Natural Products and Drug Discovery

#### **Chapter 12**

## Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress towards Successful Antimalarial Drug Discovery

*Mithun Rudrapal, Dipak Chetia and Soumya Bhattacharya*

#### **Abstract**

Among numerous life-threatening infectious diseases (HIV/AIDS, TB, NTDs and EIDs), malaria continues to be the deadliest parasitic disease caused by *Plasmodium* protozoa transmitted by an infective female *Anopheles* mosquito. *Plasmodium falciparum*, the potentially fatal malaria parasite, is believed to be responsible for most of the morbidities and mortalities associated with malaria infections. Artemisinin-based Combination Therapies (ACTs) are currently considered to be the frontline therapy against malaria caused by *P. falciparum*. Despite significant progresses in antimalarial drug discovery, the control and prevention of malaria is still a challenging task. It is primarily because of the reduced clinical efficacy of existing antimalarial therapies including ACTs due to the widespread emergence of drug-resistant strains of malaria parasites, especially *P. falciparum*. It is, therefore, necessary to discover and develop novel drug candidates and/or alternative therapies for the treatment as well as prevention of resistant malaria. In this chapter, the potential of phytomedicines as natural sources of novel antimalarial lead molecules/ drugs with recent advances in phytomedicine-based antimalarial drug discovery has been reviewed.

**Keywords:** antimalarials, phytomedicines, *P. falciparum*, lead molecules, drug discovery

#### **1. Introduction**

Malaria is a potentially life-threatening parasitic disease caused by *Plasmodium* protozoa transmitted by an infective female *Anopheles* mosquito. Along with human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS), tuberculosis (TB), neglected tropical diseases (NTDs) and viral hepatitis (hepatitis B), malaria affects billions of people, and causes more than 4 million deaths every year globally [1]. Apart from these infectious diseases, emerging infectious diseases (EIDs) are serious public health threats in the twenty-first century. Some deadly EIDs include severe acute respiratory syndrome (SARS), Ebola virus disease (EVD), Zika virus disease (ZVD), swine flu (H1N1 influenza), bird flu (avian influenza), chikungunya

(CHIKV), dengue fever (DENV), hanta pulmonary syndrome (HPS, hanta virus), antibiotic-resistant infections (superbugs) and coronavirus disease (COVID-19, SARS-CoV-2) [2, 3].

According to the latest report by World Health Organization (WHO), about 229 million clinical cases of malaria with a death toll of 409,000 have been documented for the year 2019. In the same year, 94% of all malaria cases and deaths were found in the WHO African region. In the Southeast Asian region of WHO, there were an estimated 7.9 million cases of malaria in 2018. Children under 5 years of age are considerably at higher risk of malaria. They have been accounted for 67% of all malaria deaths worldwide in 2019 [4–6]. However, *Plasmodium falciparum*, the deadliest malaria parasite, is attributed to be responsible for most of the morbidity and mortality associated with malaria [7, 8]. Artemisinin-based Combination Therapies (ACTs) are currently considered as the frontline therapy against malaria caused by *P. falciparum* [9, 10]. Due to the widespread emergence and spread of drug resistant strains of *P. falciparum*, the clinical utility of existing antimalarial therapies including ACTs has been drastically declined [11, 12]. It has, therefore, become a serious health concern, which urgently necessities the discovery and development of novel drug candidates and/or alternative therapies for the treatment as well as prevention of resistant malaria. In this chapter, the potential of phytomedicines as natural sources of novel antimalarial lead molecules/ drugs with recent advances in phytomedicine-based antimalarial drug discovery has been briefly summarized.

#### **2. Phytomedicines and antimalarial drugs**

The discovery of antimalarial drugs from plant sources was started in 200 years back when quinine (QN), a cinchona alkaloid, was isolated from *Cinchona* bark in the year 1820. Earlier, the extract of *Cinchona* bark (also known as Peruvian Bark) was traditionally used for the treatment of fever by native Peruvian Indians in 1600s [13]. QN was the only known antimalarial drug for more than three centuries, and until the 1930s was the only effective therapeutic agent for the treatment of malaria. Later, the structure of quinine served as a template for the development of several synthetic congeners as potent antimalarial agents [13, 14]. The introduction of CQ, a 4-aminoquinoline derivative of QN, in the mid-twentieth century (1940) ceased the wide spread use of QN. Soon after its introduction, CQ became the mainstay of malaria chemotherapy, since it was clinically effective, less toxic and cheaper drug [15]. Another synthetic antimalarial, primaquine (PQ, 1950) was also developed thereafter based on the

**Figure 1.** *Some QN-based antimalarial drugs.*

#### *Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress… DOI: http://dx.doi.org/10.5772/intechopen.108729*

structure of lead QN molecule. PQ is a 8-aminoquinoline analogue of QN. Mefloquine (MQ ), a synthetic quinoline methanol derivative of QN, was developed (1975) after CQ to treat resistant cases of malaria. Malaria parasites resistance to CQ and MQ began to appear within a few decades of introduction [16]. Later, several quinoline derivatives related to CQ (amodiaquine, AQ and isoquine, IQ ) and MQ [halofantrine (HL), lumefantrine (LUM) and pyronaridine (PYN)] were developed and found effective (in combination with ART-based drugs such as dihydroartemisinin, artemether and artesunate) against CQ-resistant and/or multi-drug resistant (MDR) *P. falciparum* infections. Hepatotoxicity and cardiotoxicity are some serious toxic effects associated with these drugs [17]. Moreover, rapid development of resistance has severely limited the use of QN-based drugs alone, and therefore, they are used in combination with other drugs in the treatment of resistant malaria. The increasing prevalence of MDR strains of malaria parasites, particularly *P. falciparum* in most malaria endemic areas (Southeast Asia including Myanmar, Thailand, Vietnam and India, African continent and Eastern Mediterranean region) has significantly reduced the efficacy of CQ and other potent QN-based antimalarials in the treatment of malaria [8]. **Figure 1** depicts structures of some QN-based antimalarial drugs.

QN-based antimalarials are used widely in the treatment and prophylaxis of malaria. QN still remains an important antimalarial drug due to the emergence of CQ-resistant and MDR strains of malaria parasites, especially *P. falciparum*. Due to its undesirable side effects, it is now only used as an intravenous injection (as sulphate salt) to treat severe malaria. CQ (as phosphate salt) still remains the first-line drug in the treatment of uncomplicated sensitive *P. falciparum* malaria, despite its increasing resistance to parasites, due to its easy availability, low cost and good tolerability. In CQ-resistant malaria, the next drug of choice is MQ, followed by QN in combination with tetracycline, doxycycline or sulphadoxine-pyrimethamine (SP). MQ and AQ are widely available and are used to treat cases of uncomplicated malaria in areas where CQ resistance is prevalent [18, 19].

QN-based drugs are blood stage schizonticidal. CQ/MQ is selectively active against the intra-erythrocytic mature forms (trophozoites) and also younger ring forms of malaria parasites, without any activity against gametocytes. QN-based drugs inhibit the heme polymerase enzyme resulting in specific toxicity during the developmental stage of the parasite. CQ accumulates by a weak base mechanism in the acidic food vacuole of trophozoite-infected cells and act by forming a complex with heme in the parasite food vacuole, which prevents heme polymerization and consequently, hemozoin formation. Simply, they these drugs block the polymerisation of heme to haemozoin (malaria pigment). As a result, the heme which is released during haemoglobin degradation builds up toxic accumulation of heme (haematin), thereby kills the parasite with its own toxic effects. The mode of action of QN is similar to CQ. QN binds strongly to heme protein and forms complexes that are toxic to the malaria parasite, as already delineated above. MQ also acts by inhibiting the heme polymerase, similar to CQ [8, 18–20].

ART, an active constituent of *Artemisia annua* L. (Sweet wormwood) and related compounds (semi-synthetic derivatives) showed promising antimalarial efficacy in clinical trials in 1970s (1972) and till date they are considered as the most effective and potent antimalarial agents [21]. Since ART is not soluble in water or oil, it has several limitations such as poor aqueous solubility, oral absorption and bioavailability. Reduction of ART (sesquiterpene lactones or cyclic endoperoxide) produced dihydroartemisinin (DHA), a sesquiterpene lactol, which served later as a template for the synthesis of a series of semi-synthetic analogues such as artemether (AM), arteether

**Figure 2.** *ART and some ART-based antimalarials.*

(AE) and artesunate (AS). They are collectively termed as the first-generation derivatives of ART [22, 23]. First-generation ART derivatives can be further grouped into oil soluble C(10) β-alkyl ethers (AM and AE) and water soluble C(10) β-(substituted) esters (sodium artesunate and sodium artelinate). These drugs possess better oil/ water solubility, and therefore, have superior pharmacokinetics properties with increased antimalarial efficacies over the parent compound, ART [8]. **Figure 2** represents the structures of ART and some ART-based antimalarial drugs.

Because of having excellent antiparasitic efficacy against resistant parasites, ART-based drugs mostly replaced the use of QN- and antifolate-based drugs. ART derivatives are fast-acting antimalarials effective against MDR strains of *P. falciparum* and are used for the treatment of severe and complicated malaria. ART-based drugs showed very rapid clearance of parasites and faster resolution of fever as compared to QN. In some areas of Southeast Asia, combinations of ART-based drug and MQ offer the only reliable treatment for uncomplicated MDR *P. falciparum* malaria [24, 25].

ART and its analogues are active against all blood stages, particularly against younger ring forms and gametocytes. They have no activity on hepatic stages of parasites. They reduce parasitemia very rapidly and are well tolerated in both adults and children. ART and related compounds are concentrated in parasite-infected erythrocytes and exert their parasiticidal activity subsequent to reductive activation by heme in an irreversible redox reaction, which produces toxic carbon-centred free radicals. Toxic free radicals may lead to alkylation of heme or bring about oxidative damage to parasite proteins/lipids. The endoperoxide group, therefore, appears to be crucial for the antimalarial activity. The antimalarial activity of ART may also result from the inhibition of a parasitic calcium ATPase enzyme [8, 24–26].

The development of atovaquone (ATO), a 2-hydroxy-1,4-napthoquinone antimalarial, began more than 50 years ago when the outbreak of World War II caused substantial shortages in the supply of QN. ATO is an analogue of lapachol (a prenylnaphthoquinone isolated from *Tabebuia* species, Lapacho tree, 1892). Lapachol was used as an antimalarial lead molecule for the development of ATO. It is effective against CQ-resistant *P. falciparum*, but because, when used alone, resistance develops rapidly, ATO is often given in combination with proguanil (PG). A new fixed-dose antimalarial combination of ATO and PG (Malarone, 1998) is available in the market worldwide. Malarone shows good tolerability with minimal side effects in children and adults with uncomplicated malaria. It is used as chemoprophylaxis for the prevention of malaria in travellers. ATO represents a novel class of expensive antimalarial drug.

*Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress… DOI: http://dx.doi.org/10.5772/intechopen.108729*

**Figure 3.** *Structure of ATO.*

ATO is used in combination with PG (a selective inhibitor of dihydrofolate reductase, DHFR) or tetracycline for the prevention as well as treatment of CQ-resistant malaria, including cerebral malaria caused by *P. falciparum*. It is as effective as MQ or doxycycline. ATO acts through the inhibition of electron transport at the *Plasmodium* mitochondrial cytochrome bc1 complex and depolarizes the membranes of *Plasmodial* mitochondria[15, 16]. The structure of ATO is given in **Figure 3.**

#### **3. Approaches to antimalarial drug discovery**

The objective of antimalarial drug discovery is to find out new and potent drug candidates based on the knowledge of existing and/or novel drug targets. It is necessary to develop affordable and safe drugs that would be reasonably cheaper, non-toxic to host tissues, and clinically effective against resistant malaria parasites. Suitable *in vitro* and *in vivo* experimental methods are, therefore, used for the evaluation of efficacy as well as toxicity of newer antimalarial agents. However, there are several traditional and modern approaches to antimalarial drug discovery programme, which include traditional evaluation of bioactive natural products/phytomedicines, molecular modifications of existing lead molecules, reverse pharmacological or drug repurposing approach and drug discovery based on CADD/SBDD approach [8]. Brief explanations of these approaches are given here under (**Figure 4**).

#### **3.1 Ethnomedicinal evaluation based approach**

The investigation of medicinal plants having traditional/ folkloric uses as antimalarial medicine may be potential sources of novel bioactive compounds that can be further developed into potent antimalarial drugs and/or lead molecules. Several tribes and aboriginals of Asian, African and South American continents still rely on plantbased ethnomedicines for the management of fever and malaria-like illness. QN and ART were discovered from the ethnomedicinal use of *Cinchona* and *Artemisia* plants, respectively. They served as lead structures in the development of many more potent antimalarial drugs of current use. Considering the above fact, thousands of medicinal plants and traditional formulations have been screened (*in vitro* and *in vivo*) to aid bioactive fraction guided discovery of antimalarial lead molecules [27].

#### **Figure 4.**

*Approaches to antimalarial drug discovery.*

#### **3.2 Random high-throughput screening**

Random high-throughput screening of plant extracts is one of the common approaches for antimalarial drug discovery. Scientists and researchers perform random screening of plant extracts against *Plasmodium* strains by various *in vitro* methods in search for novel antimalarial compounds. Depending upon preliminary antimalarial efficacy (IC50) and cytotoxicity profile (CC50) obtained *in vitro*, plant extracts and/or isolated pure compounds can be further subjected to *in vivo* experimental (ED50 and Pharmacokinetics) studies [28].

#### **3.3** *Plasmodium* **life cycle targeted drug discovery**

This is believed to be the most potential approach in antimalarial drug discovery programme. Specific proteins or enzymes that are essential biological components in the life cycle of *Plasmodium* parasite may provide novel targets for the discovery

of drug molecules. For instance, falcipains (FP), plasmepsins (PM), dihydrooroate dehydrogenase (DHOH), phosphatidylisositol-4-kinase (PI4K), cytochrome *bc1* (Cyt *bc1*) and Na+ -ATPase 4 are some novel drug targets discovered from the biology of *P. falciparum* [8].

#### **3.4 Indigenous phytomedicine-based reverse pharmacological approach**

Reverse Pharmacology deals with the precisely designed preclinical and clinical research of age old herbal medicine used in well documented indigenous system of medicine (*Ayurvedic* medicine, Chinese medicine etc.) with a view of better understanding of the mechanism of action (even at molecular level) followed by the isolation of bioactive molecule(s) and finally the development of lead molecule(s). In fact, the discovery and development of ART (from *A. annua*) and its derivatives are the result of reverse pharmacological approach. Another interesting example is the discovery of antiplasmodial protoberberine type alkaloids allocryptopine and protopine from *A. mexicana*. This approach is considered to be quite reliable and faster technique due to the availability of prior information about therapeutic and toxic properties of the plant species under investigation. However, the discovery of potent lead molecule(s) with desired pharmacological/toxicity profile may sometimes be difficult because herbal medicine/ plant extracts possess therapeutic efficacy due to the synergistic activity of multiple ingredients in the crude mixture [26, 29].

#### **3.5 Drug repurposing approach**

Repurposing of existing drugs with new therapeutic indications is also considered as one of the effective alternatives for the discovery of antimalarial drugs. The notable advantage of this approach is that the mechanism of action and toxicity of drugs have already been established in clinical trials for other diseases. Folate antagonists (sulphonamides, sulphones, biguanides, pyrimethamine, triazines, etc.) and several antibacterials/ antibiotics (tetracycline, doxycycline, clindamycin etc.) have been reported to exhibit promising antiplasmodial efficacy against malaria parasites. In recent days, drug repurposing involves the combined efforts of *in silico* and *in vitro* methods to identify new therapeutic uses of existing drug molecules on a rational basis. Using the same strategy, researchers have been working on existing drugs in search for new antimalarial drug candidates. Repurposing of azithromycin, auranofin, loperamide hydrochloride, amlodipine besylate, cyclosporin A, esomeprazole magnesium, omeprazole etc. with antimalarial activity have been reported in literature [30, 31].

#### **3.6 Semi-synthetic modifications or designing of analogues**

Novel antimalarial drugs can be developed from the semi-synthetic modification of naturally derived lead molecules and/or by designing of newer synthetic analogues/ derivatives of existing drugs based on the structure-activity relationship (SAR) approach. This approach mainly emphasizes on reducing the toxicity with retaining and/or enhancing the therapeutic efficacy of the basic template structure/ lead molecule. Synthetic quinolines like CQ, AQ, IQ (4-aminoquinolines), PQ (8-aminoquinolines) MQ, HL, LUM (quinoline amino alcohols), piperaquine (PIP, bisquinoline analogue) and PYN (benzonaphthyridine derivative) were developed based upon the structural template of QN. Several chemical strategies were involved in structural

modification of QN or other lead molecules in order to improve the therapeutic efficacy as well as toxicity of the parent molecule. Tebuquine (4-aminoquinoline derivative, a CQ analogue) and tafenoquine (8-aminoquinoline derivative, a derivative of PQ ), are two newer drugs developed recently. Ferroquine (4-aminoquinoline derivative, a CQ analogue, Phase II terminated), AQ-13 (4-aminoquinoline analogue, Phase II) are presently under development. Following similar approach, DHA, AM and AS were also developed from ART. Some newer drugs (belonging to different classes) that are under development include DSM265 [Pf dihydrooroate dehydrogenase (DHOH) inhibitor, a triazolopyrimidine-based drug, Phase II], MMV390048 [Pf phosphatidylisositol-4-kinase (PI4K) inhibitor, Phase I] and KAE609 or cipargamin (Na+-ATPase 4 inhibitor) [8, 32–38].

#### **3.7 Combination therapy approach**

The concept of combination therapy (CT) is based on the synergistic or additive activity of two or more drugs, which improves therapeutic efficacy and also delays the development of resistance to the individual drugs of the combination. In antimalarial combination therapy, two or more drugs are used together that act with independent mode of action probably at different biochemical targets in the life cycle of *Plasmodium* parasite. WHO recommended combining the rapid schizonticidal ART derivative (DHA, AM or AS) with one or more partner drugs (from different class of antimalarials having longer biological half-lives) for the treatment of resistant *P. falciparum* malaria. Such combined antimalarial drug regimens (for examples, AM + LUM (Co-Artem, fixed dose, AL), AS + MQ (AM), AS + CQ, AS + SP, AS + DOX, AS + DOX + CQ etc.) are known as ACTs. Some ACTs which are in pipeline include AS + PYN, DHA + PIP (Artekin), DHA-PIP- Trimethoprim and DHA + PIP + MQ [8, 25].

#### **3.8 Drug discovery by CADD/SBDD approach**

Traditionally, drugs are discovered by testing naturally derived or synthetically obtained compounds in time-consuming multi-step processes against a battery of *in vitro* and *in vivo* screening methods. Compounds having promising therapeutic potential are further investigated for their development as drug candidates after pharmacokinetic, metabolism and toxicity studies. Today's modern drug discovery process involves rational design and development of novel drug molecules based on a particular disease target using modern tools and techniques of virtual and experimental screening techniques. In virtual screening, computational methods screen large chemical libraries targeted towards a specific biological receptor, using advanced high performance computing environments, data management software and internet. It delivers new drug candidates quickly and at lower costs. Virtual screening is an approach of structurebased drug design (SBDD) that uses computer-based (*in silico*) methods to discover and develop new drug molecules on the basis of biological structures of particular disease of interest. SBDD methods mainly focus on the design of molecules for a disease target with known three dimensional structures followed by the determination of their binding affinity for the target by molecular docking along with other *in silico* screening methods (ADMET and toxicity screening) for optimization of molecules during development. The process of SBDD proceeds through design and development of a series of consecutive steps from hit identification to lead optimization followed by preclinical and clinical development of drug candidates [38, 39]. Antimalarial drug

*Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress… DOI: http://dx.doi.org/10.5772/intechopen.108729*

**Figure 5.** *Antimalarial drug discovery based on SBDD approach.*

discovery based on SBDD approach involves the application of modern tools of molecular modelling and other *in silico* techniques in the development of novel antimalarial drug candidates (**Figure 5**)**.**

#### **4. Phytomedicines and antimalarial lead molecules: recent developments**

Phytomedicines (i.e., plant-based/ herbal traditional medicine systems) served as potential sources of lead molecules for the development of several clinically useful antimalarial drug candidates. For example, QN isolated from *Cinchona* bark was used as a template for the development of CQ and MQ. ART isolated from *Artemisia annua* has been utilized for the successful development of various semi-synthetic derivatives (DHA, AM and AS) which are currently used in the treatment of CQ-resistant *P. falciparum* malaria [40, 41]. Apart from QN and ART, some examples of antimalarial natural products that were developed from plants include yingzhausu A, febrifugine, sergeolide, chaparrin, glaucarubin, tehranholide and brusatol [42].

During the last few decades, a large number of plant species have been identified to be effective as antimalarial agents. Pure phytochemicals isolated from these plants have been reported to exhibit antimalarial effectiveness, particularly, against CQ-sensitive and CQ-resistant strains of *P. falciparum*. It is, therefore, imperative that antimalarial phytochemicals reported with promising *in vitro* and *in vivo* activities can be further subjected to preclinical and clinical confirmation for their development as novel antimalarial lead molecules and/ drug candidates. Plant-derived antimalarial compounds belong to several phytochemical classes of natural products such as alkaloids, terpenoids, quassinoids, limonoids, Polyphenols and flavonoids, coumarins, steroids, anthraquinones, naphthoquinones etc.

#### **Figure 6.**

*Structures of some recently developed plant-derived antimalarial compounds.*

Terhanolide (artediffusin), a sequiterpene lactone isolated from *A. diffusa* exhibited antimalarial efficacy against *P. falciparum* (*in vitro*) and *P. berghei* (*in vivo*) [43]. Halofuginone, an analogue of febrifugine (an alkaloid originally isolated from the plant *Dichroa febrifuga*) exhibited antiplasmodial effects against CQ-sensitive and CQ-resistant *P. falciparum (in vitro*) with curative effects in *P. berghei-*infected mice [44]. Sergeolide, a quassinoid from *Picrolemma pseudocoffa* showed antimalarial activities *in vitro* against *P. falciparum* and *in vivo* against *P. berghei* in mice [45]. Further, the antimalarial property licochalcone A (oxygenated chalcone) obtained from Chinese licorice has been reported to exhibit antimalarial activity against CQsensitive and CQ*-*resistant *Plasmodium* strain. Lichochalcone-A was the first natural


*Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress… DOI: http://dx.doi.org/10.5772/intechopen.108729*



**Name of specific phytochemical(s) Type of compound(s) Plant source (Family) Antimalarial/ Antiplasmodial activity** Miliusacunines A Oxoprotoberberine *Miliusa cuneata* (Graib). (Annonaceae) *In vitro* antimalarial activity against TM4 strain of *P. falciparum* with IC50 value of 19.3 ± 3.4 μM Hymenocardine *N*-oxide Cyclopeptide alkaloids *Hymenocardia acida* Tul. (Phyllanthaceae) Antiplasmodial activity against *P. falciparum* with IC50 value of 12.2 ± 6.6 μM Microthecaline A Quinoline alkaloid *Eremophila microtheca* F.Muell. (Scrophulariaceae) Moderate antimalarial activity against *P. falciparum* (3D7 strain) with IC50 value of 7.7 *μM* Sauristolactam Pyridocoumarin alkaloid *Goniothalamus australis* Jessup. (Annonaceae) Potent antimalarila activity against CQ-sensitive *P. falciparum* (3D7 strain) with IC50 value of 9.0 μM Normelicopidine *Acridone Alkaloid Zanthoxylum simullans* Hance (Rutaceae) Active against drug resistant Dd2 strain of *P. falciparum* with IC50 value of 18.9 ug/mL Carpaine Macrocyclic dilactone *Carica papaya* L. (Caricaeae) Potent antimalarial activity activity against 3D7 (sensitive) and Dd2 (resistant) strains of *P. falciparum* with IC50 values of 4.21 μM and 4.57 μM, respectively Palmitine and jatrorrhizine Indole alkaloid *Penianthus longifolius* Miers. (Menispermaceae) In vitro antimalarial activity against *P. falciparum* with IC50 values ranging from 0.28 to 0.35 μg mL<sup>−</sup><sup>1</sup> Liriodenine Indole alkaloid *Glossocalyx brevipes* Benth. (Siparunaceae) Antimalarial activity against drug sensitive D-6 strain and NF54 strains of *P. falciparum* with IC50 values of 2.37 μM and 1.32 μM, respectively Fagaronine Indole alkaloid *Fagara zanthoxyloides* (Lam). (Rutaceae) Antimalarial activity *in vitro* against *P. falciparum* with IC50 value of 0.018 μg mL<sup>−</sup><sup>1</sup> Strychnopentamine chrysopentamine Indole alkaloid *Strychnos usambarensis* Glig ex Engl. (Loganiaceae) Antimalarial activity against CQ-sensitive (FCA 20) ( IC50 = 117 to 579 nM), moderately CQ-resistant (FCB1-R) (IC50 = 107–550 nM) and CQ-resistant (W2) ( IC50 = 145–507 nM)

strains of *P. falciparum*

*Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress… DOI: http://dx.doi.org/10.5772/intechopen.108729*



*Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress… DOI: http://dx.doi.org/10.5772/intechopen.108729*


#### **Table 1.**

*Phytomedicines as potential sources of antimalarial compounds [41, 47, 48, 52–58].*

derivative of chalcones with antimalarial effectiveness against CQ-resistant strain of *P. falciparum* [43]. **Figure 6** displays structures of some recently developed plantderived antimalarial compounds.

Herein, phytomedicine-derived antimalarial compounds are categorized into two broad groups, viz. alkaloids and non-alkaloids [46]. Different alkaloids such as indoles, bisindols, isoquinolines (naphthyl and benzyl), piperidines, pyrroles, quinolones, steroidal alkaloids have been reported to possess antimalarial effectiveness. Polyphenolic compounds and bioflavonoids including dietary flavonoids such as kaempferol, myricetin, quercetin and isoquercitrin possess *in vitro* antimalarial activities. Different terpenenoids (farnesol, nerolidol, limonene, and linalool), quassinoids, coumarins and limonoids also exhibited antiplasmodial activity when tested *in vitro* against *P. falciparum* strains [47, 48]. Semi-synthetic triterpenes such as balsaminoside B, karavilagenin C, *S*-farnesylthiosalicylic acid, and karavoates B and D have been reported to exhibit *in vitro* and *in vivo* antimalarial activity [49–51]. **Table 1** describes phytomedicines as potential sources of novel antimalarial compounds.

#### **5. Challenges in antimalarial drug discovery**

There are several challenges that exist in the domain of antimalarial drug discovery from plant sources. Some major challenges are low natural abundance of phytoconstituents, difficulty in isolation of the specific active compound in pure form, safety/ toxicity and ADMET/pharmacokinetics issues, and high cost of production. Due to synergistic nature of crude plant extracts, it is also difficult to select the specific phytochemical responsible for the antimalarial action for isolation. Other issues include limited oral bioavailability and target specificity of natural molecules isolated

#### *Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress… DOI: http://dx.doi.org/10.5772/intechopen.108729*

from plants [59, 60]. Natural products with high degree of structural complexity and chemical instability are the other notable hindrances in the drug discovery pipeline of antimalarial drugs from plants. *In vitro* screening using parasitic cell cultures is a tedious work protocol which requires an expensive experimental set up and skilled laboratory personnel for the successful evaluation of antiparasitic activity. Similarly, the *in vitro* toxicity evaluation on normal cell lines requires extensive efforts, skills and labours. Compounds having high *in vitro* efficacy (IC50 ≤ 1μM) and sufficient oral bioavailability can be considered for further *in vivo* testing. Compounds with ED90 values of less than 10 mg/kg per os in *in vivo* murine model is essential for further development [12, 17]. An important challenge is the lacking of efficacy in preclinical trials after the successful *in vitro* and *in vivo* studies. Further, development of semi-synthetic derivatives from the natural lead(s) is a challenging task in context of designing scheme of synthesis, synthetic modification, purification of compounds and finally chemical characterization of pure compounds. High-throughput experimental assays eliminate potent antimalarial compounds due to toxicity issues and lack of pharmacokinetic properties [42]. Another challenge is the geochemical and climatic variation of plants. One more important challenge is that since no molecular mechanism and target specificity is known, it is very difficult to choose the *in vitro* or *in vivo* models for preliminary screening, and final confirmation of antimalarial efficacy with the exploration of mode(s) of action [59, 60]. Recently, *in silico* techniques based discovery of antimalarial drugs could reduce the chances of failure in the discovery pipeline. However, newer assays and target based approaches are required to be developed for discovery of newer congeners/ derivatives of naturally occurring potent molecules with desired antimalarial potency and less toxicity.

#### **6. Conclusion**

Re-emergence of resistance of existing drugs against *P. falciparum*, toxicity and unsatisfactory pharmacokinetics and less cost-effectiveness and poor patient compliance, particularly in South-east Asian and African regions are some major concerns in the malaria control and prevention programme worldwide. Although QN- and ART-based existing drugs/ therapies are considered as gold standards in malaria chemotherapy, the clinical utility of these drugs is challenging. Potent antimalarial compounds derived from phytomedicines could serve as potential sources of future antimalarial leads/ agents after a plethora of drug development (pre-clinical and clinical studies) processes. Target-based discovery of bioactive phytochemical entities is required for their successful development as effective and safe antimalarial drug molecules.

#### **Conflict of interest**

Authors declare that there is no conflict of interest.

#### **Author details**

Mithun Rudrapal1 \*, Dipak Chetia<sup>2</sup> and Soumya Bhattacharya<sup>3</sup>

1 Rasiklal M. Dhariwal Institute of Pharmaceutical Education and Research, Pune, Maharashtra, India

2 Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India

3 Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, India

\*Address all correspondence to: rsmrpal@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.

*Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress… DOI: http://dx.doi.org/10.5772/intechopen.108729*

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#### **Chapter 13**

## Effects and Pharmacological Use of Alkaloids on the Eyes

*Jin-Ho Joo*

#### **Abstract**

Alkaloids can have a variety of effects on the eyes. Some alkaloids are used as a treatment for eye diseases, such as keratoconjunctivitis, but they are also toxic to the retina. Other alkaloids are known to protect neuroretina from damage caused by oxidative stress. Numerous ophthalmic drugs, such as glaucoma and antibiotic eye drops, have long been developed through alkaloids. In this chapter, we will introduce the beneficial and detrimental effects of alkaloids on the eye. In addition, the action of alkaloids as existing eye drops and the possibility of developing them as drugs in the future will be discussed.

**Keywords:** alkaloid, eye, mydriasis, miosis, repurposing, myopia, presbyopia, intraocular pressure, retina, cataract, glaucoma, optic neuropathy, angiogenesis

#### **1. Introduction**

Alkaloid is a generic term for compounds derived from natural substances and having a nitrogen atom as a base. Alkaloids can be obtained from a variety of organisms, including bacteria, fungi, plants, and animals. The first alkaloid to be isolated was morphine from opium in 1804 by Friedrich Sertürner, a German pharmacist [1, 2]. Alkaloids with pharmacological effects are often known to be used as medicines, for example, physostigmine and pilocarpine as a treatment for glaucoma, and cocaine as a topical ocular anesthetic. However, in some cases, they are toxic, just as cocaine is highly toxic to corneal epithelial cells. Sometimes alkaloids cause undesirable constriction or dilation of the pupil, making us uncomfortable.

Recently, several studies have shown the potential of alkaloids as new drugs in the field of ophthalmology. Previously used, atropine plays a role in inhibiting the progression of myopia, and pilocarpine is attracting attention as a new treatment for presbyopia. In addition, some alkaloids are known to have antioxidant effects to prevent the progression of cataracts, protect the optic nerve through various mechanisms, and protect the retina by inhibiting angiogenesis.

Therefore, in this chapter, we would like to introduce the positive effects of using alkaloids as medicines and the various effects of alkaloids on the eyes. And among the recent studies, alkaloids would like to introduce the possibility of novel treatment in the field of ophthalmology.

#### **2. Medicinal use of alkaloids in the field of ophthalmology**

#### **2.1 Atropine**

Atropine (C17H23NO3) is a drug widely used by ophthalmologists for ophthalmic diagnosis and treatment since the 1800s and not only derived from the leaves of *Atropa belladonna* but is also found in other plants mainly from the Solanaceae family, such as *Datura stramonium, A. belladonna, Hyoscyamus niger*, and *Mandragora officinarum* [3]. It is an anticholinergic drug that causes powerful and long-lasting mydriasis and paralyzes the ciliary body, causing cycloplegia. For muscarinic receptors, it competes with acetylcholine or muscarine to inhibit parasympathetic nerves and selectively block the action of acetylcholine or muscarine. Acetylcholine secreted by stimulation binds to muscarinic receptors to continue signal transmission, and then, acetylcholine must be degraded by an enzyme called "acetylcholinesterase" to continue normal signal transmission. Atropine binds to muscarinic receptors but does not cause signal transduction, and since atropine and acetylcholine competitively bind to muscarinic receptors, atropine acts to inhibit the action of acetylcholine [4].

Until now, atropine eye drops have been used in ophthalmology to make mydriasis for diagnosis and surgical treatment, to help reduce intraocular inflammation and control the spasm of the near reflex. Recently, low concentrations of atropine have been found to be effective in controlling myopia. In a randomized clinical trials study, it was known that 0.05% atropine was less effective at the optimal concentration and minimized the side effects of near blurry and photophobia [5, 6].

Although the mechanism by which atropine suppresses the progression of myopia is not known, the following hypotheses are known to be highly likely through several studies. First, atropine affects the sclera, which is a fibrous connective tissue that protects the eye. It has been reported that atropine reduces the activity of the epidermal growth factor receptor in sclera fibroblasts, thereby reducing the proliferation of these cells, increasing the thickness of the scleral fibrous layer in the myopic eye, and reducing extracellular matrix production by reducing glycosaminoglycan synthesis. This can explain that myopia is prevented by suppressing the increase in the axial length of the eye. Second, atropine may affect the choroid, a layer of blood vessels that supply oxygen and nutrients to the outer retina. Originally, the choroid responds to optic defocus and controls the choroid thickness to focus. Atropine blocks the muscarine receptors of the choroid retinal pigment epithelium (RPE), modulates the transforming growth factor and basal fibroblast growth factor, and eventually suppresses choroid thinning, which is known to prevent the progression of myopia [7].

#### **2.2 Physostigmine**

In 1862, Thomas Fraser discovered the first intraocular pressure (IOP) lowering medication, physostigmine (C15H21N3O2), from the Calabar beans [8]. Physostigmine is a highly toxic parasympathomimetic alkaloid and a reversible cholinesterase inhibitor. After instillation into the eye, it increases the activity of free acetylcholine in the pupil sphincter, causing miosis leading to contraction of the ciliary muscle. Contraction of the ciliary muscle has been shown to decrease IOP by increasing the drainage of aqueous humor into the trabecular pathway. However, physostigmine has been replaced with safer drugs, which will be introduced below, due to side effects,

such as headache, spasm of accommodation, blurred vision due to miosis, increased risk of retinal detachment, and inflammation of the conjunctiva, cornea, and iris [9].

#### **2.3 Pilocarpine**

Pilocarpine (C11H16N2O2) is a cholinergic agent that was isolated by Hardy and Gerrard from *Pilocarpus* in 1875 and used as an eye drops for the treatment of glaucoma. Installation of pilocarpine reduces the size of the pupil, which can help reduce glare.

Pilocarpine is a cholinergic parasympathomimetic agent that acts through direct stimulation of muscarinic receptors and smooth muscles, such as the iris [10]. Aqueous humor is secreted from the ciliary body, travels through the pupil to the anterior chamber, and exits through the trabecular meshwork into Schlemm's canal. In angle closure glaucoma, IOP rises because aqueous flow obstruction occurs by the pupillary block. This can cause vision loss and pain in the eyeball. The therapeutic principle in angle closure is by removing the pupillary block. Pilocarpine contracts the iris sphincter muscle and pulls it away from the trabecular meshwork, widening the anterior chamber angle. As a result, it is used as an important treatment for angle closure glaucoma by resolving a pupillary block [11, 12].

Pilocarpine is also used for diagnostic purposes. Dilated pupils can appear for a variety of reasons. Among them, Adie's tonic pupil is caused by damage to the postganglionic parasympathetic nerve of the iris sphincter muscle. Denervation supersensitivity is a characteristic sign in Adie's tonic pupil that is confirmed by pharmacologic testing with a direct-acting weak muscarinic agonist, dilute pilocarpine [13].

Recently, pilocarpine 1.25% eye drops have been approved by the FDA for the treatment of presbyopia. Presbyopia is a condition in which near vision loss occurs due to a progressive physiological loss of accommodation. Accommodation is adjusting refraction to make focus on a near object. This can be achieved by increasing lens thickness by reducing zonular tension with ciliary muscle contraction, pupillary constriction, and convergence of both eyes. Presbyopia is known to occur due to the stiffening of the lens due to aging. About 1.25% pilocarpine is a muscarinic agent that induces miosis and ciliary body contraction and has been demonstrated to improve near vision without significantly impairing distance vision [14, 15].

#### **2.4 Cocaine**

It was first used in 1884 by Karl Köller as cocaine (C17H21NO4) for topical ocular anesthesia. As a local anesthetic, cocaine reduces pain by blocking sodium channels in the membranes of sensory nerve endings. However, cocaine is highly toxic to corneal epithelial cells and is no longer used for anesthesia. Since then, local anesthetics for ophthalmic use have changed to tetracaine, proparacaine, and lidocaine [16, 17].

Cocaine inhibits norepinephrine reuptake and causes pupillary dilation. High concentrations can cause cycloplegia, and chronic users can cause exophthalmos and retraction of the upper eyelid [18]. Cocaine users may develop superficial punctate keratitis, epithelial defects, and ulcers through eye rubbing or retrograde passage through the nasolacrimal duct [19]. Although not directly affected by drugs, unilateral vision loss along with proptosis and ophthalmoplegia may occur due to orbital congestion and ophthalmic/central retinal artery occlusion due to continuous pressure on the orbital socket while sleeping in an abnormal posture due to unconsciousness after excessive drug abuse. Orbital congestion and proptosis improved with time, but the visual prognosis was poor [20].

#### **2.5 Pyrrolizidine alkaloid**

*Heliotropium Indicum* is used traditionally as a remedy for conjunctivitis. This plant is an annual, hirsute plant that is a common weed in waste places and settled areas. It is native to Asia. It is widely used in native medicine in India. The extract from the pounded leaves of this plant contains several pharmacologically active alkaloids, such as indicine (C15H25NO5), acetyl-indicine (C17H27NO6), indicinine-N-oxide (C15H25NO6), heleurine (C16H27NO4), heliotrine (C16H27NO5), supinidine (C8H13NO), and lindelofidine (C8H15NO). These alkaloids have anti-allergic effects, possibly by immunomodulation or immunosuppression in allergic conjunctivitis. Also, this extraction exhibits an anti-inflammatory effect on uveitis, possibly by reducing the production of pro-inflammatory mediators. It was confirmed that this extract significantly reduced the concentrations of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and monocyte chemoattractant protein-1 (MCP-1) in rabbits with uveitis [21, 22].

In another study, consuming extracts of this plant could inhibit the progression of cataracts in rats. Total lens proteins glutathione and superoxide dismutase (SOD) levels in the crystalline lens were also significantly preserved. This can be the basis for a new treatment that can prevent cataract progression by suppressing oxidative stress [23]. In addition, it lowers IOP and has anti-oxidant and possible neuroprotective effects. When treated with this extract, IOP was significantly reduced in rabbits with glaucoma, and the concentration of glutathione in the aqueous humor was preserved, proving that the eyes were protected from oxidative damage. So, it has the potential to develop into a drug helpful in the treatment of glaucoma [24].

#### **3. Various effects of alkaloids on the eyes**

#### **3.1 Caffeine**

In modern society, caffeine (C8H10N4O2) is one of the most widely used dietary constituents. Caffeine is an adenosine receptor antagonist and makes a pharmacological effect on various organ systems. The lens progresses to a cataract due to the formation of reactive oxygen species (ROS) by ultraviolet light or diabetes. Caffeine has been shown to protect the lens from oxidative damage in various animal models of cataracts [25–27]. One study has shown that there is a significant negative correlation between coffee consumption and cataract incidence [28]. Given that it reduced the incidence of UV-induced cataracts in animal models, it is thought that caffeine could be an important candidate for future cataract-preventive eye drugs.

It is known that the administration of caffeine induces ocular vasoconstriction in healthy individuals. About 5% of vasoconstriction in the retinal arterioles occurred 1 hour after ingestion of 200 mg of caffeine. How caffeine induces vasoconstriction is not known in detail. Caffeine-induced vasoconstriction may represent autoregulatory myogenic smooth muscle contraction in response to elevated blood pressure. When caffeine was administered, retinal vessel diameter showed a negative correlation with mean arterial pressure, suggesting that it originates from a myogenic response [29]. Caffeine can also induce vasoconstriction by increasing sympathetic tone. Since the choroidal and ciliary circulations receive sympathetic innervation, the increased sympathetic tone may contribute to vasoconstriction of the ocular circulation [30].

#### *Effects and Pharmacological Use of Alkaloids on the Eyes DOI: http://dx.doi.org/10.5772/intechopen.110257*

Controversy has arisen about the increase in IOP after caffeine intake in normal young people, but it has been found that caffeine intake increases IOP in glaucomatous eyes [31]. Caffeine elevates IOP probably because it antagonizes the actions of adenosine, which reduces IOP. Adenosine receptors A1 and A2 are known to induce vasodilation and decrease IOP [32]. Glaucomatous eyes are known to result from damage to the aqueous humor outflow system. Several studies have shown that patients with glaucoma have abnormal vascular reactivity and peripheral microvascular circulation [33]. The action of caffeine can alter the adenosine signaling pathway, leading to differential vascular effects of caffeine in normal and glaucomatous eyes.

For a long time, studies have shown caffeine to be a potential drug for neurodegenerative diseases because of its adenosine-antagonizing properties. Since the retina is also a neurosensory organ and an extension of the brain, there is an opinion that caffeine may play a role in protecting the retina by blocking the adenosine A2A receptor and controlling the reactivity of microglia [34]. In oxygen-induced retinopathy in the mouse model, caffeine intake attenuated hypoxia-induced pathologic angiogenesis and vascular occlusion without interfering with normal retinal vascular development [35]. There are suggestions that the cellular response to hypoxia is extracellular adenosine production and the markedly induced adenosine receptors, which are thought to be novel targets for pathological angiogenesis. Among them, three adenosine receptor subtypes (A1R, A2AR, and A2BR) are expected to play a role [36]. Therefore, it is considered that caffeine can be an important candidate for new drugs for retinal diseases, such as diabetic retinopathy (DR), retinal vascular occlusion, retinopathy of prematurity, and age-related macular degeneration (ARMD), by using the effects of caffeine on the nerve and vascular protection.

#### **3.2 Nicotine**

Cigarette smoking is one of the most common and serious health problems today. Chemical toxicity and free radical-related oxidative damage can affect multiple structures in the body. In particular, nicotine (C10H14N2) is known to cause changes in the conjunctival flora, irritation, redness, dry eye, ocular surface inflammation, and meibomian gland dysfunction. Tear film breakup time is known to decrease, indicating an unstable tear film. As a result, dry eye syndrome can become more severe [37–41]. Although it cannot be limited to that caused by nicotine, it is known that cigarettes have various harmful effects on the eyes. It increases the risk of squamous metaplasia of bulbar conjunctiva and conjunctival intraepithelial neoplasia [39, 42], delays corneal wound healing [43], reduces endothelial cell count or hexagonality of endothelial cells [44, 45], and can lead to cataract formation [46]. Smoking is also known to increase the risk of age-related macular degeneration [47], increase IOP [48], and induce non-arteritic anterior ischemic optic neuropathy (NAION) [49].

#### **3.3 Opiates**

Morphine (C17H19NO3) causes miosis by acting on opioid receptors [50, 51]. The triad of coma, pupillary constriction, and depressed respiration suggests opioid addiction. Morphine abuse can cause downbeat nystagmus, transient disturbances of eye fixation, saccadic intrusions, and oscillations [52]. Intravenous abuse of this drug may cause embolization of the retinal vasculature and may result in endophthalmitis.

#### **3.4 Quinine**

Quinine (C20H24N2O2) was first isolated in 1820 from the bark of a cinchona tree. It has been used as a remedy for malaria since 1632. Quinine is a flavor component of tonic water and bitter lemon drink mixers. Tonic water was initially marketed as a means of delivering quinine to consumers to offer antimalarial protection. Because of the various complications of quinine and resistance to malaria, as of 2006, the World Health Organization no longer recommends it as a first-line treatment for malaria [53].

Chloroquine (C18H26ClN3) and hydroxychloroquine (C18H26ClN3O), derivatives of quinine, were developed and used as antimalarial drugs, but are now widely used to treat connective tissue disorders, such as systemic lupus erythematosus and rheumatoid arthritis. Retinopathy can be caused by the use of hydroxychloroquine and chloroquine, which is a serious complication. This is largely related to the dose, and it is known that the incidence of retinopathy increases when the hydroxychloroquine dose exceeds 5.0 mg/kg or the chloroquine dose exceeds 2.3 mg/kg. Although the mechanisms of chloroquine and hydroxychloroquine retinopathy have not been clarified, these drugs bind to melanin and deposit in the retinal pigment epithelium. They are thought to increase cell lysosomal pH, thereby preventing autophagosomal attachment to lysosomes, and leading to photoreceptor degradation [54].

#### **3.5 Scopolamine**

Scopolamine (C17H21NO4) is an alkaloid used to treat motion sickness and postoperative nausea and vomiting. It was the first drug to be made commercially available in a transdermal therapeutic system delivering alkaloids. It competitively inhibits all four muscarinic receptors (M1, M2, M3, and M4) for acetylcholine and acts as a nonselective muscarinic antagonist, producing both peripheral antimuscarinic properties and central sedative, antiemetic, and amnestic effects [55]. It is used to prevent motion sickness in the form of a transdermal patch. There have been reports of mydriasis and reduced near vision occurring when rubbing the eyes with the hand that touched the patch. There are many reasons for the occurrence of mydriasis, but if there is no specific cause, contamination by scopolamine transdermal patches should also be considered [56].

It was confirmed that continuous systemic administration of scopolamine in rats could induce dry eye due to inflammation of the lacrimal gland by cholinergic blockade induced by scopolamine [57].

#### **4. Alkaloids as candidates for new drugs in ophthalmology**

#### **4.1 Piperine**

Piperine (C17H19NO3) was discovered by Hans Christian Ørsted in 1819, and piperine was isolated from *Piper nigrum*, the source plant of both black and white pepper. Piperine is known to be able to inhibit free radicals and ROS, thereby protecting apoptotic cell death from oxidative damage. In a steroid-induced chick embryo lens model, it was confirmed that piperine exerted an effect as an antioxidant substance and prevented the development of cataracts by reducing the increase in the level of ROS [58].

The effect of piperine was also confirmed to have a protective effect on the retina in a mouse model with diabetic retinopathy. In a hypoxia-induced DR mouse model, intraperitoneal injection of piperine was found to reduce the expression of hypoxiainducible factor-1α and vascular endothelial growth factor (VEGF) A, which are known to have an angiogenic effect [59].

#### **4.2 Matrine**

Matrine (C15H24N2O) is an alkaloid found in *Leguminosae* plants, *including Sophora flavescens Ait*. It is known to have potent antitumor activity by inhibiting tumor cell proliferation through a variety of mechanisms, including inducing cancer cell differentiation and apoptosis, altering the tumor cell cycle, and inhibiting telomerase activity. Antitumor effects of matrine were found in vincristine-resistant retinoblastoma cells. Retinoblastoma is a malignant tumor of the retina and usually affects children under the age of 6 years. Retinoblastoma is a threat to both a child's vision and life. Treatment for retinoblastoma includes chemotherapy, radiotherapy, surgery, laser treatment, and freezing, among which vincristine is the most commonly used chemotherapy. However, resistance to chemotherapeutic agents can lead to treatment failure. When the drug-resistant retinoblastoma cell line was treated with matrine, it was confirmed that the proliferation of tumor cells was suppressed, apoptosis was suppressed, and the cell cycle was arrested. Matrine appears to induce apoptosis by downregulating the protein Bcl-2, which affects the antiapoptotic process. Matrine was also confirmed to regulate the cell cycle of tumor cells by reducing cyclin D1 expression. Matrine may be a potential treatment for vincristine-resistant retinoblastoma [60].

Matrine has been shown to inhibit optic nerve infiltration and demyelination in optic neuritis. Optic neuritis is a condition in which inflammation, demyelination, and axonal injury occur in the optic nerve, resulting in demyelination leading to temporary or permanent loss of vision. Retinal ganglion cells (RGCs) are known to undergo significant loss during apoptosis in optic neuritis. The death of RGCs has been considered the main cause of vision loss after an episode of optic neuritis. It was confirmed that matrine can promote survival by protecting RGCs from inflammation-induced apoptosis. When matrine was injected intraperitoneally in optic neuritis in the experimental autoimmune encephalomyelitis rat model, it was confirmed that the increased numbers of CD4+ T cells and Iba1+ microglia/macrophages in the optic nerves were reduced. Matrine also inhibits the production of proinflammatory cytokines, such as IFN-γ, TNF-α, and IL-17, and blocks the migration of peripheral immune cells. What causes RGCs apoptosis is a shift toward a more proapoptotic ratio in the Bcl-2 family and reduced phosphorylation of protein kinase B (Akt) proteins. Matrine is thought to protect RGCs from apoptosis by shifting the Bcl-2/Bax ratio back to an antiapoptotic one and promoting Akt phosphorylation. Matrine reduced optic nerve inflammation, demyelination, and axonal loss, and protected retinal ganglion cells from inflammation-induced cell death. Thus, matrine shows promise as a novel treatment of optic neuritis, which can lead to blindness [61].

#### **4.3 Vincamine**

Vincamine (C21H26N2O3) is a monoterpenoid indole alkaloid found in the Apocynaceae *Vinca* plant (lesser periwinkle). It is used as a treatment for primary degenerative and vascular dementia. It can improve the metabolism of ischemic tissue and protect the neuron. A recent study demonstrated that vincamine has a potential neuroprotection effect in NAION. Vincamine can rescue the death of retinal ganglion cells and reduce the number of apoptotic cells. The protection of vincamine might play through the phosphoinositide 3-kinases (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) signaling pathway. Therefore, vincamine can be an effective therapy method NAION [62].

#### **4.4 Papaverine**

Papaverine (C20H21NO4) was discovered in 1848 by Georg Merck. Papaverine is a nonselective phosphodiesterase inhibitor and is mainly used for cerebral thrombosis, pulmonary embolism, and arterial spasms by relaxing cardiovascular, respiratory, and gastrointestinal smooth muscles. Recent studies have confirmed evidence that papaverine can protect the optic nerve. Cyclic adenosine 3,5′-monophosphate (cAMP) is known to play an important role in ATP metabolism. It is known that the exogenous addition of cAMP increases the content of synaptic binding protein in axons, promotes the survival of neurons and outgrowth of axons due to nerve injury, and accelerates functional recovery of the central nervous system. Intracellular cAMP levels are regulated by the activity of phosphodiesterase, and phosphodiesterase inhibitors increase cAMP levels by inhibiting the hydrolysis of cAMP. Papaverine regulates the expression of cAMP by inhibiting lipopolysaccharide-induced retinal microglial activation, which plays a role in phagocytosis and secretion of inflammatory mediators by regulating the nuclear factor-kB (NF- kB) and mitogen-activated protein kinase (MEK) /extracellular signal-regulated kinases (ERK) pathways. This was eventually confirmed to induce axonal regeneration of RGCs. This showed potential as a treatment for optic nerve damage, such as glaucoma [63–65].

#### **4.5 Berberine**

Berberine (C20H18NO4 + ) is a natural bioactive alkaloid derived from a variety of Chinese Medicinal herbs, including *Rhizoma Coptidis*. It has been reported with various pharmacological effects, such as anti-inflammation, anti-oxidation, hepatic protection, and anticancer. In a recent study, berberine was found to be effective in insulin-induced diabetic retinopathy. When Akt/mTOR signaling is activated by insulin, the risk of neovascularization in the retina of diabetic animals may increase due to an increase in hypoxia-inducible factor-1α (HIF-1α)/VEGF in retinal endothelial cells. When insulin-induced neovasculature of retina endothelial cells was treated with berberine, it was found to improve insulin-induced DR by inhibiting Akt/ mammalian target of rapamycin (mTOR) activity and reducing the expression of the HIF-1α/VEGF pathway [66].

In addition, studies have shown that berberine can protect the retina from light-induced photoreceptor degeneration. In the light-damaged retina, RPE65 and Mct3 proteins were down-regulated, resulting in photoreceptor damage. It has been shown that the PI3K/AKT/ERK pathway plays a major role in ultraviolet-induced RPE damage. The mice treated with berberine had more photoreceptor nuclei in the outer retina and photoreceptor inner/outer segments and higher RPE65 and Mct3 in the RPE than the control group. Berberine was found to protect against light-induced retinal damage by activating the PI3K/AKT/ERK pathway. This can be considered to show the potential of a drug that can protect photoreceptors from ARMD [67].

#### **4.6 Sanguinarine**

Sanguinarine (C20H14NO4) is a type of benzophenanthridine alkaloid extracted from the root of the herbaceous plant *Sanguinaria canadensis*. It is known to have antimicrobial, anti-inflammatory, anti-oxidative, and tumor-suppressing properties. Sanguinarine has been found to be effective in preventing after-cataracts. Aftercataract refers to the posterior capsule opacification that occurs after cataract surgery and is caused by the regeneration of residual lens epithelial cells. Sanguinarine significantly reduced the viability of human lens epithelial B-3 cells and induced apoptosis. Apoptotic effects probably induce reactive oxygen species generation and promote phosphorylation of c-Jun N-terminal kinase (JNK) and p38 kinases, suggesting that the mitogen-activated protein Kinase (MAPK) pathway is involved in apoptosis. Sanguinarine may be used as a potential drug for after-cataract prevention [68].

Sanguinarine has been shown to have antiangiogenic effects in wet ARMD. A major feature of wet ARMD is choroidal neovascularization, in which pathological neovascularization originating from the choriocapillaris breaks through Bruch's membrane and creates leakage in the subretinal space, resulting in reduced visual acuity. The treatment of wet ARMD is to suppress angiogenesis by administering intravitreal injections of antibodies against VEGF. Intravitreal injection of sanguinarine chloride was performed in the choroidal neovascularization mouse model, and as a result, the formation of choroidal neovascularization was suppressed and the expression of VEGF was reduced. Sanguinarine inhibited VEGF-induced AKT, ERK, and MAPK signaling pathways. Sanguinarine has been suggested as a potential treatment for wet ARMD [69].

#### **4.7 Galantamine**

Galantamine (C17H21NO3) is an alkaloid used as a treatment for Alzheimer's disease, a cognitive disorder. These are the bulbs and flowers of *Galanthus nivalis* (Common snowdrop), *Galanthus caucasicus* (Caucasian snowdrop), *Galanthus woronowii* (Voronov's snowdrop), and some other members of the family *Amaryllidaceae*, such as *Narcissus* (daffodil), *Leucojum aestivum* (snowflake), and *Lycoris,* including *Lycoris radiata* (red spider lily). Galantamine acts as an acetylcholinesterase inhibitor and an allosteric ligand of nicotinic acetylcholine receptors. Recent studies have shown that it also has neuroprotective effects. In one study, galantamine was found to promote the protection of RGCs in a rat glaucoma model. Galantamine-induced ganglion cell survival was caused by the activation of types M1 and M4 muscarinic acetylcholine receptors. This showed the potential of galantamine as a neuroprotectant for glaucoma [70]. A further study by the same authors confirmed that galantamine preserved microvasculature density and improved retinal blood flow in the glaucomatous retina, strengthening the evidence for its neuroprotective effect in glaucoma [71].

#### **5. Conclusions**

Since ancient times, alkaloids have been extracted from natural substances and have various effects on the eyes. Several alkaloids have been used medicinally since that time. Atropine induces mydriasis and has been used for diagnosis and treatment. Physostigmine and pilocarpine were first used as treatments for glaucoma because they constrict the pupil and reduce IOP. Cocaine was used as an ophthalmic anesthetic but is not currently used due to toxicity. However, there are cases where

existing alkaloids are used for new purposes. Recently, atropine has attracted attention as a therapeutic agent that inhibits myopic progression, and pilocarpine has been recognized and used as a treatment for presbyopia.

Alkaloids also had various effects. Caffeine inhibits cataract progression from oxidative damage and reduces hypoxia-induced angiogenesis, but is known to induce an increase in IOP. Nicotine is known to aggravate dry eye syndrome and blepharitis by influencing the ocular surface and to induce the formation of conjunctival tumors and cataracts. Chloroquine and hydroxychloroquine, derivatives of quinine, are drugs widely used in rheumatic diseases, but can cause retinopathy.

Finally, alkaloids are being studied in some studies as new drugs in the field of ophthalmology. Matrine, vincamine, papaverine, and galantamine were newly found to be able to protect the optic nerve, confirming the possibility of developing a treatment for diseases, such as glaucoma or optic neuropathy. In addition, piperine and sanguinarine have been found to be associated with the formation of cataracts. Matrine is expected to be effective in treating vincristine-resistant retinoblastoma. Piperine, berberine, and sanguinarine are expected to be helpful in treating diseases related to retinal neovascularization. They are expected to become therapeutic agents for various ophthalmic diseases in the future.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Acronyms and abbreviations**


*Effects and Pharmacological Use of Alkaloids on the Eyes DOI: http://dx.doi.org/10.5772/intechopen.110257*

### **Author details**

#### Jin-Ho Joo

Department of Ophthalmology, College of Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbu-si, Gyeonggi-do, Republic of Korea

\*Address all correspondence to: oph.jhjoo@gmail.com

© 2023 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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### *Edited by Mithun Rudrapal*

Drug repurposing (or drug repositioning) is defined as the process of identifying new pharmacological indications of old, existing, investigational, or FDA-approved drugs for use in the treatment of diseases other than the drugs' original intended therapeutic use. *Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery* delivers up-to-date information on the identification of newer uses, molecular mechanisms, and novel targets of existing drug candidates through the application of various experimental, biophysical, and computational approaches and techniques. Chapters discuss recent advances in drug repurposing strategies that are currently being used in the discovery and development of drugs against difficult-to-treat, rare, and life-threatening diseases, including microbial infections, COVID-19, parasitic diseases, cardiovascular diseases, neurological disorders, and cancer. The book also discusses the modern experimental assays (HTS) and computational techniques including informatics and databases, molecular docking and dynamics, artificial intelligence and machine learning, virtual screening and pharmacophore modeling, proteomics and metabolomics, and network pharmacology and systems biology approaches. Some of the key features of the book are:


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Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery

Drug Repurposing

Advances, Scopes and Opportunities

in Drug Discovery

*Edited by Mithun Rudrapal*