*2.1.1.1 True alkaloids*

These alkaloids are produced from amino acids and share a heterocyclic ring containing nitrogen. They are biologically active and extremely reactive. They generate water-soluble salts, and many of them are crystalline, forming a salt when conjugated with acid. Except for nicotine, which is a dark liquid, almost all genuine alkaloids have a bitter taste and are solid [15]. Their presence in plants takes three forms: (a) free-state, (b) N-oxide, or (c) salts. Various amino acids like l-phenylalanine, l-tyrosine, l-ornithine, l-histidine, l-lysine, and other amino acids are the main sources of true alkaloids (**Table 1**) [16]. The most prevalent genuine alkaloids found in nature are cocaine, morphine, and quinine.


#### **Table 1.**

*Amino acid and their involvement in alkaloid synthesis.*


#### **Table 2.**

*Involvement of parent compound in pseudoalkaloids synthesis.*

#### *2.1.1.2 Proto alkaloids*

This class of alkaloids has a nitrogen atom obtained from an amino acid but does not belong to the heterocyclic ring system. The major precursors of these categories of alkaloids are l-tryptophan and l-tyrosine. This small category structurally consists primarily of simple alkaloids. The primary alkaloids in this category include yohimbine, mescaline, and hordenine. They are used to treat a variety of medical conditions, including mental illness, pain, and neuralgia [17].

#### *2.1.1.3 Pseudo alkaloids*

Pseudoalkaloids' fundamental carbon skeleton is not generated directly from amino acids. Instead, they are linked to amino acid pathways, where they are produced from forerunners or postcursors of amino acids via amination or transamination processes [16, 18]. Pseudoalkaloids can also be produced by nonamino-acid precursors. They can be generated from phenylalanine or acetate. Pseudoalkaloids are commonly found in capsaicin, caffeine, and ephedrine (**Table 2**).

#### *2.1.2 Classification established upon the ring structure*

Based on the existence of a fundamental heterocyclic nucleus in their structure, this is the most fully recognized categorization.

#### *2.1.2.1 Tropane alkaloid*

The tropane (C4N skeleton) nucleus characterizes this class of alkaloids. They are plentiful in the Solanaceae family. They are created by combining ornithine with acetoacetate. Pyrolines are the structural precursors of these alkaloids. The majority of them are mono, di, and trihydroxytropane esters with a variety of hydroxylation configurations. Cocaine, atropine, scopolamine, and their derivatives have been

*Secondary Metabolites: Alkaloids and Flavonoids in Medicinal Plants DOI: http://dx.doi.org/10.5772/intechopen.108030*

extensively researched since the nineteenth century because of their significant pharmacological activities [19–21] (**Figure 1A**).

#### *2.1.2.2 Pyrrolizidine alkaloids*

The pyrrolizidine nucleus distinguishes this class of alkaloids. They are found in plants of the Asteraceae and Fabaceae families. The majority of pyrrolizidine alkaloids are found in plants as N-oxides; senecionine is the most well-known alkaloid of this kind (**Figure 1B**) [22–27].

#### *2.1.2.3 Piperidine alkaloids*

The fundamental ring system of this category of alkaloids is the piperidine nucleus. True piperidine alkaloids are distinguished by the presence of monocycle molecules with the C5N nucleus. Piperidine alkaloids are distinguished by the presence of odor. They cause long-term neurotoxicity. Many of them evolved from plants. Lobeline is an important alkaloid in this class (**Figure 1C**) [28].

#### **Figure 1.**

*(A) Basic structure of the tropane nucleus, (B) basic structure of the pyrrolizidine nucleus, (C) basic structure of the piperidine nucleus, (D) basic structure of the quinoline nucleus, (E) basic structure of the isoquinoline nucleus, (F) basic structure of the indole nucleus, (G) basic structure of the steroidal alkaloid nucleus, (H) basic structure of the imidazole nucleus, (I) basic structure of the purine nucleus, (J) basic structure of the pyrrolidine nucleus.*

#### *2.1.2.4 Quinolines alkaloids*

This quinolone-nucleus-containing alkaloid can only be obtained from the bark of the Cinchona plant. However, many simple heteroaromatic quinolines have been identified from diverse marine sources (4,8-quinolinediol from cephalopod ink and 2-heptyl-4-hydroxyquinoline from a marine pseudomonad). Cinchonine, Cinchonidine, Quinine, and Quinidine are the primary alkaloids in this category (**Figure 1D**) [29, 30].

#### *2.1.2.5 Isoquinoline alkaloids*

Isoquinoline alkaloids are a diverse category of alkaloids found mostly in higher plants. However, only a few classes of isoquinolinoid marine alkaloids exist. These alkaloids offer a wide range of therapeutic effects, including antiviral, antifungal, anticancer, antioxidant, antispasmodic, and enzyme inhibitor activities. Morphine and codeine are the most well-known and researched isoquinoline alkaloids. They are made from either tyrosine or phenylalanine. They are created by combining a precursor of dopamine (3,4-dihydroxytryptamine) with a ketone or aldehyde. This group of alkaloids is further classified as follows: Simple isoquinoline alkaloids (e.g., salsoline, mimosamycin), benzyl isoquinoline alkaloids (e.g., reticuline, imbricatine), bisbenzyl isoquinoline alkaloids (e.g., fumaricine), manzamine alkaloids (e.g., manzamine a), pseudo benzyl isoquinoline alkaloids (e.g., polycarpine, ledecorine),

Seco bisbenzyl isoquinoline alkaloids (e.g., baluchistanamine), bis benzyl isoquinoline alkaloids containing one ether link (e.g., dauricine), bis benzyl isoquinoline alkaloids containing two ether links (e.g., berbamine), bis benzyl isoquinoline alkaloids containing aryl links only (e.g., pisopowetine), bis benzyl isoquinoline alkaloids containing one aromatic link and one or two ether links (e.g., rodiasine) (**Figure 1E**) [31].

#### *2.1.2.6 Indole alkaloids*

This is the most significant and intriguing alkaloid group produced from tryptophan. Simple tryptamine derivatives, carbazoles (where the ethanamine chain has been removed), a variety of alkaloids with one or more prenyl residues mixed with tryptamine, and others with the integration of typical monoterpenoid or diterpenoid units are examples of notable alkaloids from this category. Although structural diversity differs depending on the terrestrial and marine sources, traditional research investigations on alkaloids from both sources and the fungal source have been conducted. Polyhalogenation is a characteristic of these alkaloids. They are further classified as follows: simple indole alkaloids (e.g., Aplysinopsin, Gramine), bisindoles (e.g., Indirubin, 6,6′-dibromoindigotin), simple tryptamine alkaloids (e.g., tryptamine), cyclotryptamine alkaloids (e.g., Physostigmine), quinazolinocarbazole alkaloids (e.g., Rutaecarpine), β-carboline alkaloids (e.g., Harman), carbazole alkaloids (e.g., ekeberginine), indolonaphthyridine alkaloids (e.g., Canthin-6-one), ergot alkaloids (e.g., ergotamine) (**Figure 1F**) [32–38].

#### *2.1.2.7 Steroidal alkaloids*

The 1,2-Cyclopentane phenanthrene ring structure is unique to this class of alkaloids. They are mainly derived from higher plants of the Liliaceae, Solanaceae, Apocynaceae, and Buxaceae families, although some have also been isolated from

#### *Secondary Metabolites: Alkaloids and Flavonoids in Medicinal Plants DOI: http://dx.doi.org/10.5772/intechopen.108030*

amphibians. These alkaloids are further subdivided into several subtypes, the most basic of which are various forms of aminopregnanes. The others types of steroidal alkaloids are Salamandra type (e.g., cyclo neosamandione), jerveratrum type (e.g., jervine), spirosolane type (e.g., soladulcidine), solanidine type (e.g., rubijervine), cerveratrum type (e.g., 3,6-cevanediol), conanine type (e.g., didymeline), Buxus type (e.g., cyclobuxine), pregnane type (e.g., 20α-dimethylamino-3β-senecioylamino-16βhydroxy-pregn-5-ene), cephalostatins/ritterazines (e.g., ritterazinesa), miscellaneous steroidal alkaloids (e.g., bufotoxin) (**Figure 1G**) [39–43].

#### *2.1.2.8 Imidazole alkaloids*

This class of alkaloids is distinguished by its imidazole ring structure. Because the imidazole ring of these alkaloids is already formed at the precursor stage, they are exempt from the structural transformation operation. This class of alkaloids includes several structurally distinct instances, notably among marine and microbial alkaloids. They exhibit a diverse range of biological activity as well as great medicinal promise. Pilocarpine is the most important imidazole alkaloid in medicine (**Figure 1H**) [44, 45].

#### *2.1.2.9 Purine alkaloids*

Purine is a nitrogenous nucleotide (a building unit of DNA and RNA) that consists of a purine ring, pentose sugar, and another base, pyrimidine. Purine alkaloids include caffeine, theophylline, and theobromine. They are well-known as plant alkaloids, but they may also be found in marine species as substituted purines (e.g., Phidolopin) and a variety of terpenoid-purine alkaloids, including the age lines and others (**Figure 1I**) [46, 47].

#### *2.1.2.10 Pyrrolidine alkaloids*

The fundamental nucleus of pyrrolidine alkaloids is pyrrolidine (C4N skeleton). Plants have a large number of pyrrolidine alkaloids. Some examples of this class of alkaloids are Hygrine (biosynthesized from ornithine), Ficine (where the pyrrolidine ring is associated with a flavone nucleus), and Brevicolline (where it is coupled to a ß-carboline unit) (**Figure 1J**) [48].

#### *2.1.3 The biological activity of alkaloids*

Plant secondary metabolites are a broad group of physiologically active compounds with a variety of pharmacological activities such as antibacterial, stimulant, analgesic, anthelmintic, anticoagulant, antiacne, and antioxidant [49, 50]. For many millennia, humans from practically every culture have used plant-derived substances to predict and manage a variety of health problems.

#### *2.1.3.1 The biological activity of indole alkaloids*

The most important indole alkaloids are reserpine (an antihypertensive agent) from Rauvolfia serpentine [51] vinblastine and vincristine (an anticancer lead) from Catharanthus roseus [52]. Other indole alkaloids have important and powerful pharmacological activity such as antibacterial, antifungal, CNS stimulant, and antiviral properties. They have antiparasitic, cytotoxic, serotonin and antagonistic realms, anti-inflammatory, and antiviral properties [53]. This unique class of phytochemicals has a variety of medicinal and pharmacological properties, which will be addressed in this section.

#### *2.1.3.1.1 Anti-cancer activity*

The vinca alkaloids, vincristine, and vinblastine have mostly been employed as chemotherapeutic agents in cancer therapy. They possibly limit the development of several cancer cell lines, such as neuroblastoma cells in mice, human leukemia HL-60 cells, HeLa cells, S49 lymphoma cells from mice, and IC50 values for mouse leukemia L1210 cells were 33 and 15 nM, respectively. 4.1 and 5.3 nM, 1.4 and 2.6 nM, 5 and 3.5 nM, 4.4 and 4.0 nM, respectively. The cytotoxic activity of vinca alkaloids (vincristine and vinblastine) is mostly related to the disruption of mitotic spindle construction via interactions with tubulin in the microtubules that compose the mitotic spindles, resulting in metaphase arrest [54–58].

Vallesiachotamine (derived from the leaves of Palicourea rigida) exhibits substantial anticancer efficacy against human (SK-MEL-37) melanoma cells via an apoptotic mechanism [59]. Eudistomin K (derived from the Caribbean ascidian Eudistoma olivaceous) is an indole alkaloid with a new oxathiazepine ring that is an anti-tumor in L-1210, A-549, HCT-8, and P-388 cell lines [53]. Topsentin (discovered from the Caribbean deep-sea sponge Spongosorites ruetzleri) has in vitro cytotoxic effect against P-388 with IC50 of 3.0 and 20 μg/mL for human tumor cells, respectively (HCT-8, A-549, and T47D). At concentrations of 150 mg/kg and 37.5 mg/kg, the drug also exhibits in vivo anticancer efficacy against P-388 (T/C 137 percent) and B16 melanoma (T/C 144 percent) [53]. Dragmacidin D, a bis (indole)-derived sponge metabolite (isolated from the sponge Spongosorites sp. Dragmacidin D), has anticancer activity in vitro against P-388 and A-549, with IC50 values of 1.4 and 4.4 μg/mL, respectively [53]. Gelliusines A and B (derived from the deep-water New Caledonian sponge Gellius or Orina sp.) showed anticancer efficacy against KB, P-388, P-388/dox, HT-29, and NSCLCN-6 cell lines, with IC50 values ranging from 10 to 20 μg/mL [53, 60]. Kapakahine B, a peptide derived from the marine sponge Cribrochalina olemda, has shown promising anticancer activity against P-388 murine leukemia cells, with an IC50 value of 5.0 μg/mL [53]. Convolutamydine A (derived from the marine bryozoan Amathia convolute) has shown anticancer efficacy against HL-60 (human promyelocytic leukemia cells). At concentrations ranging from 0.1 to 25 μg/mL, this indole alkaloid alters culture plate adherence, produces growth arrest, and stimulates phagocytosis [53].

#### *2.1.3.1.2 Anti-oxidant activities*

The DPPH radical-scavenging test revealed that reserpine inhibits the DPPH radical by 42%. Lind et al. investigated the antioxidant activity of Barettin using two distinct biochemical tests, FRAP (Ferric-Reducing Antioxidant Power) and ORAC (Oxygen Radical Absorbance Capacity). According to their findings, Barettin has a possible antioxidant profile that is dose-dependent. Barettin showed FRAP and ORAC values of 77 and 5.5 μM Trolox equivalents (TE) at a concentration of 30 μg/mL, respectively [61].

#### *2.1.3.1.3 Anti-hypertensive activities*

Reserpine is widely used as first-line therapy in the treatment of primary hypertension. A reserpine dosage of 0.5 mg/day or higher resulted in statistically significant

### *Secondary Metabolites: Alkaloids and Flavonoids in Medicinal Plants DOI: http://dx.doi.org/10.5772/intechopen.108030*

SBP (systolic blood pressure) effects [62]. The fundamental mechanism of reserpine's antihypertensive activity is that it lowers the levels of catecholamines in peripheral sympathetic nerve terminals. Reserpine has a greater affinity for VMAT2 (vesicular monoamine transporter), binds to their receptors irreversibly, and inhibits VMAT2 irreversibly [63]. VMATS transports released and liberated nor-adrenaline or norepinephrine, dopamine, and serotonin (5-HT) from the presynaptic nerve terminal cytoplasm into storage vesicles for subsequent release into the synaptic cleft [64, 65]. Reserpine has a greater affinity for VMAT2 and binds to their receptors permanently. It is an effective antihypertensive and sedative, but long-term use promotes prolactin secretion and causes breast cancer.
