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Back to Journal »Drug Design, Development and Treatment» Volume 15
The role of pyridine and dihydropyridine stents in drug design continues to expand
Authors: Ling Y, Hao Ziyuan, Liang D, Zhang CL, Liu Yifeng, Wang Y
Published on October 13, 2021, the 2021 volume: 15 pages 4289-4338
DOI https://doi.org/10.2147/DDDT.S329547
Single anonymous peer review
Editor approved for publication: Professor Manfred Ogris
Yong Ling,1 Hao Zhiyou,2 Liang Dong,3 Zhang Chunlei,4 Liu Yanfei,5 Wang Yan6,7 1 Department of Pharmacy, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province; 2School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan; 3Guangxi Normal University State Key Laboratory of Medicinal Resources Chemistry and Molecular Engineering, School of Chemistry and Pharmacy, Guilin, Guangxi; 4 State Key Laboratory of Natural Medicines, School of Chinese Materia Medica, China Pharmaceutical University, Jiangsu Key Laboratory of Evaluation and Translational Development of Traditional Chinese Medicine, Nanjing, Jiangsu; 5 China Academy of Medical Sciences, Institute of Materia Medica, Peking Union Medical College, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines; 6HEJ Institute of Chemistry, International Center for Chemistry and Biological Sciences, Karachi University, Karachi, Pakistan; 7 Food Science and Technology Research, Chinese Academy of Agricultural Sciences Institute, Beijing, People’s Republic of China Address: Yan Wang HEJ Institute of Chemistry, International Center for Chemistry and Biological Sciences, Karachi University, Karachi 75270, Pakistan Tel 92 21 111 -222-292 ext 164 Fax 92 21 34819018-9 Email [email protected] Abstract: Pyridine-based ring systems are one of the most widely used heterocycles in the field of drug design, mainly due to their profound influence on pharmacological activities, which has led to the discovery of many broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved drugs derived from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), and abiraterone acetate ( Prostate cancer), tacrine (Alzheimer’s disease), ciclopirox (tinea and athlete’s foot), crizotinib (cancer), nifedipine (Raynaud’s syndrome and preterm birth), piroxicam ( NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), etc. Their extraordinary therapeutic applications encourage researchers to prepare a large number of bioactive compounds modified with pyridine or dihydropyridine, expanding the scope of finding treatments for other diseases. Therefore, it is expected that countless new drugs containing these two heterocycles will come out in the next ten years. This review examines the prospects of highly effective bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the latest developments from 2010 to the present, highlighting the expanding role of these two stents in the fields of medicinal chemistry and drug development. Keywords: nitrogen heterocycles, drugs, biologically active compounds, trends, substitution effects
The basic processes of heterocycles and life are intricate and play a vital role in the pharmaceutical and agrochemical industries. 1 In terms of pharmacological, physicochemical, pharmacokinetic and toxicological properties, heterocyclic structures have been found in more than 90% of newly synthesized and marketed drugs. 2 Medicinal chemistry is developed from empirical practices that involve synthesizing new substances and then measuring their biological activity. 3 A large number of synthetic compounds with heterocyclic structure frameworks—the privileged six-membered nitrogen-containing pyridine and dihydropyridine rings—connect 4-7. In the field of six-membered heterocyclic structures, they have unique and interesting properties. Due to its therapeutic potential, medicinal chemists have recently begun to use stents to synthesize various new types of bioactive molecules. 8
Among drug targets, pyridine and its precursor molecule, dihydropyridine, are one of the most common structural units. 9,10 In plants, they are mainly found in alkaloids. 11 In biological systems, the redox reaction of nicotinamide adenine dinucleotide (NAD) reduces its pyridine ring and converts it into dihydropyridine to generate NADH. Similar redox reactions also exist in anabolic reactions involving the mutual conversion of NAD phosphate (NADP /NADPH). 12 The US Food and Drug Administration (FDA) database shows that pyridine and dihydropyridine-containing drugs account for nearly 14% and 4%, respectively. N-heterocyclic drugs approved by the agency (Figure 1). For these 18% of drugs, the main therapeutic areas of concern are infectious diseases, inflammation, nervous system and oncology. Figure 1 The distribution of N-heterocyclic drugs in the FDA database.
Figure 1 The distribution of N-heterocyclic drugs in the FDA database.
Analysis of the substitution type of pyridine-containing drugs showed that the ring in the database is mainly mono-substituted (60%), while the two, three, and four substitutions represent 22%, 12%, and 6%, respectively (Figure 2A). For drugs containing dihydropyridine, no single or double substitution of N-heterocycles was observed. However, the tri-substitution of the dihydropyridine ring is the most abundant type of substitution in this class of drugs. The four, five, and six substitutions on the N-heterocycle are 11%, 21%, and 5%, respectively (Figure 2B). Figure 2 Analysis of alternative types of FDA-approved drugs containing pyridine (A) and dihydropyridine (B).
Figure 2 Analysis of alternative types of FDA-approved drugs containing pyridine (A) and dihydropyridine (B).
In recent years, synthetic chemists have been committed to developing new analogs using pyridine or dihydropyridine templates in molecular design to study their mechanism of action to discover new drug leaders. The importance of these two heterocyclic compounds in medicinal chemistry and chemical science can be seen in the numerous publications published between 2010 and 2020 (Figure 3). Figure 3 Publications on pyridine and dihydropyridine compounds, 2010–2020 (source: Scopus and SciFinder).
Figure 3 Publications on pyridine and dihydropyridine compounds, 2010–2020 (source: Scopus and SciFinder).
Most of the comments on this subject are related to synthetic strategies for the preparation of pyridine- or dihydropyridine-containing compounds. 2,10,13–16 For any of these two stents, one can also find many reviews describing their therapeutic potential for specific diseases. 17-28 Most reviews on pyridine-containing compounds only study their anti-cancer potential. 21,22 Similarly, some reviews of dihydropyridine-containing compounds usually scrutinize their ability to block calcium channels in the treatment of hypertension and related diseases. 19,24,26-28 The neuroprotective ability of dihydropyridine derivatives has also been tested. 23 Lapidot et al. summarized the antibacterial activity of peptide mimics containing dihydropyridines. 25 For substituted 1,4-dihydropyridines, drug versatility and predictable therapeutic effects have been the focus of past reviews. 29 –31 For example, Khedkar et al. briefly discussed the pharmacological importance of such molecules. 30 Best to the best of our knowledge, a review of the therapeutic potential of pyridine and dihydropyridine compounds has never been published. Here, we introduce commercially available drugs and discuss the main therapeutic potential of synthetic bioactive molecules with either of the two stents. This review covers a considerable period of time in the scientific literature, including publications from 2010 to the present, and thus provides a broad picture of the approved drugs and the reported biological activities of pyridine or dihydropyridine compounds. For people interested in exploring this type of compound, it is a valuable material for further medical and clinical applications.
When creating compound libraries with different functional groups to screen different biological targets, pyridine and dihydropyridine have multiple uses. Many natural products contain pyridine-based rings (Figure 4), including vitamins (niacin and vitamin B6), coenzymes (NAD, NADP), alkaloids (trigonelline, [–]-ethylene oxide, []-anabasine , Huperzine A, paecilomide, cystine), antibiotics (nikkomycin, clomycin) and many more compounds. 11 Figure 4 Pyridine and dihydropyridine ring systems in natural products with important medicinal value.
Figure 4 The pyridine and dihydropyridine ring systems in natural products with important medicinal value.
In medicine, nitrogen-containing heterocycles are considered to be instrumental structural components. 32 The presence of the pyridine or dihydropyridine ring system can have a significant impact on the pharmacological characteristics of drugs and biologically active molecules. 33 For example, the pyridine motif in drugs can improve their biochemical efficacy and metabolic stability, enhance permeability, and solve protein binding problems. 33 Figure 5 highlights some interesting examples of the pyridine effect: Vanotti et al. were able to develop effective Cdc7 kinase inhibitors by substituting pyridine for the phenyl group of 1. 2.34 Similarly, thioureidonicotinamide phosphoribosyltransferase inhibitors The metabolic stability of 3 is increased by 160 times when its terminal benzene ring is replaced by pyridine. 4.35 The heterocyclic pyridine ring in the molecule can also enhance its cell permeability. For example, Doller et al. identified a positive allosteric modulator 6 containing pyridine, which has a cell permeability of 190 times that of 5.36. It is used for the treatment of schizophrenia. The protein binding problem of positive allosteric modulator 7 passed 8.37. It can be said that the substitution of nitrogen-containing heterocycles profoundly affects the physical and chemical properties of biologically active molecules. 33 Figure 5 The effect of pyridine on key pharmacological parameters.
Figure 5 The effect of pyridine on key pharmacological parameters.
There are a large number of commercially available drugs containing pyridine rings on the market, such as abiraterone for the treatment of prostate cancer, empilovin 38 for the treatment of malaria, empilovin 39 for the treatment of pellagra, nicotinamide for the treatment of pellagra, 40 Respiratory stimulant nicoxamide, 41 piroxicam for arthritis, isoniazid 42 for tuberculosis, 43 pyridostigmine is used for the treatment of myasthenia gravis, 44 toppicamide is used as an antimuscarinic drug, 45 Doxylamine is used for allergies, 46 omeprazole is used for ulcers, 47 delavirdine is used as an anti-HIV/AIDS virus drug, 48 ammonium iodide is used for influenza, 49 and tacrine are used as AChE enzyme inhibitors 50 diseases Prevention (Figure 6). Figure 6 Some commercially available drugs containing pyridine stents.
Figure 6 Some commercially available drugs containing pyridine stents.
Drugs containing dihydropyridine rings are mainly used as calcium channel blockers, 51 and are often used to treat high blood pressure and heart-related problems. 52 Such drugs include nilvadipine, nifedipine, amlodipine, azenidipine, clevidipine, felodipine, and pradipine. Some of these drugs are also used to treat many other therapeutic diseases. 53 For example, nifedipine is used to treat Raynaud’s syndrome and preterm birth. 54 Huperzine containing dihydropyridine is a natural product that can be used as an AChE inhibitor and used to treat Alzheimer’s disease, while ciclopirox is widely used as an antifungal agent to treat ringworm and tinea pedis (Figure 7). Figure 7 Some commercially available drugs containing dihydropyridine stents.
Figure 7 Some commercially available drugs containing dihydropyridine stents.
Milrinone and Amrinone are two commercially available vasodilators, 55 containing both pyridine and dihydropyridine ring systems in their structure (Figure 8). Generally speaking, drugs containing pyridine and dihydropyridine are mainly used as antibacterial, antiviral, anticancer, antioxidant, antihypertensive, antidiabetic, antimalarial and antiinflammatory drugs, psychopharmacological antagonists and antiamebic drugs . 56-62 A comprehensive list of commercially available drugs containing pyridine and/or dihydropyridine stents and their mechanisms of action are summarized in Table 1. Table 1 Commercially available drugs containing pyridine and/or dihydropyridine and their applications Figure 8 FDA-approved vasodilators containing pyridine and dihydropyridine stents.
Table 1 Commercially available pyridine and/or dihydropyridine-containing drugs and their applications
Figure 8 FDA-approved vasodilator containing pyridine and dihydropyridine stents.
The analysis of the substitution pattern in FDA-approved drugs shows that the 1,4-dihydropyridine ring in the drug is mainly substituted at the para position (4). Two di-substitutions at the ortho position (2 and 6) were observed in 11 drugs, while one drug had a single substitution at the ortho position (2). Similarly, three drugs have a single substitution at the meta position (3), while ten drugs have a double substitution at the meta position (3 and 5) of the 1,4-dihydropyridine ring. For brevity, Figure 9 illustrates the substitution pattern of pyridine and dihydropyridine ring systems in FDA-approved drugs. Figure 9 Analysis of substitution patterns of pyridine and dihydropyridine in FDA-approved drugs.
Figure 9 Analysis of substitution patterns of pyridine and dihydropyridine in FDA-approved drugs.
In terms of treatment, pyridine and dihydropyridine-containing compounds have a variety of biological activities, so they are part of many drugs. The literature reveals many examples in which such compounds show promising pharmacological properties.
Hypertension is one of the main risk factors for cardiovascular disease. Many different types of antihypertensive drugs are used to treat this problem. The main categories of such drugs include α- and β-adrenergic inhibitors, renin inhibitors, vasodilators, diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors, etc. (Figure 10). Torsemide containing pyridine is a drug approved by the FDA to promote diuresis, thereby lowering the blood pressure of patients. Amrinone and milrinone, which contain pyridine and dihydropyridine, are β-adrenergic blockers, also known as β-blockers, which can help control high blood pressure through vasodilation, and ultimately make The patient was saved from a second heart attack. Interrupting calcium movement through cell channels is another strategy to lower blood pressure. Most calcium antagonists in the FDA database contain dihydropyridine scaffolds, and a five-ring substitution pattern was observed (Figure 11). Figure 10 The dodecylpyridinium moiety of dihydropyridine with strong calcium antagonism in the A7r5 cell line. Figure 11 Drugs containing pyridine or dihydropyridine stents approved by the FDA for the treatment of hypertension.
Figure 10 The dodecylpyridinium moiety of dihydropyridine with strong calcium antagonism in the A7r5 cell line.
Figure 11 Drugs containing pyridine or dihydropyridine stents approved by the FDA for the treatment of hypertension.
In 2014, Rucins et al. synthesized N-propargyl substituted derivatives of 1,4-DHP derivatives. They incorporated the pharmacophore part into their structure and studied their calcium channel blocking activity. In SH-SY5Y neuroblastoma cells (containing L-type and N-type Ca2 channels) and A7r5 cells (they are rat aortic muscle cells expressing L-type Ca2 channels), and the newly synthesized compounds have an effect on intracellular calcium The effect of concentration [Ca2] was studied. In this series, compounds 9 and 10 with n-dodecylpyridinium moiety as an amphiphilic group were found in SH-SY5Y neuroblastoma cells (IC50 = 5-14 mM) and A7r5 cell lines (IC50 = 0.6 -0.7 mM) showed the strongest calcium antagonistic activity). These compounds show moderately effective antioxidant activity. At a dose equivalent to that used to block L-type calcium channels, Compound 10 had no effect on mitochondrial function, and no damage was observed in vivo. Therefore, the compound can be considered safe at up to 100 mg/kg and is non-toxic. It has been observed that the propargyl group on the 1,4-DHP ring has no significant effect on the biological activity of the tested derivative. Therefore, compounds with a n-dodecylpyridinium moiety in the para position (Figure 11) may be the lead molecules for subsequent modification and in vivo studies of cardiovascular and neurological diseases. 176
Nitrendipine 11 is a DHP type calcium antagonist with a simple structure but low potency. The antihypertensive effect of nitrendipine analogs can be improved by increasing the length of the 3- or 5-position alkyl chain. 177,178 Zhou et al. synthesized nitrendipine analogs and evaluated their antihypertensive properties in spontaneously hypertensive rats by intravenous injection of immunoglobulin. The S- and R-enantiomers have different calcium antagonistic activities in various studies179. It was found that the antihypertensive properties of the S-enantiomer were 100 times that of the R-enantiomer (Figure 12). In addition, the effect of nitrendipine analogs is further enhanced by extending the carbon chain length. These findings indicate that the length of the alkyl chain at position 5 is closely related to the antihypertensive effect of nitrendipine analogs. The antihypertensive effect of DHP is weakened by the 5-position ultra-long or ultra-short alkyl chain. At position 5 of DHP, an alkyl chain containing seven carbon atoms is the most suitable length. Therefore, for 5-n-heptyl-3-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate [(±)-12]. Comparing the antihypertensive effects of (±)-12 and -12, the -isomer is 1.79 times more potent than the racemate at a dose of 2 mg/kg. 180 Figure 12 High-potency calcium channel antagonist.
Figure 12 High-potency calcium channel antagonist.
Zarghi et al. also studied the calcium channel antagonistic activity of the phenylaminoimidazole group with 1,4-dihydropyridine. His research group substituted the 2-methylthio-1-phenylamino-5-imidazolyl substituent for the o-nitrophenyl group in the para position of nifedipine. Then, calcium channel antagonist activity (IC50) was measured in guinea pigs, which indicated that the contractile response caused by these novel dihydropyridine-containing compounds inhibited the higher K concentration in a dose-dependent manner. In the sarcolemma, these effects are comparable to those shown by nifedipine, possibly due to the inhibition of Ca2 entry through voltage-dependent calcium channels. However, it should be pointed out that the intestine has a complex tissue network, and we cannot rule out the possibility that these compounds have different effects on different muscles and neurons. The comparison of the activity of the alkyl ester series in these compounds shows that by increasing the chain length of the methylene group at the C3 and C5 ester substituents, the activity decreases. For example, compounds containing tert-butyl esters are the least active in this series. The overall results show that, except for the two compounds 13 and 14 that are more active than nifedipine, most of the compounds have the same activity as nifedipine (Figure 13). Therefore, they can be potential clues for the design of calcium channel blockers. 181 Figure 13 Calcium channel antagonist.
Kumar et al. reported the anticoagulant activity of compounds containing dihydropyridine, which was evaluated using activated partial thromboplastin time and prothrombin time coagulation assays. The clotting time of compound 15 (Figure 14) at 30 mg/mL was 720.35 seconds. The standard drug heparin is used in similar concentrations. 182 Figure 14 N-aryl-1,4-dihydropyridine containing thiosemicarbazide.
Figure 14 N-aryl-1,4-dihydropyridine containing thiosemicarbazide.
Dyslipidemia is a complex disease that can cause atherosclerosis and cardiovascular problems. 183 In 2001, the pyridine-containing drug cerivastatin was withdrawn from the market due to the risk of rhabdomyolysis. Later, another drug in the statin class, pitavastatin, was developed to lower blood cholesterol (Figure 15). Figure 15 Statins cholesterol-lowering drugs.
Figure 15 Statins cholesterol-lowering drugs.
In 2016, a (benzoylphenyl)pyridine-3-carboxamide type anti-hyperlipidemic compound was reported (Figure 16), and 16-17 showed excellent in vivo activity. 184 The anti-dyslipidemia activity of these compounds was tested in vivo. Figure 16 Anti-hyperlipidemia (benzoylphenyl) pyridine-3-carboxamide compound.
Figure 16 Anti-hyperlipidemia (benzoylphenyl) pyridine-3-carboxamide compound.
These compounds can reduce total cholesterol (TC) from 11.0% to 24.8%. These compounds showed a plasma phospholipid lowering (PL) activity of 5.7% to 28.5%. The most active compound in this series is 17 (-28.5%), while gemfibrozil (39.1% lowering PL activity) is the least active. 100 and 200 mg/mL allopurinol was also used to test the scavenging ability of the compound to prevent the generation of superoxide ions (O2–). The series of compounds have strong antioxidant activity, and compounds with tert-butyl ester functional groups have the strongest activity. Compound 18-22 showed potential anti-dyslipidemia potential, but compound 21-22 showed considerable antioxidant activity (Figure 17). It can be temporarily assumed that the ester group plays a key role in distinguishing anti-dyslipidemia from antioxidant activity. Compounds containing methyl/ethyl ester groups show anti-dyslipidemia potential, while compounds with tert-butyl ester functional groups show antioxidant activity. 185 Figure 17 Cholesterol-lowering compounds containing dihydropyridine ring (18-22).
Figure 17 Cholesterol-lowering compounds containing dihydropyridine ring (18-22).
Although many drugs containing dihydropyridine can be used to treat hypertension, we believe that further research on pyridine-dihydropyridine compounds will lead to the discovery of new drugs to deal with complications related to cardiovascular disease.
Antibiotic resistance is a serious threat to public health and has promoted research on new bacterial inhibitors. Most antibiotics are resistant to bacterial pathogens, which makes the development of new and more effective antibacterial drug candidates a key requirement. In the past 10 years, the FDA has approved many pyridine-containing antibiotics, such as ceftaroline axetil, tedizolamide, ceftazidime, and drafloxacin (Figure 18). Figure 18 Pyridine-containing antibiotics approved by the FDA in the past ten years.
Figure 18 Pyridine-containing antibiotics approved by the FDA in the past ten years.
Jo et al. synthesized a pyridine derivative containing oxazolidinone, which has potent antibacterial activity. In vitro and in vivo antibacterial studies have been conducted on difficult gram-negative and gram-positive bacterial strains and two antibiotic-resistant strains. The pyridine moiety can tolerate several substituted (hetero)aromatic rings, and the presence or orientation of the methyl group in the (hetero)aromatic ring has a profound effect on the antibacterial activity. The most active derivative 23-25 (Figure 19) shows effective activity against a variety of resistant bacteria, Moraxella catarrhalis and Haemophilus influenzae, and has a longer half-life in the body than linezolid. Their in vitro activity is 4-16 times that of linezolid, and their in vivo efficacy is also doubled. 186 Figure 19 Oxazolidinone-pyridine substituted antibacterial agent.
Figure 19 Oxazolidinone-pyridine substituted antibacterial agent.
In another study, oxazolo[4,5-b]pyridine derivatives were synthesized to derive antimicrobial agents. These compounds have excellent activity against methicillin-resistant Staphylococcus aureus, which is responsible for a wide range of hospital-acquired infections. Compared with conventional drugs, compounds 28 and 31 are the most potent, with MIC values of 1.56–25 µg/mL, while 26, 27, 29, 30, 32, and 33 show moderate activity (6.25–50 µg/mL) of Streptomyces And ampicillin (Figure 20). Further studies have shown that oxazolo[4,5-b]pyridine analogs have a stronger effect on Gram-positive bacteria than Gram-negative bacteria. Compounds 28 and 31 have strong activity against methicillin-resistant Staphylococcus aureus, with an activity of 1.56–3.12 µg/mL, while the MIC value of standard drugs (ampicillin and streptomycin) is 6.25–12.5 µg/mL. These compounds have also been found to be active against other bacterial strains. In addition, the synthesized compound is docked in Staphylococcus aureus enterotoxin protein, which is a type A Staphylococcal enterotoxin. Compared with the standard drugs ampicillin and streptomycin, the significant antibacterial activity of 28 and 31 has been further verified by in vitro and computer studies. The compound is then tested for its ligand-protein binding (MRSA protein) affinity to Staphylococcus aureus, where the compound has a higher ligand-protein binding affinity than standard drugs. 187 Figure 20 Oxazolo[4,5-b]pyridine containing antibacterial agent and significant activity.
Figure 20 Oxazolo[4,5-b]pyridine containing an antibacterial agent with significant activity.
New pyrazolo[3,4-b]pyridine derivatives and azetidine-2-ones of 4-thiazolidinone Schiff base have also been synthesized and screened for antibacterial activity. 188 Most compounds show moderate to high activity at 0.12–62.5 µg/mL, among which amphotericin B, ampicillin and gentamicin are used as standard antibacterial agents. Against the fungal strain of Fusarium oxysporum, the MIC of compound 37 is 0.98 µg/mL, which is equivalent to the standard antibacterial drug amphotericin B. These compounds have been observed to have significant cytotoxic activity against HepG2 cell lines, with IC50 of 0.0158-71.3 µM compared to doxorubicin (IC50 = 0.008 µM). Compound 34-38 also has anti-proliferative activity against MCF7 cell line (IC50 = 0.0001-0.0211 µM) (Figure 21). Specifically, compound 37 showed very significant anti-proliferative effects on MCF7 cells and HepG2, with IC50 of 0.0001 µM and 0.0158 µM, respectively. These results indicate that these compounds may contribute to the development of promising new antibacterial and antiproliferative drug candidates. There is no doubt that these compounds have great potential in the development of new anti-proliferative and antibacterial agents. 188 Figure 21 Compounds containing pyrazolo[3,4-b]pyridine have significant effects on various Gram-positive and Gram-negative bacterial strains.
Figure 21 Compounds containing Pyrazolo[3,4-b] pyridine have significant effects on various Gram-positive and Gram-negative bacterial strains.
Dihydropyridine compounds with thiazole derivatives were initially evaluated by computer simulation of molecular docking simulations to study their possible DNA gyrase inhibitory activity. The antibacterial activity was then evaluated to verify the results of the calculation study, in which compound 39 showed the highest efficacy against Aspergillus flavus, while compound 40 had significant efficacy against Candida albicans and Aspergillus flavus (Figure 22). Due to the size and induction of the benzene ring, the presence of electron withdrawing groups may be the reason for the excellent activity. 189 Figure 22 Antibacterial dihydropyridine with thiazole moiety.
Figure 22 Antibacterial dihydropyridine with thiazole moiety.
Lak et al. explored the pyridine ring containing 1,3,4-oxadiazole derivatives. 190 The antibacterial activity of all synthetic compounds against Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Bacillus cereus and Gram-positive bacteria was evaluated and showed greater inhibition than Gram-negative bacteria. active. Most synthetic compounds are very effective against Staphylococcus aureus and Staphylococcus epidermidis. Compounds 41 and 42 have strong antibacterial effects, with excellent MIC and selectivity index values (Figure 23). The focus of this study is the one-step synthesis of oxadiazole-pyridine derivatives. This fully molecularly modified method can be used as a cost-effective strategy to produce potent antibacterial agents. 190 Figure 23 Highly effective antibacterial agent against staphylococcal infection.
Figure 23 Highly effective antibacterial agents against staphylococcal infections.
In another study, a 1,3,4-oxadiazole derivative containing indole and pyridine was synthesized and targeted two Mycobacterium tuberculosis strains-H37Ra and BCG-in dormant and active conditions Under evaluation. Compounds 43-45 showed significant anti-tuberculosis activity (Figure 24). We also tested the anti-proliferative activity of synthetic compounds using modified MTT analysis on HeLa, PANC1 and A549 cell lines. Most are non-cytotoxic. Based on the MIC value and cytotoxicity results, a selectivity index value of 43-45 was determined. They are very effective against Mycobacterium bovis BCG, and the compound index value is ≥10. In addition, molecular docking studies of compounds 43-45 at the active site of enoyl reductase (InhA) were carried out. Encouraging results confirmed by selectivity, potency and low cytotoxicity indicate that these derivatives are potential anti-tuberculosis lead drugs. 9 Figure 24 A highly effective anti-tuberculosis compound (43–45) with an anti-Mycobacterium bovis BCG MIC value (μg/mL).
Figure 24 Highly effective anti-tuberculosis compounds (43–45) with anti-Mycobacterium bovis BCG MIC value (μg/mL).
In the FDA database, you can find many pyridine-containing drugs, such as isoniazid, ethionamide, and prothiazamide, which are very effective in the treatment of tuberculosis mycobacteria (Figure 25). Figure 25 Anti-mycobacterial pyridine-containing drugs.
Figure 25 Anti-mycobacterial pyridine-containing drugs.
Further efforts were made to discover new biologically active compounds, synthesized 2-(1-adamantylthio) pyridine derivatives, and screened for antibacterial activity against 27 strains, antimalarial activity against Plasmodium falciparum, and HepG2, A549, HuCCA1 and MOLT3 cell lines with anticancer activity. The results show that 2-(1-adamantyl)pyridine compounds constitute a new class of antibacterial, antimalarial and anticancer drugs with potential therapeutic applications. All compounds are highly active against streptococci, showing an anti-growth activity of 15-30 µg/mL. Compounds 46-49 are effective antimalarial, anticancer and antibacterial agents (Figure 26). Surprisingly, 6-(1-adamantylthio)nicotinonitrile 49 has selective antibacterial activity against β-hemolytic streptococcus, Edwardsiella tarda, Vibrio parahaemolyticus and Vibrio cholerae. These findings indicate that compound 49 may be a promising antibacterial agent with potential or further improvement in its therapeutic properties. 191 Figure 26 2(1-adamantylthio)pyridine derivative with strong antibacterial activity.
Figure 26 2(1-adamantylthio)pyridine derivative with strong antimicrobial activity.
In short, pyridine-containing compounds have great promise for the development of drugs for drug-resistant bacteria because they have a significant inhibitory effect on pathogens. However, more research is needed to find feasible solutions to drug-resistant pathogens.
The recent increase in multi-drug resistant (MDR) fungal infections has prompted researchers to search for new antifungal agents. The triazolyl derivatives containing pyridine exhibit significant antifungal properties. For example, triazolopyridines containing thiadiazole have been found to have antifungal activity against Pseudoperonospora cubensis, Pseudomonas syringae pv. Lachrymans and Corynespora cassiicola. 192 In 2016, Mu et al. reported a series of triazolopyridine derivatives containing hydrazone, which had significant antifungal activity against dried tomato leaves, Botrytis cinerea and Fusarium oxysporum. 193 In 2019, Wei pyrine et al. designed triazolopyridine derivative rings containing bases and evaluated their in vitro antifungal properties against Phomopsis asparagi, F. oxysporum f. sp. 194 Pyridine grafted chitosan polymer has also been reported to have improved antifungal properties. 195 Pyridine has been grafted onto starch to control different fungi. 196 In conclusion, the fusion of triazole and pyridine derivatives may lead to extensive development. A broad-spectrum antifungal drug against MDR fungal infections.
Heba et al. described a series of new pyridyl-indole hybrids that were designed using fragment-based strategies. These compounds were tested for their antimalarial activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Compound 50-55 (Figure 27) showed the most effective antimalarial activity (IC50 for D6 = 1.47-9.23 μM, IC50 for W2 = 1.16-7.66 μM). The selectivity index value of D6 is 1.47-8.3, and W2 is 1.7-10. Compounds 50, 51 and 54 showed antimalarial activity against D6 and W2. The distinguishing feature of these compounds is that there is no substitution at the C2 position of the pyridine ring. In addition, the binding interaction of these compounds with the quadruple mutant Plasmodium falciparum dihydrofolate reductase was studied through molecular docking studies. Compounds 50-52 have the highest activity in the binding cavity of the active site of the quadruple mutant Pf DHFR-TS, indicating that the appropriate binding association may be the mechanism that affects its activity as an antimalarial drug. 197 Figure 27 Highly active antimalarial pyridine-indole hybrid.
Figure 27 Highly active antimalarial drug pyridine-indole hybrid.
Xue et al. reported that a fosmidomycin derivative containing a pyridine scaffold can inhibit Plasmodium falciparum DXR with a Ki value of 1.9-13 nM. The most effective compound (Figure 28) is 11 times more active than fosmidomycin. 198 Figure 28 Phosphomycin derivatives containing pyridine, a highly effective antimalarial drug.
Figure 28 Phosphomycin derivative of a highly effective antimalarial drug containing pyridine.
We believe that pyridine compounds have great potential for the development of antimalarial drugs because they exhibit antimalarial effects due to the hydrogen bond interaction between the pyridine nitrogen and the cysteine of the target protein in the pathogen. Resistance is very effective. Strain. 198
For the treatment of HIV infection, the FDA database contains many drugs containing pyridine and dihydropyridine, such as nevirapine, tiranavir, doravirin, and indinavir (Figure 29). Figure 29 Pyridine/dihydropyridine-containing drugs used in the treatment of HIV/AIDS on the market.
Figure 29 Pyridine/dihydropyridine-containing drugs used in the treatment of HIV/AIDS on the market.
In the past decade, research on new antiviral drugs has led to the synthesis of pyridotriazines, furanopyridines, and pyridothiadiazepines. 199 Among the synthesized molecules, a few molecules have obvious effects on adenovirus type 7 and rotavirus Wa strain. Compound 56 inhibited the viral titer of rotavirus Wa strain and adenovirus type 7 by 60% and 53.3%, respectively, and compound 57 showed a reduction of 50% and 53.3%, respectively. These compounds (Figure 30) can potentially be used as therapies for rotavirus and adenovirus type 7, and there are currently insufficient treatment options. 199 Figure 30 The pyridine-furan hybrid compound reduces the virus titer of adenovirus 7 strain by 50%.
Figure 30 Pyridine-furan hybrid compound with a 50% reduction in virus titer against adenovirus 7 strains.
In recent years, antiviral drugs have been developed due to the search for feasible viral treatments. Click chemistry is one of the most effective methods for producing bio-organic molecules (such as antiviral therapy). In a recent study, pyridine derivatives were combined with propargyl via O-propargylation 58-59 (Figure 31). Cu-catalyzed cycloaddition of azido sugars with substituted (propargyl)oxypyridines or propargyl sugars with azidoethoxypyridine derivatives results in high yields of the desired 1,2,3-triazole. MTT and plaque reduction assays were performed against H5N1 influenza strains to evaluate antiviral activity. Triazolyl glycoside 58 demonstrated high activity and low toxicity. The SAR correlation was used to study the effect of the combination of the pyridyl fragment and the glycotriazole moiety on the antiviral activity. Most compounds have weak to moderate inhibitory properties at different concentrations, except for compound 59, which has the strongest activity. All tested compounds showed a dose-dependent inhibitory behavior. It was observed that compounds 58 and 59.200 have low cytotoxicity. Figure 31 A potent antiviral compound 59 with anti-H5N1 influenza virus activity.
Figure 31 A potent antiviral compound 59 with anti-H5N1 influenza virus activity.
Cofactor 2, also known as cyclin G-related kinase (GAK), has been shown to affect the initial and late stages of the virus life cycle, thereby acting as a major regulator against viral infections. This host-based strategy provides many advantages, such as the development of broad-spectrum antiviral drugs and high barriers to drug resistance. Asquith et al. originally discovered SGC-GAK-1 60, which has excellent GAK affinity and a KD value of 1.9 nm. 201 Later, Jonghe et al. developed potent and selective GAK inhibitors 61-62, which are basically isothiazolopyridines with morpholine residues (Figure 32). These compounds have high GAK affinity but moderate activity against dengue fever and hepatitis C virus. 202 Subsequent studies showed that the introduction of dimethyl on the morpholine residue of 62 had a good antiviral effect, which led to the discovery of 63. The compound is active against chikungunya fever, dengue fever and Zika virus. 203 However, the replacement of morpholine residues with carboxamides, alkoxides and amines results in a weaker antiviral effect. 204,205 Figure 32 Antiviral GAK inhibitor with isothiazolopyridine scaffold.
Figure 32 Antiviral GAK inhibitor containing isothiazolopyridine scaffold.
The pyridine core of 63 has been further modified to further improve the antiviral effect. The new compound is highly active against dengue fever, and the binding affinity of GAK is in the nanomolar range. For example, compound 64 strongly inhibits GAK (Figure 33) and is equally effective against dengue fever. 206 Figure 33 Antiviral compounds capable of targeting the cyclin G-related kinase of Dengue virus.
Figure 33 Antiviral compounds capable of targeting dengue virus cyclin G-related kinases.
A series of novel isothiazolopyridines containing 3.4-dimethoxyphenyl residues have also been synthesized, 206 of which the GAK IC50 value is 0.1–0.5 µM. Compound 65 has the highest GAK affinity (IC50 = 0.124 µM), while compound 66, which contains N-morpholinyl residues, is five times less active (Figure 34). However, different structural modifications at the active site at position 4 of the 6-phenyl moiety can be used to alter the antiviral activity. 206 Figure 34 Antiviral compounds with high GAK binding affinity.
Figure 34 Antiviral compounds with high GAK binding affinity.
Although many pyridine-containing drugs can be used to treat HIV/AIDS, further research on isothiazolopyridine compounds may provide viable solutions for other types of viral infections (such as dengue fever).
Oxicam compounds are used in the treatment of musculoskeletal diseases: acute and chronic inflammation caused by the inhibition of cyclooxygenase isoforms COX1 and COX2. 207 FDA-approved oxicam NSAIDs containing a pyridine moiety are shown in Figure 35. These drugs are mainly used to treat musculoskeletal diseases, such as osteoarthritis and rheumatoid arthritis, by relieving painful inflammatory conditions. 208 Figure 35 FDA-approved oxicam non-steroidal anti-inflammatory drugs for musculoskeletal diseases such as osteoarthritis and rheumatoid arthritis.
Figure 35 FDA-approved oxicam NSAIDs for musculoskeletal diseases (such as osteoarthritis and rheumatoid arthritis).
Clonixin (Figure 36) is another FDA-approved drug that has analgesic and antipyretic effects in chronic arthritis. 69 For etoricoxib, the FDA requires additional safety data for approval. However, it has been licensed in more than 80 countries around the world. The drug is a COX2 inhibitor, mainly used to treat gout, ankylosing spondylitis, osteoarthritis, psoriatic arthritis and rheumatoid arthritis. 209 Figure 36 Commercial NSAID containing pyridine ring.
Figure 36 Commercial NSAID containing pyridine ring.
Recently, it has been reported that many biologically active molecules can process inflammation markers. 210,211 Thirumurugan et al. synthesized indole-containing pyridine derivatives and evaluated their anti-inflammatory activity on rat paw edema. All compounds have significant anti-inflammatory activity, especially 67-68, whose activity is significantly higher than that of the standard drug indomethacin (Figure 37). The analgesic activity of dihydropyridine derivatives was also compared with that of aspirin. Compound 68-70 has quite high analgesic activity. 212 Figure 37 Indolylpyridine (67-68) and dihydropyridine-containing compounds (69-71) have significant anti-inflammatory activity in animal models.
Figure 37 Indolylpyridine (67-68) and dihydropyridine-containing compounds (69-71) with significant anti-inflammatory activity in animal models.
In order to broaden the scope of anti-inflammatory research, Liu et al. designed thienopyridine derivatives (Figure 38). When performing NO production analysis, most compounds can inhibit NO production. The most effective analog 72 significantly reduced NO production at lower doses (IC50 = 3.30 µM). The anti-inflammatory properties were further studied by evaluating the TNFα inhibitory activity of the most effective compound 72. Interestingly, compounds 74 and 75 with piperazine residues showed considerable effectiveness. These results indicate that 72-75 thienopyridine-containing compounds may represent a new class of anti-inflammatory drugs that require more attention. 213 Figure 38 Thienopyridine derivatives (72-75) with anti-inflammatory and immunomodulatory properties. The IC50 value corresponds to the inhibition of NO production by murine RAW264.7 macrophages.
Figure 38 Thienopyridine derivatives (72-75) with anti-inflammatory and immunomodulatory properties. The IC50 value corresponds to the inhibition of NO production by murine RAW264.7 macrophages.
Yaqoob et al. recently reported a highly effective anti-inflammatory compound designed by using pyridine-containing isonicotinic acid (Figure 39). It was observed that compounds 76-79 have significant ROS inhibitory activity. Compound 76 is one of the most effective anti-inflammatory agents with IC50 of 1.42±0.1 µg/mL. 214 Figure 39 Highly potent anti-inflammatory compounds.
Figure 39 Highly potent anti-inflammatory compound.
The antagonistic hormone glucocorticoid stimulates liver glucose synthesis and inhibits insulin-assisted glucose absorption in skeletal muscle and adipose tissue. 215 Glucocorticoid stimulation is coordinated by the 11β-HSD2 and 11β-HSD1 enzymes and is usually used to measure the activity of glucocorticoid target tissues. 216 Enzyme 11-HSD1 is believed to play a key role in lipid and glucose metabolism in adipose tissue. Therefore, 11-HSD1 inhibitors are a new family of drugs that are being developed to solve the complications of diabetes. The role of 11-HSD1 in the development of insulin resistance and obesity has been confirmed in a number of preclinical studies. Recently, a new set of triazole-containing dihydropyridine derivatives was used to test the α-glucosidase inhibitory activity in vitro. Compared with the acarbose standard (IC50 = 395.17 µM), these compounds showed considerable α-glucosidase inhibitory activity (IC50 = 72.71–283.41 µM). Compound 80-82 (Figure 40) seems to have the highest inhibitory effect on the enzyme, with IC50 values of 72.71±1.09, 73.83±1.17 and 85.96±1.84 μM, respectively. In order to understand the mechanism of action, the most effective compounds in the series (80 and 81) were evaluated using an in vitro enzymatic test to evaluate their 11β-HSD1 enzyme inhibitory activity. The use of molecular docking analysis further confirmed the mechanism of action of 80 and 81, which indicated that these two compounds bind strongly in the cavity of the 11β-HSD1 receptor, resulting in considerable docking fraction, electrostatic energy and hydrogen bond interaction of the desired molecules. Complex (both sides and back chain). Overall, compounds 80 (-9.758) and 81 (-8.595) showed highly stable 11β-HSD1 binding modes in molecular docking studies. 217 Figure 40 Effect of 11β-HSD1 inhibitor on diabetes.
Figure 40 Anti-diabetic 11β-HSD1 inhibitor.
Larijani et al. reported that coumarin fusion pyridine has excellent α-glucosidase activity (Figure 41). Most of their compounds have IC50 values of 101.0±2.0 to 227.3±1.4 μM, while the standard drug acarbose has IC50 values of 750.0±1.5 μM. Compounds 83–85 are the most effective, with IC50 values of 101.0±2.0, 111.3±1.5, and 114.3±1.8 μM, respectively. 218 Figure 41 Coumarin-fused pyridine has potent α-glucosidase activity.
Figure 41 Coumarin fusion pyridine with powerful α-glucosidase activity.
Although many pyridine-containing NSAIDs can be used for musculoskeletal diseases such as osteoarthritis and rheumatoid arthritis, further research on pyridine or dihydropyridine-containing oxicams may lead to the development of effective treatments for acute and chronic inflammation drug.
Neuroprotection can be defined as the maintenance, preservation and stability of neuron function and structure. It is the mechanism by which the nervous system works smoothly and prevents nerve damage. 219 The brain is a very sensitive part of the body, so it is very vulnerable to pathogens and neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, brain tumors and Alzheimer's disease. 220,221 These diseases are the main cause of neuronal death, including neurostroke, which is the result of various complications such as loss of calcium homeostasis, cytotoxicity, metabolic failure, and oxidative stress. 222 Many pyridines or dihydropyridines are being evaluated for the treatment of neurodegenerative diseases with drugs223 (Figure 42). Figure 42 Drug reuse candidates containing pyridine or dihydropyridine for the treatment of neurodegenerative diseases.
Figure 42 Drug reuse candidates containing pyridine or dihydropyridine for the treatment of neurodegenerative diseases.
Nimodipine is a broad-spectrum neuroprotective drug, which is widely used as an anti-ischemic drug to treat Alzheimer's disease, migraine and vasospasm after bleeding. 224 Nimodipine (Figure 43) is known for its relaxing potential on the cerebrovascular system. 225 Figure 43 The broad-spectrum neuroprotective drug nimodipine.
Figure 43 The structure of the broad-spectrum neuroprotective drug nimodipine.
Alzheimer's disease is a neurodegenerative disease characterized by memory dysfunction and cognitive impairment. Many compounds based on pyridine and dihydroxypyridine have been synthesized and evaluated for their anti-Alzheimer's disease activity. León et al. developed a series of tacrine-dihydropyridine hybrids decorated with pyrin scaffolds. 226 The inhibitory potential of this series on acetylcholinesterase was evaluated. The activity of compound 86 (IC50 = 0.0048±0.001) is ten times that of donepezil standard (0.049±0.005; Figure 44). Figure 44 A highly effective AChE inhibitor.
Figure 44 A highly effective AChE inhibitor.
Huperzine A 94 (Figure 45) is widely known for its neuroprotective properties, which leads to increased NGF production and expression, which involves enhanced neuronal function, their survival, and the prevention of neurodegenerative diseases such as Alzheimer’s Disease) damage. It protects neurons from glutamate toxicity by reducing glutamate-induced calcium mobilization. It can also protect rat pheochromocytoma cells from oxidative stress caused by hydrogen peroxide. Since oxidative stress can aggravate the neurodegeneration of Alzheimer's disease, Huperzine A 94 is widely used to treat the complications of Alzheimer's disease. 227 Figure 45 The structure of natural Huperzine A.
Figure 45 The structure of natural Huperzine A.
Recently, it has been discovered that a dihydropyridine derivative having a pyridinium moiety 87 has high activity as a gene transfection agent and exhibits excellent mitochondrial targeted antioxidant activity. 228 It has been found to play an important role in preventing nerve damage (Figure 46), and it leads to increased protein expression in the hippocampus and cerebral cortex. Studies have found that increased expression of the GAD67 enzyme in the hippocampus converts glutamate into GABA, and that GABA can protect the brain from nerve damage. It regulates the development of spatial memory and balances neurotransmitters, consolidation and memory stability by synthesizing GABA. Because of its ability to improve memory and neuroprotection, it can be used to treat Alzheimer's disease. Figure 46 Compound 87 can increase the expression of GAD67 enzyme in the hippocampus.
Figure 46 Compound 87 can increase the expression of GAD67 enzyme in the hippocampus.
Dihydropyridine derivatives with pyridinium moieties can be a viable solution for the treatment of Alzheimer's disease because they can enhance the expression of key proteins in the hippocampus and cerebral cortex. In the next few years, extensive research on this type of compound is expected.
It is reported that pyrazoline-containing pyridine derivatives exhibit anti-Parkinson's disease activity. 229 For example, compounds 88 and 89 have significant anti-Parkinson's disease activity, and their relative potency is 0.8 compared to the reference drugs benztropine and volteram (Figure 47). Figure 47 The anti-Parkinson's disease activity of compounds 88 and 89 is comparable to that of the reference drug.
Figure 47 The anti-Parkinson's disease activity of compounds 88 and 89 is comparable to that of the reference drug.
Several dihydropyridines have amino acids in their structure and are peptide mimetics in nature. The most studied are Glutapyrone 90 and Tauropidone 91 (Figure 48). Both of these compounds protect cerebellar granule cells from damage by reducing lactate dehydrogenase, thereby avoiding ischemia/hypoxia (lack of oxygen and glucose) and glutamate excitotoxicity. Tauropyrone 91 can be used to treat Parkinson's disease because it inhibits the inflammatory process in rats at a dose of 6.25 g/L per day in the 6-hydroxydopamine model for 7 and 14 days. Tauropyrone 91 (1 mg/kg) shows a dual effect in the brain. In some cases, it shows inflammation and pro-apoptotic effects, but in the toxicity of azidothymidine, it acts as an anti-inflammatory and anti-apoptotic agent. Monocyclic dihydropyridines containing amino acids represent a new group of atypical DHPs, and data show that they have neuromodulation potential and normalize protein expression in the brain. 230–233 Figure 48: Structures of Glutazone (left) and Tauropridone (right).
Figure 48 The structures of Glutapyrone (left) and Tauropirketone (right).
Although pyrazoline-containing pyridine derivatives have been reported to have anti-Parkinson's disease activity, many reports in the literature indicate that 1,4-dihydropyridine derivatives, which are non-calcium agonists, exhibit significant neuroprotective effects. There is great potential in drug design for Parkinson's disease in the future.
Cerebral ischemia is also a neuronal disease, in which many harmful by-products and free radicals are produced, leading to changes in enzyme activity, leading to the breakdown of cellular phospholipids, proteins and nucleic acids. Cerebral edema is a complication that occurs due to the overexpression of AQP4. A large amount of water enters the brain, and the swollen brain is pressed on the skull. This increased pressure in the skull can cause hernia and cerebral ischemia, which can lead to death. This condition is treated with piroxicam (Figure 49), which has an inhibitory effect on AQP4 (the most abundant water channel in the brain). Piroxicam 92, which contains a pyridine ring, binds to AQP4 and regulates it in the brain in this way to avoid cerebral ischemia and edema. 234 Figure 49 Piroxicam binds to the water channel AQP4 to prevent cerebral ischemia.
Figure 49 Pyroxicam combines with the water channel AQP4 to prevent cerebral ischemia.
Schizophrenia is a mental illness characterized by behavioral, neurochemical, and morphological disorders. Although significant progress has been made in drug development for schizophrenia, antipsychotic drugs that act on molecular targets other than monoaminergic receptors have not yet been produced. GABA dysfunction may be related to this disease. 235 Marcinkowska et al. recently discovered the imidazopyridine neuroprotective agent 93 (Figure 50), which shows potential affinity for serotonin 5HT2 and 5HTx receptors and antipsychotic-like activity. Compound 93 also showed positive allosteric modulator properties, high metabolic stability and no hepatotoxicity. 235 Figure 50 Neuroprotective agents.
Senna is a well-known source of natural alkaloids of piperidine and pyridine. 236,237 Francisco et al. isolated five new pyridine-containing alkaloids from senna and cassia seeds (Figure 51): 8'-multijuguinol 95, 7'-multijuguinol 96, methyl multijuguinate 97, 12'-hydroxy-8'- Multijuguinol 98 and 12'-hydroxy-7'-multijuguinol 99 are isolated from senna. All these compounds have an acetylcholinesterase inhibitory activity comparable to that of the standard drug physostigmine. SAR studies have shown that the hydroxypyridine moiety is the key interaction site responsible for this activity, and the alkyl side chain also affects the acetylcholinesterase inhibitory effect of alkaloids. A summary of 236 neuroprotective compounds and their potential applications and tentative mechanisms is shown in Table 2. Table 2 Summary of neurogenic/neuroprotective compounds with pyridine or dihydropyridine stents Figure 51 Isolated from senna and cassia Pyridine alkaloid with neurogenic activity.
Table 2 Summary of neurogenic/neuroprotective compounds with pyridine or dihydropyridine stents
Figure 51 Neuroactive pyridine alkaloids isolated from senna and cassia seeds.
Cancer is considered a major challenge to public health. There are many pyridine-containing drugs in the FDA database (Figure 52), such as axitinib (a tyrosine kinase inhibitor) developed by Pfizer. For the treatment of cancer, other kinase inhibitors containing the pyridine ring system are shown in Figure 53. Figure 52 Anticancer drugs containing pyridine in the FDA database. Figure 53 FDA-approved kinase inhibitor with pyridine scaffold.
Figure 52 Anticancer drugs containing pyridine in the FDA database.
Figure 53 FDA-approved kinase inhibitor with pyridine scaffold.
Recently, the effectiveness of chemotherapeutic drugs has been severely limited by tumor drug resistance. 238,239 In a recent study, Alqahtani et al. studied pyridine-thiazole hybrid compounds. These hybrids contain (hydrazone methyl) phenoxy-acetamide spacers, and the new compounds have been evaluated for normal fibroblasts (WI38), breast cancer (MCF7), laryngeal cancer (Hep2), prostate cancer (PC3) and The cytotoxic potential of liver cancer. HepG2). In these experiments, the drug 5-fluorouracil (5-Fu) was used as the standard. It is reported that compounds 100 and 101 have promising anticancer activity against HepG2 and MCF7 cell lines, with IC50 values of 5.36 and 8.76 μM, respectively (Figure 54). Interestingly, these two compounds have weak cytotoxic effects on normal cell lines (WI38). Docking analysis reveals valuable information about the binding site, where the synthesized compound interacts with the ROCK1 protein kinase cavity. It can be safely assumed that combining the pyridine and thiazole moieties in a molecular platform through the phenoxyacetamide spacer may produce new compounds with significant synergistic anticancer effects. 240 Figure 54 Pyridine-thiazole hybrid has a significant anti-cancer effect in MCF7 breast cancer.
Figure 54 Pyridine-thiazole hybrid with significant anticancer effect in MCF7 breast cancer.
Schiff-based pyridine derivatives containing 4-thiazolidinone and azetidine-2-one with pyrazolo[3,4-b]pyridine moiety were also prepared. Their antiproliferative activity was tested using the sulforhodamine B assay. In hepatocellular carcinoma (HB8065) cells, these compounds showed significant cytotoxicity. Among the tested compounds, 102–106 have extremely high antiproliferative activity (IC50 = 0.0091–0.0211 µM) against breast cancer cells (MCF7), while the IC50 of the standard drug doxorubicin is 0.099 µM. Compound 102 showed significant anti-proliferative effects on MCF7 and HB8065, with IC50 of 0.0211 µM and 1.65 µM, respectively. These findings imply that these compounds (Figure 55) are very promising leaders in the search for new antiproliferative agents. 188 Figure 55 Compounds derived from pyrazolo[3,4-b]pyridine and dihydropyridine.
Figure 55 Compounds derived from pyrazolo[3,4-b]pyridine and dihydropyridine.
Enasidenib and ivosidenib (Figure 56) were recently approved by the FDA for the treatment of leukemia. 241 Both are first-class drugs containing pyridine. Figure 56 Tumor drugs that have recently been approved by the FDA for the treatment of leukemia.
Figure 56 Tumor drugs that have recently been approved by the FDA for the treatment of leukemia.
In 2015, Sailaja et al. studied pyridine-indole hybrids and obtained promising cytotoxic results, 242 of which compounds 107-109 have good activity on K562 leukemia cells (Figure 57). Figure 57 The effect of substituents on the cytotoxicity of pyridine-indole hybrid compounds.
Figure 57 The effect of substituents on the cytotoxicity of pyridine-indole hybrid compounds.
Viradiya et al. synthesized a series of dihydropyridines with benzylpyridinium (Figure 58). In the MTT assay, these compounds have excellent anticancer activity against colorectal adenocarcinoma Caco2, lung cancer A549 and glioblastoma U87MG cell lines. For these cell lines, compounds 110-113 showed better anticancer activity than the widely used drugs carboplatin, gemcitabine and daunorubicin. Compound 112 is the most effective in this series, 3.6 times that of carboplatin and 4.2 times that of gemcitabine. The mechanism of action indicates that the test compound induces cell death through apoptosis. The excellent anti-cancer ability of dihydropyridine containing benzylpyridinium may help fight against MDR cancer strains. However, in order to better understand their mode of action, more in-depth mechanism verification of these types of compounds is still needed. 243 Figure 58 1,4-Dihydropyridine-containing benzylpyridinium moiety with significant anticancer activity.
Figure 58 The benzylpyridinium moiety containing 1,4-dihydropyridine with significant anticancer activity.
Naglaa et al. recently designed a series of pyridine-containing anticancer agents (Figure 59). The in vitro growth activity of the newly synthesized compound on breast cancer (MCF7) and human hepatocellular carcinoma (HepG2) cell lines was studied. Under the same conditions, the anticancer drug doxorubicin was used as the comparison standard. For HepG2 and MCF7, most of the newly synthesized compounds showed significant and effective anticancer activity. Derivatives 114-116 showed significant activity. To further confirm the hypothetical mechanism, molecular docking studies were performed to evaluate the affinity between the compounds and their binding energy to enzymes. For effective compounds, the calculated binding energy is very consistent with their activity on MCF7 and HepG2 cell lines. 244 Figure 59 Condensed heterocyclic derivatives containing a pyridine moiety.
Figure 59 Condensed heterocyclic derivatives containing pyridine moiety.
Recently, Eman et al. reported an important contribution to new anticancer agents through the development of a series of tetrahydronaphthalene-pyridine hybrids, starting with 2-(pyridin-2-yl[oxy])acethydrazine, with considerable yields (Figure 60). ). The MTT assay is used to evaluate the cytotoxic activity of these compounds on human MCF7 and HCT116 cells. The IC50 value for HCT116 cancer cells is 7.7–9.0 µM, which is equivalent to the standard drug doxorubicin (IC50 = 8 µM). The IC50 values of derivatives 117-119 against MCF7 cells were 21.0, 33.3 and 60.3 µM, respectively. It can be temporarily assumed that the tetralin-pyridine skeleton is an effective anti-tumor part of MCF7 cells. These findings indicate that all test compounds are more active against human colon cancer cells than human breast cancer cells. 245 Figure 60 Tetrahydronaphthalene-pyridine hybrid.
Figure 60 Tetrahydronaphthalene-pyridine hybrid.
Phosphodiesterase (PDE) has been recognized as an important target in cancer treatment because they play a key role in the induction of apoptosis and the inhibition of tumor cell growth. Some non-selective PDE inhibitors, such as aminophylline and theophylline, have been considered as growth regulators in various cancer cell lines, indicating their potential as anticancer drugs for PDE inhibition. Atieh et al. synthesized and evaluated a series of dihydropyridine compounds containing imidazole aryl groups and their 2-oxo isostere derivatives as PDE inhibitors. The cytotoxic effects of HeLa and MCF7 cell lines were also examined. Compound 120 demonstrated an abnormally high PDE3A inhibitory effect with an IC50 of 3.76 ± 1.03 nM (Figure 61). Compound 89 also showed significant high cytotoxicity to MCF7 and HeLa cells (IC50 of 50.18±1.11 and 34.3±2.6 µM, respectively). The strong correlation between the IC50 value of cytotoxicity and PDE3A inhibition supports the idea that PDE3 inhibitors can be used as cytotoxic entities. According to SAR investigations and docking studies, it was found that hydrophobic interactions are equally important in the formation of hydrogen bonds, which are used to inhibit the cytotoxic effects of PDE3 and the proposed derivatives. 246 Figure 61 A highly effective anticancer compound with PDE3 inhibitory effect.
Figure 61 A highly effective anticancer compound with PDE3 inhibitory effect.
Telomerase's key role in tumor growth makes it a promising target for cancer treatment and other age-related diseases. Telomeres and telomerase are known to be involved in the progression of gastric cancer. Xin-Hua and others synthesized flavonoids containing 2-chloro-pyridine derivatives to inhibit telomerase (Figure 62). An improved telomere repeat amplification protocol was used to evaluate the compound's telomerase inhibitory effect. 121 and 122 showed significant activity against SGC7901 gastric cancer cell line, with IC50 of 18.45±2.79 µg/mL and 22.28±6.26 µg/, respectively Milliliters, respectively. In order to determine the possible binding mode, a docking simulation study was performed on the active site of 3DU6. By binding to the active site of telomerase, compound 122 is a more effective telomerase inhibitor. 247 Figure 62 Antitumor agent with telomerase inhibitory effect.
Figure 62 Antitumor agent with telomerase inhibitory effect.
Fatma et al. also reported double-substituted pyridines (Figure 63) and studied their anti-cancer activity on HepG2 cells. Compounds 123-125 were found to have promising activities comparable to standard drugs and 5-fluorouracil. 248 Figure 63 Compounds with significant activity on HepG2 liver cancer cells.
Figure 63 Compounds with significant activity on HepG2 liver cancer cells.
In 2016, compounds containing the pyridine-pyrimidine hybrid ring system were screened against various cancer cell lines at 10 µM. 249 and compound 126 (Figure 64) showed promising inhibitory effects on the NCI60 cell line, and the IC50 of UO31 It is 1.40 µM, SNB75 is 1.55 µM, M14 is 1.60 µM, SKMEL5 is 1.62 µM, and Colo205 cells are 1.77 µM. Figure 64 The pyridine-pyrimidine hybrid ring system containing compound 126 which has inhibitory effect on the NCI60 cell line.
Figure 64 The pyridine-pyrimidine hybrid ring system containing compound 126 which has inhibitory effect on the NCI60 cell line.
Süss-Fink et al. reported highly effective pyridine-based compounds [14] and evaluated their anticancer potential in A2780 (ovarian cancer) and A2780cisR (cisplatin-resistant cancer) cells. Pyridine-4-carboxylate contains a lipophilic chain with 10 carbon atoms of 127 and is highly cytotoxic. The IC50 values of the A2780 and A2780cisR cell lines are 5 µM and 11 µM, respectively (Figure 65). Surprisingly, the arene ruthenium complex of 127 has very high anti-cancer activity on both cell lines, and the IC50 of 128 (A2780 is 2 µM) is five times that of 127.250. Figure 65 Isonicotinic acid esters containing compounds 127 and 128.
Figure 65 Isonicotinic acid esters containing compounds 127 and 128.
Interestingly, the introduction of the OH group into 127 produces a new compound 129, which is almost inactive (IC50 of A2780 = 162 µM, IC50 of A2780cisR = 208 µM; Figure 66). However, the p-cymene ruthenium complex 130 shows very high anticancer activity in the submicromolar range, with an IC50 of 0.18 µM. 251 Figure 66 P-cymene-ruthenium complex 130 has submicromolar anticancer activity against ovarian cancer cell lines.
Figure 66 p-cymene-ruthenium complex 130 has submicromolar anticancer activity against ovarian cancer cell lines.
The pyridine hybrid of isatin has been found to show anti-proliferative effects in MCF7, HT29 and HepG2 cells, among which compounds 131-133 have significant activity (Figure 67). 252 Figure 67 The simplified structure of the pyridine-isatin hybrid leads to better IC50 values.
Figure 67 The simplified structure of the pyridine-isatin hybrid leads to better IC50 values.
Recently, [1,2,4]triazolo[1,5-a]pyridylpyridine was used to study the higher activity in MCF7, U87MG and HCT116 cells. 253 Compound 134 has a very high anti-cancer effect in these cell lines (Figure 68). Figure 68 A highly effective anticancer agent containing [1,2,4]triazolo[1,5-a]pyridylpyridine.
Figure 68 A highly effective anticancer agent containing [1,2,4]triazolo[1,5-a]pyridylpyridine.
Among diphenyl-1-(pyridin-3-yl) ethyl phosphonates, 254 compounds 135 and 136 also showed cytotoxic effects on MCF7 and HepG2 cells (Figure 69). Figure 69 Anticancer agent containing diphenyl 1-(pyridin-3-yl) ethyl phosphonate.
Figure 69 Anticancer agent containing diphenyl 1-(pyridin-3-yl) ethyl phosphonate.
Pyridine and dihydropyridine are considered to be attractive scaffolds for the development of anti-cancer drugs, because many drugs containing these parts are already on the market and show significant effects. By incorporating these scaffolds into the skeleton of biologically active molecules, and then using computational methods to analyze them to predict high-efficiency drug candidates, the rational design of new anti-cancer drugs can be realized. The reuse of existing drugs containing pyridine and dihydropyridine should also be explored to accelerate the discovery of new anti-cancer drugs.
This review is a critical analysis of various drugs and research on the design and development of various derivatives of pyridine and dihydropyridine-based compounds. They have been characterized based on their pharmacological activity. It also discusses specific structural features related to specific activities. The pyridine core has greater ease of handling in the production of anti-infectives and anti-cancer agents. This is evident from the fact that the FDA has recently approved many pyridine-containing antibiotics, such as ceftaroline fosamil (2010), tedizolid (2014), ceftazidime (2015) and delafloxacin (2017). In the database, you can also find isoniazid, ethionamide and prothiazamide, which are very effective for the treatment of tuberculosis mycobacteria. The combination of pyridine scaffolds and oxazolidinones has great prospects in this regard, because many such compounds with significant antibacterial effects have recently appeared in contemporary literature. For example, in in vitro and in vivo evaluations, compound 23-25 has effective activity against a variety of drug-resistant bacteria as well as catarrhalis and Haemophilus influenzae. The FDA database also contains many pyridine-containing antiviral drugs, such as nevirapine, tipranavir, doravirin, and indinavir, which are being used to control HIV infection. In the past 10 years, many isothiazolopyridine-based compounds (such as 61-66) have been developed as selective GAK inhibitors to prevent the initial and late life cycles of the virus. It has also been found that pyridine-containing oxicam compounds are expected to treat musculoskeletal diseases such as osteoarthritis and rheumatoid arthritis. For cancer treatment, pyridine is a component of many FDA-approved kinase inhibitors, such as acalabrutinib, neratinib, abemaciclib, alpelisib, lorlatinib, and pexidartinib, and many compounds containing pyrazolo[3,4-b]pyridine (102-106 ), has extremely high anti-proliferative activity against MCF7 cells (IC50 = 0.0091–0.0211 µM), while the standard drug doxorubicin has an IC50 of 0.099 µM. Süss-Fink et al. found that aromatic hydrocarbon-ruthenium complexes with pyridine scaffolds have a strong anti-cancer effect, with IC50 values in the submicromolar range. Ruthenium compounds containing pyridine are expected to replace cisplatin-based anticancer drugs. Drugs containing dihydropyridine rings are mainly used as calcium channel blockers, often used to treat high blood pressure and heart-related problems. Such drugs include nimodipine, ciclopirox, ifodipine, nifedipine, milrinone, and amrinone. Because this stent has different anti-dyslipidemia and anti-oxidant effects, cholesterol-lowering compounds containing dihydropyridine rings have been developed (18-22). 80-82 containing dihydropyridine can inhibit 11β-HSD1 to potentially cure diabetes. In the literature, one can also find many compounds containing pyridine or dihydropyridine (86-94) for potential treatment of neurodegenerative diseases, as well as many examples of drug reuse, such as dolutegravir, martinib, nilvadipine, Nilotinib, Chlorioquinol, and Imatinib. Despite years of research, further work is still needed to optimize their effects and understand their mechanism of action. In short, the combination of pyridine and dihydropyridine-containing compounds with a broadened chemical space will help medicinal chemists design biologically active molecules for specific targets. In short, in view of the huge structural diversity of pyridine and dihydropyridine compounds, the existing literature hardly touches the surface of its pharmacological application possibilities. Therefore, interest in them is unlikely to disappear anytime soon. We will see an increase in the structure, application and diversity of pyridine and dihydropyridine compounds, which have great potential in the next ten years and can be used to develop new types of cardiovascular, anti-inflammatory and anti-infectives containing these two heterocycles. , Neurogenic and anticancer drugs.
AChE, acetylcholinesterase; COX, cyclooxygenase; DHP, dihydropyridine; FDA, Food and Drug Administration; GABA, γ-aminobutyric acid; GAK, G-related kinases; HepG2, hepatocellular carcinoma; MDR, multiple Resistance; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; NAD, nicotinamide adenine dinucleotide; NADP, NAD phosphate; NO, nitric oxide; NSAIDs, non-steroidal antibacterial Inflammatory drugs; PDE, phosphodiesterase; PL, lower phospholipids; ROS, reactive oxygen species.
The author thanks the China-Pakistan Cooperation Center for Traditional Chinese Medicine at the International Center for Chemistry and Biological Sciences, Karachi University, Karachi, Pakistan for granting GZYYGJ2020023. Thanks also to the Affiliated Hospital of Qingdao University in Qingdao, Shandong, China and HEJ Institute of Chemistry, International Center for Chemistry and Biological Sciences of Karachi University.
All authors have made substantive contributions in concept and design, data acquisition or data analysis and interpretation, participated in the drafting of the article or critically revised important knowledge content, agreed to submit to the current journal, and finally approved the version for publication, and agreed Responsible for all aspects of work.
The author declares that there is no conflict of interest in this work.
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