response towards Cu+2 ions with high selectivity and sensitivity in the presence of wide range of metal ions in aqueous media [76].

A fluorescent chemosensor based on BODIPY with two pyridine ligands was synthesized (**Figure 50**) and examined for detection of various cations and anions. It was found to display very high selectivity and sensitivity towards Cu+2 ions by giving a visible color change from pink to blue and quenching of fluorescence emission. Further, it was noted that on addition of S<sup>2</sup> anions to the Cu+2 complex the color could be restored [77].

**Figure 47.** *Fluorescent chemosensor based on 2-(7,10-diphenylfluoranthen-8-yl)-pyridine.*

**Figure 48.** *Fluorescent chemosensor based on pyridine-carbazole based compound.*

**Figure 49.** *Schiff base derived from naphthalimide based compound and pyridine-3-aldehyde.*

**Figure 50.** *Fluorescent chemosensor based on BODIPY with two pyridine ligands.*

A schiff base ligand was synthesized from 4-hydroxy-3,5-dimethoxybenzaldehyde and pyridine dicarbohydrazide (**Figure 51**) which was then examined for its ion sensing ability and it was found to recognize Cu+2 ions over the other metal ions. Further the Schiff base complex with Cu+2 ions was able to detect CN ion over different anions [78].

A Schiff base was synthesized from 2,6-diaminopyridine and salicylaldehyde whereas another schiff base was synthesized from pyridine-3-carbohydrazide and 2,5 dimethoxybenzaldehyde (**Figure 52**). Both of them were evaluated for their cation sensing properties and were found to form complexes with transition metal ions such as Co+2, Ni+2, Cu+2, Zn+2 and Cd+2, thus had potential to act as chemosensors for detection of these ions over other competing ions in aqueous media [45].

A chemosensor derived from pyridine-dicarbohydrazide and benzothiazole aldehyde (**Figure 53**) for the detection of various cations and anions. The sensor allowed the naked eye recognition of toxic Cu+2 ions in presence of many other cations as well as the recognition of some biologically relevant anions like F, AcO and AMP<sup>2</sup> ions with great sensitivity [79].

**Figure 51.** *Schiff base derived from 4-hydroxy-3,5-dimethoxybenzaldehyde and pyridine dicarbohydrazide.*

#### **Figure 52.**

*a. Schiff base derived from 2,6-diaminopyridine and salicylaldehyde. b. Schiff base derived from 2,5 dimethoxybenzaldehyde and pyridine-3-carbohydrazide.*

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

**Figure 53.** *Schiff base derived from pyridine dicarbohydrazide and benzothiazole aldehyde.*

A chemosensor was designed from schiff base based on the condensation reaction between pyridoxal and 2-aminoethanol (**Figure 54**). The chemosensor produced a selective chromogenic behavior towards Ag<sup>+</sup> ions by changing the color of solution from light yellow to red observable by naked eye and also have excellent specificity and sensitivity towards Ag+ ions over various other interfering cations in aqueous solution [80].

A Schiff base was derived from 4-E-2-phenyldiazenylaniline and pyridine-2 carboxaldehyde (**Figure 55**) and investigated for its cation recognition ability. The schiff base was found to be highly sensitive and selective for sensing of Ag<sup>+</sup> ions and Cd+2 ions and could act as chemosensor for the detection of Ag<sup>+</sup> and Cd+2 in presence of other interfering ions [81].

A porphyrin appended terpyridine compound was synthesized (**Figure 56**) and designed as chemosensor for its cation recognition ability. It was observed that the synthesized compound exhibited enhanced fluorescence in the presence of Cd+2 ions

**Figure 54.** *Schiff base derived from pyridoxal and 2-aminoethanol.*

**Figure 55.** *Schiff base derived from 4-E-2-phenyldiazenylaniline and pyridine-2-aldehyde.*

**Figure 56.** *Fluorescent chemosensor based on porphyrin appended terpyridine compound.*

with high selectivity and sensitivity and could act as fluorescent chemosensor for Cd+2 ions in the presence of various other metal ions [82].

A schiff base based on 2,6-diaminopyridine was synthesized (**Figure 57**) and evaluated for its binding affinity with various metal ions. It was observed that the synthesized compound has prominent selectivity towards Pb+2ions among various other metal ions and therefore could act as chemosensor for detection of Pb+2 ions [83].

A new bipyridine based ruthenium complex was synthesized (**Figure 58**) and investigated for its cation recognition ability. It was found that the synthesized compound was able to recognize Hg+2 ions in aqueous solution with high selectivity and could be used as chemosensor for the selective and sensitive detection of Hg+2 ions over various other cations [84].

A pyridine-based derivative of (Z)-2-(4-amino-phenyl)-3-(pyridine-4-yl) acrylonitrile was designed (**Figure 59**) and evaluated for its cation recognition properties. It was observed that the compound could selectively recognize Hg+2 ions by exhibiting a visible color change from light yellow to orange and could be used as a naked-eye sensor for detection of Hg+2 ions in presence of various other cations [85].

#### **Figure 57.**

*Schiff base derived from 2,6-diaminopyridine and salicylaldehyde derivative.*

**Figure 59.** *Colorimetric sensor based on (Z)-2-(4-amino-phenyl)-3-(pyridine-4-yl) acrylonitrile.*

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

Isoniazid functionalized silver nanoparticles were synthesized by wet chemical method (**Figure 60**) and it was observed to exhibit good absorbance and emission peaks with visible color change in the presence of Hg+2 ions. Therefore, these isoniazid capped silver nanoparticles could act as a selective chemosensor for the detection of Hg+2 ions in aqueous media [86].

Two schiff bases derived from fluorescein by condensation with 3-aminopyridine and 4-aminopyridine respectively (**Figure 61**) were evaluated for their ion recognition properties for various cations and anions. The compound 1 was able to detect Ce+3 cation in presence of various other metal ions and also F anion over other interfering anions and therefore could act as chemosensor for Ce+3 and F ions [87].

A simple, colorimetric and fluorimetric chemosensor was designed from an acylhydrazone based schiff base synthesized from Isoniazid and 2 hydroxynaphthaldehyde (**Figure 62**). The sensor was found to produce an immediate

**Figure 60.** *Chemosensor based on isoniazid functionalized silver nanoparticles.*

**Figure 61.** *Schiff bases derived from fluorescein with 3-aminopyridine and 4-aminopyridine.*

**Figure 62.** *Schiff base derived from Isoniazid and 2-hydroxynaphthaldehyde.*

visible color change from colorless to yellow in the presence of CN� ions in aqueous media with high selectivity and sensitivity [88].

Two schiff bases were prepared from pyridine-2-hydrazide with 5-nitrofuran-2 carboxaldehyde and 5-nitrothiophene-2-carboxaldehyde respectively (**Figure 63**) and tested for their anion sensing properties. The compound could selectively detect F� and CO3 �<sup>2</sup> ions over other interfering anions whereas compound could detect CO3 �2 ion with high selectivity and sensitivity. Finally, the compound was able to distinguish between F� and CO3 �<sup>2</sup> due to difference in their bathochromic shift [89].

A Hantzsch ester fluorescent probe based on thienyl-pyridine appended to dihydropyridine ring was synthesized (**Figure 64**) and applied for fluorescent sensing of nitric oxide in aqueous solution. The sensor showed extremely strong blue fluorescent which was switched off in the presence of NO and also possessed high selectivity and sensitivity towards NO [90].

A chemosensor based on 3,3<sup>0</sup> -(4-(2-amino-4,5-dimethoxyphenyl) pyridine-2,6 diyl) dianiline was synthesized (**Figure 65**) and found that it could detect formaldehyde through fluorescence enhancement and show the visible color change from yellow to blue. The compound could act as chemosensor for detection of formaldehyde qualitatively as well as quantitatively [91].

A simple Schiff base chemosensor was developed by the condensation reaction between 8-hydroxyjulolidine-9-carboxaldehyde and 2-hydrazinylpyridine (**Figure 66**). The ion recognition ability was determined for four transition metal ions

**Figure 63.**

*Schiff bases derived from pyridine-2-carbohydrazide with 5-nitrofuran-2-aldehyde & 5-nitrothiophene-2 aldehyde.*

**Figure 64.** *Fluorescent probe based on thienyl-pyridine appended to dihydropyridine.*

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

#### **Figure 66.**

*Schiff base derived from 8-hydroxyjulolidine-9-carboxaldehyde and 2-hydrazinylpyridine.*

**Figure 67.**

*Schiff base derived from 2-phenoxyaniline and pyridine-2-aldehyde.*

Co+2, Ni+2, Cu+2 and Zn+2 using colorimetric and fluorescent analysis. It was revealed that the chemosensor can serve as an effective tool for the detection of all the four ions in environment as well as in biological applications [92].

A new fluorescent probe was designed from Schiff base 2-(pyridine-2 ylmethylene)-phenoxyaniline (**Figure 67**) and used for selective detection of Cd+2 ion. A significant fluorescence enhancement was observed and it gave satisfactory results for detection of Cd+2 ions in tap water and river water samples [93].

#### **4. Conclusion**

Pyridine is among the most valuable nitrogen-based heterocyclic compounds known for its important chemical and biological properties. The pyridine moieties are widely distributed in nature as in many naturally occurring compounds, vitamins, essential oils and metabolites which are required for various cellular functions. Additionally, pyridine derivative is used on large scale as precursor or intermediates in chemical and agrochemical products. Further, these derivatives possess therapeutic potentials due to their important bioactivities and with their proper structural modification or derivatization they can be led to important prodrugs or drugs. Literature review reveals that when pyridine-based nucleus is modified to some extent by introducing new functional group or even new molecule at appropriate positions, the bioactivity may be enhanced significantly. Thus, Schiff bases are continuously designed from amino or carboxaldehyde derivatives of pyridine since last few years and evaluated for their biological potential. As they possess a wide variety of biological activities, they are considered as a versatile pharmacophore and emerged as a potent class of pharmaceuticals for new drug development and continue to be an active area of research in medicinal chemistry. Development of novel drugs as a pharmacophore group is a constantly growing need that concerns researchers throughout the world as increasing number of diseases continue to be an emerging problem. The chemistry of pyridine-based Schiff bases is less extensive and not much work has been done in this field. In the view of the stated pharmacological properties of pyridine compounds, it is expected that they have high potential in the field of various biological activities that are still unexplored. Further, owing to their strong binding abilities towards various ions and unique photophysical properties, Schiff bases find applications in ion recognition and widely used as chemosensors for selective detection of ions. The ion recognition studies have gained extreme importance in recent years in the field of chemical, biological and environmental sciences. There is an urgent need to develop some efficient approaches to detect metal ions with high selectivity and sensitivity so that to control their harmful effect on human health and environment. It can be expected that the chemosensors derived from Schiff bases of pyridine derivatives do not have much complex structure and can be synthesized easily with good yield and purity as compared to most of other chemosensors. Thus, designing of specific chemosensor for the recognition of various ions is one of the most demanding areas of present chemical research due to their significant contribution in analytical, industrial, agricultural, environmental and biological fields. Keeping all these facts in the mind, it is of extreme importance to synthesize some Schiff bases derived from pyridine derivatives and to evaluate their potential as bioactive ligands and chemosensors. This chapter covers not solely the chemistry and biological significance of pyridine derivatives, but also reflects the light on Schiff bases derived from them with their pharmacological importance and ion recognition properties. It is worthwhile to have a full overview about pyridine, its derivatives and Schiff bases derived from them, all at one place with recent researches that will provide a single platform for potential researchers of these fields. Thus, the main objective of this chapter is to promote the research and development of some new pyridine-based Schiff bases and to evaluate their various biological activities for their effective use in drug designing process as well as their applications in ion recognition studies to develop more efficient chemosensors.

#### **Acknowledgements**

The author is greatly thankful to Dr. Gurpinder Singh for his valuable guidance with immense support and also the Department of Chemistry, Lovely Professional University for providing necessary facilities.

#### **Conflict of interest**

The author declares no conflict of interest.

### **Author details**

Kaushal K. Joshi Lovely Professional University, Phagwara, India

\*Address all correspondence to: kaushalj28@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

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[92] Liu H, Ding S, Lu Q. A versatile Schiff base chemosensor for the determination of trace Co+2, Ni+2, Cu+2 and Zn+2 in the water and its bioimaging *Chemistry with Schiff Bases of Pyridine Derivatives: Their Potential as Bioactive Ligands… DOI: http://dx.doi.org/10.5772/intechopen.106749*

applications. ACS Omega. 2022;**7**: 7585-7594

[93] Ma J, Dong Y, Yu Z. A pyridinebased Schiff base as a selective and sensitive fluorescent probe for cadmium ions with "turn-on" fluorescence responses. New Journal of Chemistry. 2022;**46**(7):3348-3357

#### **Chapter 10**

## 2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum Metals

*Liliya Sergeevna Ageeva, Nikolai Alekseevich Borsch and Nikolay Vladimirovich Kuvardin*

#### **Abstract**

The specific behavior of aromatic amines in the coordination and extraction processes of isolation and separation of platinum and other metals is discussed using the example of 2(4)-aminopyridines (2(4)-AP). As intrasphere ligands, 2(4)-AP have a high electron-donor capacity due to the pumping of an easily polarizable π-electron density. The chemistry of the extraction of platinum metals, iridium in particular, is considered: depending on the conditions, ion associates, coordination-solvated compounds or compounds containing an amine in the inner and outer coordination sphere of the metal are extracted. In the extraction of simple singly charged anions, there is a violation of the exchangeextraction series established for a large set of aliphatic amines. Soft anions (according to Pearson), for example, SCN- and I-, are best extracted, while for aliphatic amines such an anion is hard СlO4 . In the coordination compounds of platinum metals, 2(4)-AP acts as an electron donor, is coordinated by heterocyclic nitrogen with a redistribution of electron density not only to the accepting metalcomplexing agent, but also further along the N-Me-X chain (X is an acido ligand in the composition of the complex), which leads to even greater covalence of the molecule as a whole.

**Keywords:** 2(4)-aminopyridines, platinum metals, extraction, complex formation, coordination compounds

#### **1. Introduction**

In recent years, interest has increased in the study of the extraction properties of high-molecular-weight aromatic amines, primarily because 2(4)-octylaminopyridines turned out to be good extractants for the isolation and separation of platinum metals [1–3]. Particularly interesting is the question of the specificity with respect to platinum metals of aromatic amines, as ligands, which differ from aliphatic amines in that the lone pair of electrons of the nitrogen atom largely acquires an π-donor character. Compared to aliphatic amines, aromatic amines demonstrate a number of new properties in coordination and extraction chemistry [2, 4]. All this determined the interest in this class of extractants, typical representatives of which are 2(4)-octylaminopyridines (2(4)-OAP).

Research carried out by the authors [5–9], allow us to get an idea of the specifics of the behavior of 2(4)-aminopyridines in the coordination and extraction processes of isolation and separation of metals.

#### **2. Specificity 2(4)-aminopyridinesas ligands**

The specificity of 2(4)-aminopyridines as ligands is due to the nature of the nitrogen atom in aromatic amines, which can be judged from the results of studies of halides [8] and coordination compounds of 2-OAP with nickel, palladium, and platinum [9]. In metal complexes, 2-OAP, as an intrasphere ligand, has a high electrondonating capacity due to the pumping of an easily polarizable π-electron density. The mobility of the electron density in the 2-OAP molecule depending on the requirements of the acceptor is evidenced by the delocalization of the positive charge of the proton in the cation (outer sphere ligand), which is the higher, the greater the polarizability of the anion [8].

An idea of the mobility of the electron density in a 2(4)-OAP molecule can be obtained within the framework of the theory of limiting structures (the theory of resonance) [10], giving an account of a certain formalism of this theory. The conclusions obtained in the framework of the theory of resonance and the theory of perturbations of molecular orbitales (PMO), which have a deep quantum-chemical substantiation [11], are quite adequate.

Conventionally, the 2-OAP molecule (**Figure 1**) [2], as well as the 4-OAP molecule (**Figures 2** and **3**) [5], can be represented as an average between the amine and pyridonimine limiting structures.

The contribution of the pyridoniminine structure increases the electron density on the heterocyclic nitrogen and decreases the electron density on the amine nitrogen. This contribution can be estimated if the energy of the N1s level of heterocyclic and amine nitrogen atoms is known. **Figure 4** shows, as an example, the experimental X-ray electron spectra of the N1s level of 4-OAP with band separation obtained on a

*2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum… DOI: http://dx.doi.org/10.5772/intechopen.106376*

**Figure 2.**

*Limiting (resonance) structures of 4-OAP molecules and the effective charges on nitrogen atoms calculated for them.*

#### **Figure 3.**

*Limiting (resonant) structures in protonated 4-OAP and effective charges on nitrogen atoms calculated for them.*

Riber SIA-200 X-ray photoelectron spectrometer. It can be seen that the nitrogen atoms are not equivalent, the lower level refers to heterocyclic nitrogen.

The energy of the N1s level correlates with the effective charge on the nitrogen atom. Satisfactory correlation of these values for a large group of nitrogen-containing compounds of various structures was obtained in [12]. Effective charges on nitrogen atoms for limiting structures can be calculated using the concept of ionic nature (**Figures 2** and **4**) [10]. From the charge balance equations for nitrogen atoms, the contribution pyridoniminine structure in 2-OAP and 4-OAP molecules: 9 [2] and 48.6%, respectively.

Thus, in the first approximation, it can be assumed that 2(4)-OAP molecules represent a resonant structure with a contribution from the pyridoniminine component. This leads to an increased basicity of heterocyclic nitrogen compared to pyridine

#### **Figure 4.** *X-ray spectrum of 4-OAP. Peak area: 1–50.63, 2–49.37%.*

due to the pumping of electron density from the amino group in the ortho and para positions of the pyridine ring and partial delocalization of the charge in the cation. Since the "depth" of the resonance is higher in the case of 4-OAP, its basicity exceeds that of 2-OAP by two orders of magnitude.

All this points to the "soft" nature of 2(4)-AP as ligands. If we use Pearson's classification [13], then free 2(4)-AP should be attributed to "soft" bases (inner sphere ligand), protonated to "soft" acids (outer sphere ligand). Soft and intermediate bases include other aromatic amines, while aliphatic amines are "hard" bases.

Factors such as the energetic and spatial arrangement of the top donor orbital of the nitrogen atom are thought to be responsible for the "soft" or "hard" behavior of the amine. From the standpoint of the quantum theory of perturbed molecular orbitals (PMO), one can consider the energy of the metal–ligand interaction and the resulting extraction chemistry depending on the nature of the amine, metal, and extraction conditions [14].

The formation of a coordination-solvated compound or associate, where the metal is present in the composition of the acid complex, depends on the result of the competitive process of complexation of the amine and proton, on the one hand, and the metal, on the other. In the first approximation, the quantitative side of this process is expressed by the main equation of the PMO theory [14]. An ionic associate or a coordination-solvated compound is formed depending on the relative contribution of the Coulomb or covalent component to the metal-nitrogen interaction energy.

If the contribution of the covalent component is much greater than that of the Coulomb component, then the coordination of the amine by the metal in the presence

#### *2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum… DOI: http://dx.doi.org/10.5772/intechopen.106376*

of a proton is possible. The higher the energy of the donor orbital and the lower the energy of the acceptor orbital of the amine and metal, the greater the contribution of the covalent component. These energy parameters of the interacting orbitals within the PMO are characterized by the orbital electronegativity of the donor and acceptor according to Klopman [13]. In addition, the covalent component increases with the length of the amine donor orbital.

If we talk about the nature of the amine, then in the presence of a proton, only amines with a low orbital electronegativity of the lone electron pair (OELEP), which depends on the valence state of the nitrogen atom in the amine molecule, can be coordinated by the metal. The OELEP of nitrogen decreases with an increase in the ρand π-character of an unshared pair of electrons, that is, with a decrease in the energy of the donor orbital and with an increase in its population [13]. Consequently, the OELEP of nitrogen decreases as one goes from aliphatic amines to anilines and further to heteroaromatic amines. In the same series, the softness of amines and their ability to extract platinum metals in the form of coordination-solvated compounds increase.

Of no less interest is the behavior of protonated 2(4)-AP, which acts as an outersphere ligand with respect to acid complexes of platinum and other rare metals.

#### **3. Chemistry of metal extraction**

2(4)-OAP extract metals from acidic and slightly acidic solutions. The extraction of iridium and other platinum metals has been studied most fully [2, 6].

Iridium (III) is extracted with a 0.1 M solution of 2-OAP in chloroform from dilute hydrochloric acid solutions with distribution coefficients D = 100–200, however, a nonequilibrium minimum appears on the curve D = f (рН) at pH 2 (the contact time of the phases is 30 min). During extraction from 1 to 6 M HCl equilibrium is established slowly: the value of D increases by almost an order of magnitude with an increase in the duration of phase contact up to 50 hours. Iridium (IV) is reduced to iridium (III) during extraction. 4-OAP extracts iridium (IV) with high distribution coefficients from more acidic solutions [3].

When 2-OAP is introduced directly into the aqueous phase (0.1 M solution in acetone) and the solution is heated to boiling in the presence of a tin (II) chloride catalyst for 30–40 min followed by extraction of the resulting compounds with chloroform ("heterogeneous" extraction), iridium is extracted with an unusually high partition coefficient for this element. The maximum extraction is observed from 1 to 2 M HC1 and reaches 99.9% for a single extraction.

Other platinum metals, as well as Au, under conditions optimal for the extraction of iridium, are extracted much worse (**Table 1**), and gold is quantitatively, and silver and palladium are partially concentrated at the phase boundary. The distribution coefficient of non-ferrous metals and iron, from which iridium usually needs to be separated, under these conditions by 3–5 orders of magnitude lower than iridium. Of these elements, only copper in the form of Cu (II) passes into the organic phase in a noticeable amount. At a high concentration of SnCl2 in the aqueous phase, the organic phase contains tin.

Since alkylated 2(4)-AP strong organic bases, they are able to extract halide and other metal acid complexes in the form of ion associates.

On the other hand, 2(4)-OAP can be considered as a potentially coordinatingactive reagent due to the presence of heterocyclic aromatic nitrogen. In addition, during extraction, the formation of chelates due to the NH2 group in α-position to the


**Table 1.**

*Distribution coefficient of some metals in the extraction of 2-OAP under iridium extraction conditions: Ir, Pt, Au, Ag <sup>1</sup><sup>10</sup><sup>4</sup> -1<sup>10</sup><sup>5</sup> M; Rh, Pd <sup>5</sup><sup>10</sup><sup>4</sup> ; 0.05 M 2-OAP, 0.1 M SnCl2, heating for 40 min at 100°C, phase contact for 15 min, organic phase – Chloroform.*

heterocyclic nitrogen. In the course of extraction, one or another mechanism is realized depending on the conditions [13].

*Extraction of ion associates***.** In the form of ionic associates, platinum metals are extracted from HC1 solutions at a certain ratio of the concentration of components and the duration of phase contact [2]. Palladium (II) is extracted by 2-OAP predominantly in the form of an associate (OAPH<sup>+</sup> )2[PdCl4] only from concentrated solutions of HC1 and when organic diluents are used solvents with a strong protondonating ability. Platinum is extracted in the form of such a complex already from acidic solutions of HC1. Ir (III, IV) are predominantly extracted in the form of ionic associates of the composition (OAPH<sup>+</sup> )2[IrCl6] and (OAPH<sup>+</sup> )3[IrCl6] from 1 to 6 M HC1, especially with a short duration of phase contact.

According to this mechanism, Pd (II) is extracted from salicylate solutions with 4 heptylaminopyridine [15], and from oxalate solutions with 4-dodecylaminopyridine [16]. Ro (III) is extracted from citrate solutions with 2-dodecylaminopyridine [17], and from Ru (III) succinate solutions with 2-OAP [18]. From acetate solutions, 2-OAP extracts Ir (III) [19] from malonate – Au (III) [20]. 2-OAP and other metals are extracted in the form of ionic associates from chloride, malonate, succinate, salicylate, citrate media: To (IV) [21], Zr (IV) [22], V (V) [23], Mo (VI) [24], Cr (VI) [25], Bi (III) [26], Ga (III) [27], Tl (III) [28], Sm (III) [29], Hg (II) [30].

Anions of inorganic acids are also extracted as ionic associates [8].

*Extraction of coordination-solvated compounds.* Сu (II) is extracted with a solution of 2-OAP in chloroform from a neutral medium in the presence of at least 1 g-ion/ l chloride ion, apparently in the form of a neutral coordination-solvated complex. In the case of Pd (II), a neutral diamine complex of the composition Pd(OAP)2C12 is formed during extraction from solutions with a concentration of HC1 ≤ 3 M, Pt (II) in the form of Pt(OAP)2Cl2 from weakly acid solutions of HC1 (pH >1.5); the phase contact duration is 30 min [2]. Most often, the organic phase contains compounds with 2(4)-OAP in the inner and outer coordination spheres of the metal ("mixed" extraction mechanism).

*Mixed extraction mechanism.* Iridium, under conditions optimal for its extraction, is extracted in the form of compounds containing 2-OAP in the inner and outer coordination spheres of the metal [7]. In addition to 2-OAP, the extractable compounds include SnCl2, which is added to overcome the kinetic inertness of the initial

*2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum… DOI: http://dx.doi.org/10.5772/intechopen.106376*

complex iridium chlorides [6]. Complexation in the aqueous phase and subsequent extraction of the resulting compounds are described by the following Equations [7]:

$$\left[\mathrm{IrCl\_6}\right]^{3-}\mathrm{\tiny{m}} + \mathrm{m}[\mathrm{SnCl\_3}]^{-}\mathrm{\tiny{\tiny{\tiny{\tiny{\tiny{\tiny{\tiny{\tiny{\tiny{\tiny{\tiny{\tiny{\Gamma\_{\mathrm{Br}}}}}}}}}}\mathrm{I}}\mathrm{Cl\_{6-m}}}\mathrm{I\_{6-m}}\right]^{3-}\mathrm{\tiny{\tiny{\tiny{\tiny{\rm{\tiny{\rm{\tiny{\rm{\tiny{\rm{\tiny{\rm{\rm{\tiny{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\rm{\cdots}}}}}}}}}}}}}}}}}}}}}}}}}}}}}} $$

$$\begin{aligned} \left[\text{Ir}(\text{SnCl}\_3)\_\text{m}\text{Cl}\_{(6-\text{m})}\right]^{\mathfrak{J}-}\text{w} + \text{xO}\text{AIIH}^+\text{w} &\to \left[\text{Ir}(\text{SnCl}\_3)\_\text{m-x}\text{ (OAlI)}\_\text{x}\text{Cl}\_{(6-\text{m})}\right]^{\mathfrak{x}-\mathfrak{J}}\text{w} \\ + \text{xH}\_\text{w} + \text{xCl}\text{B} &\to \left[\text{SnCl}\_3\right]^-\text{w} \end{aligned} (2)$$

$$\begin{aligned} & \left[ \text{Ir} (\text{SnCl}\_3)\_{\text{m}-\text{x}} \left( \text{OAII} \right)\_{\text{x}} \text{Cl}\_{(\text{6-m})} \right]^{\text{x}-\text{3}} + (\text{x} - \text{3}) \text{OAII} \cdot \text{HCl}\_{\text{o}} \\ & \rightarrow (\text{OAIII}^{+})\_{\text{x}-\text{3}} \left[ \text{Ir} (\text{SnCl}\_3)\_{\text{m}-\text{x}} \left( \text{OAII} \right)\_{\text{x}} \text{Cl}\_{(\text{6-m})} \right]^{\text{x}-\text{3}} + (\text{3} - \text{x}) \text{Cl}^{-} \text{w} \end{aligned} \tag{3}$$

Here x = (0–2), m = 1–6; component concentration interval: 1�10�<sup>5</sup> -1�10�<sup>3</sup> g-at/l Ir; 0.05–0.2 M; **SnСl2** ≤ 0.1 M 2-OAP in acetone; 1–6 M HCl.

The ratio of ligands in the inner coordination sphere of iridium is determined by the concentration of the components in the specified range, as well as the temperature and duration of heating the solution before extraction. At a low concentration of 2-OAP, along with coordination-solvated compounds, anionic iridium chlorotin complexes are extracted that do not contain 2-OAP in the inner coordination sphere of the metal. The ratio between these two types of extractable compounds under these conditions can be estimated from the results of a physicochemical study of the extraction of iridium in the presence and absence of OAP in the aqueous phase upon heating [7].

The given chemistry of iridium extraction is confirmed by the study of extracts by high-voltage electrophoresis on paper and iridium compounds isolated from the extract using physicochemical and spectral methods of analysis [7]. These compounds are a dark brown pasty substance. The total content of the organic component (C, H, N), according to elemental analysis, is 41.95%, which indicates a high molecular weight of the anionic part of the associate; indirectly indicates the presence of tin. Direct evidence for the presence of tin in the complex is the Mossbauer spectrum of the compound on 119Sn nuclei, which is characteristic of the [SnCl3] � ligand in the iridium coordination sphere (chemical shift 1.65 mm/s, quadrupole splitting 2.33 mm/s). Significant quadrupole splitting in the Mossbauer spectrum of the compound indicates the presence of 2-OAP in the inner coordination sphere of the metal.

This conclusion most convincingly follows from the data of PMR spectroscopy of substances before and after electrophoresis: in the spectrum of the substance after the separation of the cationic part, signals from the protons of the hetero ring and the octyl radical are clearly recorded; 2-OAP is indeed part of the anionic part of the associate and is coordinated by iridium. If we take into account the results of elemental analysis (32.38% C, 4.70% H, 4.87% N), then the probable composition of the compound is (OAPH<sup>+</sup> )[Ir(OAP)2(SnCl3)3C1]�, possibly impurity of the complex (OAPH<sup>+</sup> )2[Ir(OAP)(SnCl3)2Cl3] 2�.

Compounds containing OAP in the inner and outer coordination spheres of the metal can be extracted without preliminary heating of the metal solution with OAP in the aqueous phase, if its kinetic inertness is relatively low. In particular, the results of the study of platinum extracts using electron spectroscopy and thin layer chromatography [2] can be explained if the presence of the associate (OAPH<sup>+</sup> )[Pt(OAP)C13] – is assumed in the organic phase.

In principle, more than two molecules of 2(4)-AP can enter into the coordination sphere of a metal. In this case, the formation of complexes containing the metal in the

**Figure 5.**

*Electrical conductivity of 1 10<sup>4</sup> M aqueous solution of K2[PdCl4] depending on the metal/amine molar ratio with the addition of: 1–2-AP; 2–4-AP.*

#### **Figure 6.**

*Electrical conductivity of 1 10–4 M aqueous solution of K2[PtCl4] depending on the metal/amine molar ratio with the addition of: 1–2-AP; 2–4-AP.*

cationic form is not excluded. Under the conditions of extraction of iridium, such compounds should precipitate at the phase boundary, which is observed in the extraction of palladium, as well as gold and silver, and only if 2-OAP is present during heating in the aqueous phase [2].

Another proof of the possibility of the formation of cationic complexes are the results of conductometric and spectrophotometric studies of complex formation 2(4)- AP with Pd (II), Pt (II) in aqueous solutions at concentrations of reagents 1<sup>10</sup><sup>5</sup> - <sup>1</sup><sup>10</sup><sup>4</sup> M, simulating the extraction conditions (**Figures 5** and **<sup>6</sup>**). The conductometric curves χ = f (CAm/CMe) show breaks at CAm/CMe = 2 and 4.

Thus, the chemistry of 2(4)-AP metal extraction can be quite complex. Depending on the nature of the metal and extraction conditions, associates containing 2(4)-AP only in the cationic part, and the metal in the anionic part, associates with OAP in the inner and outer coordination spheres of the metal, neutral coordination-solvated compounds can pass into the organic phase; the formation of cationic complexes is also not excluded.

#### **4. Interionic interactions in 2(4)-AP associates**

Extraction of hydrochloric acid with a solution of 2(4)-OAP in chloroform according to the neutralization mechanism is described by the equation:

*2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum… DOI: http://dx.doi.org/10.5772/intechopen.106376*


**Table 2.**

*Distribution constants of 2-AP and 4-OAP salts between chloroform and water (25 2° С, μ 1) and thermodynamic characteristics of anion hydration in infinitely dilute solutions at 298°K (\* calculated by correlation dependence ΔSh = f (R, А<sup>o</sup> ), where R radius of ions in water.*

Кex = KАmH+Cl-(KaКD) 1 , where Кex is the HCl extraction constant, KАmH+Cl- is the chloride distribution constant, Ka is the ionization constant of the protonated amine, К<sup>D</sup> is the amine distribution constant.

2-OAP chloride with an intramolecular hydrogen bond passes into the organic phase and contains practically no water molecules, which apparently explains the low over stoichiometric extraction only from 12 M HCl [1]. On the contrary, for 4-OAP, a high over stoichiometric extraction is observed already from 6 M HCl, since in this case the chelate cycle based on the intramolecular hydrogen bond is not formed [5].

In the extraction of simple singly charged anions, there is a violation of the exchange-extraction series established for a large set of aliphatic amines. This conclusion follows from the data on the distribution constants of 2-aminopyridine [8] and 4- OAP salts between chloroform and water (**Table 2**), according to which, according to the extractability of 2(4)-OAP, singly charged anions are arranged in a row:

$$\mathrm{F^{-}} < \mathrm{Cl^{-}} < \mathrm{NO\_{3}}^{-} < \mathrm{Br^{-}} < \mathrm{ClO\_{4}}^{-} < \mathrm{SCN^{-}} < \mathrm{I^{-}}$$

Soft anions (according to Pearson) are best extracted: SCN and I, while for aliphatic amines such an anion is hard СlO<sup>4</sup>. In addition, it is well known that for aliphatic amines there is a linear correlation between the exchange constants of singly charged anions and the extraction constants of monobasic acids with the heat of hydration of the anion or the free energy of hydration. In the case of 2(4)-OAP, such a correlation is observed separately in the series Br < SCN < I and F < Сl < NO3 < СlO4 , but not for the entire series as a whole (**Figures 7** and **8**).

The study of 2-OAP halides by PMR, IR and X-ray electron spectroscopy showed [8] that they all have a structure similar to chloride (**Figure 9**):

The specificity of the interionic interaction in 2(4)-OAP associates manifests itself in a decrease in the polarization of the n-electron cloud of the aromatic cation, depending on the nature of the anion, on the one hand, and the formation of a chelate cycle based on hydrogen bonds in the case of 2-OAP with another. The data of IR spectroscopy indicate that the strength of the chelate ring in the case of 2-OAP decreases on passing to an anion with better extractability [8]. Consequently, the selectivity of the extraction of soft anions is due to the redistribution of the electron density in the aromatic cation, depending on the nature of the anion. Degree of

**Figure 7.** *Dependence of distribution constants of 2-aminopyridine salts on free energy anion hydration.*

**Figure 8.** *Dependence of distribution constants of 4-OAP salts on free energy anion hydration.*

indignation π-electron cloud of an aromatic cation can be quantified by the degree of charge delocalization (α) in the cation according to the data of X-ray electron or NMR spectroscopy [8]. For 2-OAP it is 90, 56, 54 and 48% in the series I, Br, Cl, [GaCl4] , and for 4-OAP it is 90, 79, 65% in the series I, Br, Cl, respectively.

The distribution constants of 2-aminopyridine halides increase with increasing α.

Other processes involving aromatic cations show similar phenomena. In particular, on the surface of micelles RPy+ <sup>X</sup> (RPy<sup>+</sup> long chain alkyl pyridinium ion; X anions of different nature) in an aqueous solution, an interaction with charge transfer was found for soft anions, which increases in the series Br < SO3 <sup>2</sup> < N3 < I < S2O3 <sup>2</sup> according to an increase in the softness of the anion. Similarly, the interaction in the series Cl < Br < I is observed for ion pairs in chloroform and is absent in the case of hard СlO4 . Charge transfer in ion pairs and on the surface of micelles is absent in the case of hard tetraalkyl- and tetraphenylammonium cations with soft Br and I [31]. The charge transfer is due to the mixing of the wave functions of nearby excited ones with the wave function of the ground state. Since in an ion pair the ground state is charged, and the excited neutral, then it should be recognized that in the associates of a soft cation, for example, an OAPH+ or RPy+ cation with a soft anion, there is a covalent contribution (delocalization energy in terms of MO). This contribution is absent in associates with a hard cation, for example, the cation of an

*2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum… DOI: http://dx.doi.org/10.5772/intechopen.106376*

**Figure 9.** *3D structure of 2-OAP chloride.*

aliphatic amine. This is also confirmed by the results of the study of 2(4)-OAP associates.

#### **5. Structure of coordination compounds**

The extraction of platinum metals by 2(4)-OAP in the form of coordinationsolvated compounds is highly selective with respect to non-ferrous metals, in particular with respect to nickel. Therefore, it is of interest to study the structure of coordination compounds of the isovalent and isoelectronic series of metals with the composition MeCl2(OAP)2, where Me = Ni, Pd, Pt, i.e. complexes that pass into the organic phase during the coordination extraction of Pd and Pt with a solution of 2- OAP in chloroform.

The complexes were synthesized according to specially developed procedures [9]. Their composition was confirmed by the results of elemental analysis and the properties of the complexes. The formal oxidation state of the central atom of the complexes


#### **Table 3.**

*Binding energy (eV 0.1) of internal electrons of metal and ligands in Ni, Pd, Pt complexes with 2-OAP.*

is +2, which follows from X-ray electron spectroscopy data from the ionization energies of the Ni 2p3/2, Pd 3d5/2 and Pt 4f7/2 levels (**Table 3**).

The chlorine ion is a part of the coordination sphere of the central atom, which is due to the relatively high energy of the 2p3/2 level C1 in comparison with the corresponding energy values for ionically bound chlorine in the 2-OAPHC1.

Formally, 2-OAP and 2-AP are ambidentate ligands with two donor nitrogen atoms, the heterocyclic nitrogen of the pyridine ring and the nitrogen of the amine group located in the α-position. The results of electron, IR, and NMR spectroscopy testify to the mode of coordination of 2-OAP by the metal [9]. 2-OAP and 2-AP are coordinated by Pd and Pt at the nitrogen of the heterocycle; The α-amino group does not interact directly with the metal. However, the spatial arrangement of the amino group, as well as the fact that coordinated chlorine has an excess negative charge, contribute to the formation of a chelate cycle due to the intramolecular H-bond, as in the case of associates (**Figures 10** and **11A**). The chelate cycle is absent in Pd and Pt complexes with 4-AP (**Figure 11B**).

**Figure 10.** *3D structure of the Pd complex with 2-OAP.*

*2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum… DOI: http://dx.doi.org/10.5772/intechopen.106376*

**Figure 11.** *3D structures of Pt(II) complexes: A – 2-AP, B – 4-AP.*

The extraction of coordination-solvated complexes can be considered from the point of view of the formation of electron-donor-acceptor complexes by neutral halide complexes with the electron-donor OAP molecule. The results of X-ray electron spectroscopy indeed show that the binding energy of the N1s electrons of the nitrogen atom decreases upon passing from free 2-OAP to the complex for all the studied metals; 2-OAP is primarily an electron donor, and the energies of the N1s electrons of the aromatic and aliphatic nitrogen atoms are equalized during complexation. Based on the change in the energy of the N 1 s level of OAP during complex formation, the acceptor ability of Ni is significantly higher than the acceptor ability of Pd and Pt in the corresponding halides.

It is interesting to compare the electron ionization energy from the 2p3/2 level of chlorine in the compounds MeCl2(OAP)2 and MeCl2(NH3)2, where Me = Pd, Pt [32], in compounds in which the central atom in one case forms a bond with a heterocyclic nitrogen 2-OAP, and in another with ammonia nitrogen (the most rigid aliphatic amine). In complexes with 2-OAP, these values are much smaller; the electron density initially localized on the donor nitrogen atom is not only and not so much directly redistributed to the accepting complexing metal, but also further along the N—Me— C1 chain, which leads to an even greater covalence of the molecule as a whole. It is noteworthy that, in this respect, the complexes of palladium with OAP are similar to the complexes with triphenylphosphine and diphenylthiourea [33] other soft ligands.

#### **6. Conclusion**

The specific behavior of aromatic amines is considered.in coordination and extraction processes for the isolation and separation of platinum and other metals on the example of 2(4)-aminopyridines (2(4)-AP). Toas intrasphere ligands2(4)-APhave a high electron-donating capacity due to the pumping of an easily polarizable πelectron density. In a protonated amine, electron density mobility is accompanied by delocalization of the positive proton charge over the ligand molecule, depending on the requirements of the acceptor. The degree of delocalization is the higher, the greater the polarizability of the anion. Chemistry of extraction of platinum metals2

(4)-AP, iridium in particular, can be quite complex. Depending on the nature of the metal and the extraction conditions, associates containing 2(4)-AP only in the cationic part, and the metal in the anionic part, associates with 2(4)-octylaminopyridine in the inner and outer coordination spheres of the metal, coordination neutral - solvated compounds; the formation of cationic complexes is also not excluded.

In the extraction of simple singly charged anions, the exchange-extraction series established for a large set of aliphatic amines is violated. Mild anions (according to Pearson), SCN- and I-, for example, are extracted best. For aliphatic amines, this anion is hard СlO4-. In coordination compounds of platinum metals, 2(4)-APact as an electron donor, coordinate on heterocyclic nitrogenwith the redistribution of the electron density not only to the accepting metal-complexing agent, but also further along the chain N—Me—X (X-acid ligand in the complex), which leads to an even greater covalence of the complex.

### **Author details**

Liliya Sergeevna Ageeva\*, Nikolai Alekseevich Borsch and Nikolay Vladimirovich Kuvardin Southwest State University, Kursk, Russian Federation

\*Address all correspondence to: millfi@yandex.ru

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum… DOI: http://dx.doi.org/10.5772/intechopen.106376*

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### *Edited by Satyanarayan Pal*

This book discusses the chemistry and applications of pyridine derivatives. The library of pyridine derivatives is growing steadily with numerous synthetic analogues already described and the identification of new, naturally occurring pyridine-based compounds. The book includes ten chapters organized into two parts. The first part focuses on the numerous types of reactions that arise from pyridine derivatives. The second part examines the pharmaceutical applications of pyridine derivatives as well as their usefulness as sensors for metal cations and extracting agents for platinum group metals.

Published in London, UK © 2023 IntechOpen © lesichkadesign / iStock

Exploring Chemistry with Pyridine Derivatives

Exploring Chemistry with

Pyridine Derivatives

*Edited by Satyanarayan Pal*