Naturally Isolated Pyridine Compounds Having Pharmaceutical Applications

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.

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. Pyridine-based natural products consist of a variety of interesting compounds with diverse 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].

Figure 1.

Nicotine, niacin, and pyridoxine.

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 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 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].

Figure 2.

Effect of pyridine on physiochemical parameters.

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].

Figure 3.

Some commercially available drugs which contain pyridine rings.

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 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, 28, 29, 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].

Figure 4.

Terpenoid-based alkaloids.

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 5.

2-Pyridone derivatives isolated from the different plant 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, 40, 41].

Figure 6.

Fusaric acids from the mycelium species.

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]

(-)-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].

Figure 7.

Isolated from the culture extract of Kitasatospora sp. IFM10917.

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 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].

Figure 8.

Pyridine-type alkaloids isolated from Vinca major.

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

Figure 9.

New compounds obtained from the aerial parts of C. mongolica.

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 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.

Figure 10.

Poisonous compounds isolated from the skin of amphibians.

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).

Figure 11.

Isolated and semisynthetic compounds of camptothecin.

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.

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].

Figure 12.

Berberine, papaverine, and ellipticine.

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.

Acknowledgments

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.