Pyridine Compounds with Antimicrobial and Antiviral Activities

In the context of the new life-threatening COVID-19 pandemic caused by the SARS-CoV-2 virus, finding new antiviral and antimicrobial compounds is a priority in current research. Pyridine is a privileged nucleus among heterocycles; its compounds have been noted for their therapeutic properties, such as antimicrobial, antiviral, antitumor, analgesic, anticonvulsant, anti-inflammatory, antioxidant, anti-Alzheimer’s, anti-ulcer or antidiabetic. It is known that a pyridine compound, which also contains a heterocycle, has improved therapeutic properties. The singular presence of the pyridine nucleus, or its one together with one or more heterocycles, as well as a simple hydrocarbon linker, or grafted with organic groups, gives the key molecule a certain geometry, which determines an interaction with a specific protein, and defines the antimicrobial and antiviral selectivity for the target molecule. Moreover, an important role of pyridine in medicinal chemistry is to improve water solubility due to its poor basicity. In this article, we aim to review the methods of synthesis of pyridine compounds, their antimicrobial and antiviral activities, the correlation of pharmaceutical properties with various groups present in molecules as well as the binding mode from Molecular Docking Studies.


Introduction
Pyridine (from the Greek pyr = fire and idine-which is used for aromatic bases) contains a single heteroaromatic ring, which comes from the replacement of a CH group in the benzene ring with the nitrogen atom. Ramsay (1877) synthesizes pyridine for the first time, by the reaction of acetylene with hydrogen cyanide in a red-hot iron tube furnace, this being the first synthesized heterocycle [1]. Arthur Hantzsch later synthesized (1881) pyridine compounds by the synthesis that bears his name, through a multicomponent reaction, starting from a β-ketoester, an aldehyde and ammonia [2,3]. An important role of pyridine is that it is used as an organic solvent or as ligand for coordination complexes [4][5][6][7][8]. The pyridine nucleus is found in many natural products, such as vitamins, alkaloids and coenzymes, as well as in many drugs ( Figure 1) and pesticides [9,10]. The recent literature mentions various series of compounds containing the pyridine nucleus, as a unique heterocycle, and with other heterocycles or fused with other heterocycles, which have remarkable antibacterial, antifungal and antiviral properties [1,[9][10][11][12][13]. The presence of an additional heterocycle compared to the pyridine one in the bioactive molecule proved to be beneficial in the sense that it intensified the therapeutic properties of the antimicrobial and antiviral ones, and also widened their range [3][4][5][6][7][8]. Moreover, the presence of certain organic groups, such as amino, hydroxy, methoxy, sulfamide, hydrazide, etc., increase the biological activities of the compounds, as noted in the literature. Moreover, current research has been stimulated by the unexpected evolution of the SARS-CoV-2 pandemic  In the present paper, we aim to review antimicrobial and antiviral pyridine compounds, as well as their methods of synthesis. Their presentation will be based on the complexity of the molecules and their therapeutic properties.

Synthesis of Antimicrobial Compounds Containing Only Pyridine Ring
Sarova et al. [14] synthesized three dodecanoic acid derivatives 1−3 with yields of 59-61%, starting from dodecanoic acid in two steps, chlorination with thionyl chloride and reaction with the corresponding aminopyridine (Scheme 1). All compounds possessed good antibacterial activity against B. subtilis, S. aureus and E. coli and antifungal activity against A. niger and C. albicans. Narang et al. [15] synthesized a series of 18 nicotinic acid benzylidene hydrazide derivatives in three steps with total yields of 60-80% (Scheme 2). The antimicrobial screening results indicated that compounds with nitro (4, 5 and 6) and dimethoxy (7) substituents were the most active ones against tested strains (S. aureus, B subtilis, E coli, C. albicans, and A. niger), some of them having an antimicrobial activity comparable to the standard drugs fluconazole and norfloxacin. In the present paper, we aim to review antimicrobial and antiviral pyridine compounds, as well as their methods of synthesis. Their presentation will be based on the complexity of the molecules and their therapeutic properties.

Synthesis of Antimicrobial Compounds Containing Only Pyridine Ring
Sarova et al. [14] synthesized three dodecanoic acid derivatives 1−3 with yields of 59-61%, starting from dodecanoic acid in two steps, chlorination with thionyl chloride and reaction with the corresponding aminopyridine (Scheme 1). All compounds possessed good antibacterial activity against B. subtilis, S. aureus and E. coli and antifungal activity against A. niger and C. albicans. CoV-2 pandemic (COVID- 19), which required new antimicrobial and antiviral agents to treat patients with moderate or severe cases of pneumonia [13].  In the present paper, we aim to review antimicrobial and antiviral pyridine compounds, as well as their methods of synthesis. Their presentation will be based on the complexity of the molecules and their therapeutic properties.

Synthesis of Antimicrobial Compounds Containing Only Pyridine Ring
Sarova et al. [14] synthesized three dodecanoic acid derivatives 1−3 with yields of 59-61%, starting from dodecanoic acid in two steps, chlorination with thionyl chloride and reaction with the corresponding aminopyridine (Scheme 1). All compounds possessed good antibacterial activity against B. subtilis, S. aureus and E. coli and antifungal activity against A. niger and C. albicans. Narang et al. [15] synthesized a series of 18 nicotinic acid benzylidene hydrazide derivatives in three steps with total yields of 60-80% (Scheme 2). The antimicrobial screening results indicated that compounds with nitro (4, 5 and 6) and dimethoxy (7) substituents were the most active ones against tested strains (S. aureus, B subtilis, E coli, C. albicans, and A. niger), some of them having an antimicrobial activity comparable to the standard drugs fluconazole and norfloxacin. Scheme 1. Synthesis of dodecanoic acid pyridines 1-3 [14].
Brycki et al. [31] performed a Menshutkin reaction between 4-chloromethylpyridine and the N,N-dimethylalkylamines containing 8, 10, 12, 14, 16, 18 carbon atoms in an alkyl chain, respectively in acetonitrile to obtain compounds 51-56 in good yields at room temperature (Scheme 10). The minimal inhibitory concentration (MIC) values of pyridine salts 51-56 against the fungi A. niger, C. albicans, P. chrysogenum range from 0.1 to 12 mM and against bacteria S. aureus, B. subtilis, E. coli, P. aeruginosa range from 0.02 to 6 mM, as can be seen in Table 2.

Synthesis of Antimicrobial Pyridine Compounds Containing a Five-Membered Ring with Three Heteroatoms
Murty et al. [54]

Synthesis of Pyridine Compounds Containing P, Se, and B with Antimicrobial Properties
Abdel-Megeed et al. [83] synthesized a series of diphenyl 1-(arylamino)-1-(pyridin-3yl) ethyl phosphonates 200a-200e in high yields from reactions of 3-acetyl pyridine 199 with aromatic amines and triphenylphosphite in the presence of lithium perchlorate as a catalyst (Scheme 43). All compounds showed high antimicrobial activities against Escherichia coli NCIM2065, Bacillus subtilis PC1219, Staphylococcus aureus ATCC25292, Candida albicans, and Saccharomyces cerevisiae, at low concentrations (10-100 µg mL −1 , Table 13).      Sekhar et al. [84] synthesized phosphorylated nucleosides 202a-202b from the reaction between compound 201 and the corresponding pyridines (Scheme 44). Both compounds 202a-202b exhibited better activity on Staphylococcus aureus when compared to standard, Gentamycine. Devineni et al. [85] synthesized compounds 205a-205d by reaction of 2amino-2,3-dihydro-1H-2λ 5 - [1][2][3] Sekhar et al. [84] synthesized phosphorylated nucleosides 202a−202b from the reaction between compound 201 and the corresponding pyridines (Scheme 44). Both compounds 202a−202b exhibited better activity on Staphylococcus aureus when compared to standard, Gentamycine. Devineni et al. [85] synthesized compounds 205a−205d by reaction of 2-amino-2,3-dihydro-1H-2λ 5 - [1,3,2] Kumar et al. [86] synthesized organoselenium imidazo[1,2-a]pyridines compounds 207a−207c in four steps, starting with 2-aminopyridines 206a−206b (Scheme 46). Compounds 207a and 207c were observed to exhibit antibacterial activity with an MIC value of 2.48 µg mL −1 and 10.41 µg mL −1 respectively, against Gram-negative bacteria E. coli. These observed activities, in particular the one observed for compound 207a against E. coli, have been found to be more potent as compared to the few reports concerning antimicrobial activity of selenide-based compounds in the literature so far and quite similar to the Rifampicin (standard). Compound 207b was found to be exhibiting multi-spectrum activity against A. fumigates, C. krusei, A. niger, and C. parapsilosis with observed MIC values of 9. 96, 9.96, 19.93, and 19.93 µg mL −1 respectively. Abdellattif et al. [87] synthesized organo-selenium compounds 210a−210c starting from 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 208, in two steps (Scheme 47). Selanone 210c was found to be the most potent antibacterial agent against all tested strains, S. aureus, S. pyogenes, E. coli, and P. aeruginosa, as well as a good antifungal agent, against C. albicans, A. niger, and A. clavatus. A computational study of selenium compounds was performed for prediction of ADME properties by the QikProp3.2 tool available in Schrödinger 9.0 version (USA) and Molinspiration online property calculation toolkit to understand whether the compounds have the optimum pharmacokinetic prop- Kumar et al. [86] synthesized organoselenium imidazo[1,2-a]pyridines compounds 207a-207c in four steps, starting with 2-aminopyridines 206a-206b (Scheme 46). Compounds 207a and 207c were observed to exhibit antibacterial activity with an MIC value of 2.48 µg mL −1 and 10.41 µg mL −1 respectively, against Gram-negative bacteria E. coli. These observed activities, in particular the one observed for compound 207a against E. coli, have been found to be more potent as compared to the few reports concerning antimicrobial activity of selenide-based compounds in the literature so far and quite similar to the Rifampicin (standard). Compound 207b was found to be exhibiting multi-spectrum activity against A. fumigates, C. krusei, A. niger, and C. parapsilosis with observed MIC values of 9. 96, 9.96, 19.93 Kumar et al. [86] synthesized organoselenium imidazo[1,2-a]pyridines compounds 207a−207c in four steps, starting with 2-aminopyridines 206a−206b (Scheme 46). Compounds 207a and 207c were observed to exhibit antibacterial activity with an MIC value of 2.48 µg mL −1 and 10.41 µg mL −1 respectively, against Gram-negative bacteria E. coli. These observed activities, in particular the one observed for compound 207a against E. coli, have been found to be more potent as compared to the few reports concerning antimicrobial activity of selenide-based compounds in the literature so far and quite similar to the Rifampicin (standard). Compound 207b was found to be exhibiting multi-spectrum activity against A. fumigates, C. krusei, A. niger, and C. parapsilosis with observed MIC values of 9. 96, 9.96, 19.93, and 19.93 µg mL −1 respectively. Abdellattif et al. [87] synthesized organo-selenium compounds 210a−210c starting from 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 208, in two steps (Scheme 47). Selanone 210c was found to be the most potent antibacterial agent against all tested strains, S. aureus, S. pyogenes, E. coli, and P. aeruginosa, as well as a good antifungal agent, against C. albicans, A. niger, and A. clavatus. A computational study of selenium compounds was performed for prediction of ADME properties by the QikProp3.2 tool available in Schrödinger 9.0 version (USA) and Molinspiration online property calculation toolkit to understand whether the compounds have the optimum pharmacokinetic properties to enter higher phases of the drug development process or not. It was found that Scheme 46. Synthesis of selenium containing pyridines 207a-207c [86].
Abdellattif et al. [87] synthesized organo-selenium compounds 210a-210c starting from 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 208, in two steps (Scheme 47). Selanone 210c was found to be the most potent antibacterial agent against all tested strains, S. aureus, S. pyogenes, E. coli, and P. aeruginosa, as well as a good antifungal agent, against C. albicans, A. niger, and A. clavatus. A computational study of selenium compounds was performed for prediction of ADME properties by the QikProp3.2 tool available in Schrödinger 9.0 version (USA) and Molinspiration online property calculation toolkit to understand whether the compounds have the optimum pharmacokinetic properties to enter higher phases of the drug development process or not. It was found that compound 210c displayed the highest energy interaction (−8.48 KcalMol −1 ) within the binding pocket in the molecular docking study, as can be seen in Figure 20. Fontaine et al. [88] reported the synthesis of the boronic pyridines 212a and 212b (Scheme 48), which showed a 4-fold increase in activity compared to 6-(benzyloxy)pyridin-3-ylboronic acid. Furthermore, they emerged as potential Staphylococcus aureus NorA inhibitors as they potentiate the activity of Ciprofloxacin and Norfloxacin, have no significant intrinsic antibacterial activity, show a reduced cytotoxicity, and do not inhibit the mammalian P-gp efflux pump.
Abdellattif et al. [87] synthesized organo-selenium compounds 210a−210c starting from 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 208, in two steps (Scheme 47). Selanone 210c was found to be the most potent antibacterial agent against all tested strains, S. aureus, S. pyogenes, E. coli, and P. aeruginosa, as well as a good antifungal agent, against C. albicans, A. niger, and A. clavatus. A computational study of selenium compounds was performed for prediction of ADME properties by the QikProp3.2 tool available in Schrödinger 9.0 version (USA) and Molinspiration online property calculation toolkit to understand whether the compounds have the optimum pharmacokinetic properties to enter higher phases of the drug development process or not. It was found that compound 210c displayed the highest energy interaction (−8.48 KcalMol −1 ) within the binding pocket in the molecular docking study, as can be seen in Figure 20. Fontaine et al. [88] reported the synthesis of the boronic pyridines 212a and 212b (Scheme 48), which showed a 4-fold increase in activity compared to 6-(benzyloxy)pyridin-3-ylboronic acid. Furthermore, they emerged as potential Staphylococcus aureus NorA inhibitors as they potentiate the activity of Ciprofloxacin and Norfloxacin, have no significant intrinsic antibacterial activity, show a reduced cytotoxicity, and do not inhibit the mammalian P-gp efflux pump.  Figure 20. 3D interaction of selenium compound 210c with 1kzn protein [87].

Synthesis of Antitubercular Pyridine Compounds
Tuberculosis (TB) remains a major threat to global public health, with at least 10 million new cases and 1.2 million deaths in 2019. The high incidence and mortality rates of TB can be attributed to the capacity of its etiological agent, intracellular bacterium Mycobacterium tuberculosis (MTb), to adapt to and survive in the aggressive physiological environment within the host [89]. The need for new tuberculostatic agents arises due to bacterial resistance to first-line drugs: Isoniazid (INH), Rifampicin (RIF), Ethambutol (ETH), Streptomycin (STR), and Pyrazinamide (PYR).

Synthesis of Antitubercular Pyridine Compounds
Tuberculosis (TB) remains a major threat to global public health, with at least 10 million new cases and 1.2 million deaths in 2019. The high incidence and mortality rates of TB can be attributed to the capacity of its etiological agent, intracellular bacterium Mycobacterium tuberculosis (MTb), to adapt to and survive in the aggressive physiological environment within the host [89]. The need for new tuberculostatic agents arises due to bacterial resistance to first-line drugs: Isoniazid (INH), Rifampicin (RIF), Ethambutol (ETH), Streptomycin (STR), and Pyrazinamide (PYR).

Synthesis of Antitubercular Pyridine Compounds
Tuberculosis (TB) remains a major threat to global public health, with at least 10 million new cases and 1.2 million deaths in 2019. The high incidence and mortality rates of TB can be attributed to the capacity of its etiological agent, intracellular bacterium Mycobacterium tuberculosis (MTb), to adapt to and survive in the aggressive physiological environment within the host [89]. The need for new tuberculostatic agents arises due to bacterial resistance to first-line drugs: Isoniazid (INH), Rifampicin (RIF), Ethambutol (ETH), Streptomycin (STR), and Pyrazinamide (PYR).
TB can be attributed to the capacity of its etiological agent, intracellular bacterium Mycobacterium tuberculosis (MTb), to adapt to and survive in the aggressive physiological environment within the host [89]. The need for new tuberculostatic agents arises due to bacterial resistance to first-line drugs: Isoniazid (INH), Rifampicin (RIF), Ethambutol (ETH), Streptomycin (STR), and Pyrazinamide (PYR).
Navarrete-Vázquez et al. [90]  Patel et al. [91] reported two series of compounds 215 and 216 with poor activity against M. tuberculosis when compared with Rifampicin ( Figure 21). Furthermore, compounds showed a very good activity against C. albicans and possessed moderate to poor activity against A. niger and A. clavatus when compared to the standard, Griseofulvin. Sangani et al. [92] reported the synthesis of pyrido[1,2-a]benzimidazole derivatives 219a−219c, via a base-catalyzed microwave-assisted multicomponent cyclocondensation reaction (Scheme 50). Evaluation of antitubercular activity shows that compounds 219b and 219c were found to have better antitubercular activity when compared to standards Isoniazid and Rifampicin, and compound 219a appeared as the promising antimicrobial compound with a significant antitubercular activity. Scheme 49. Synthesis of (1,3,4-oxadiazol-2-yl)pyridines 214a-214b [90].
Patel et al. [91] reported two series of compounds 215 and 216 with poor activity against M. tuberculosis when compared with Rifampicin ( Figure 21). Furthermore, compounds showed a very good activity against C. albicans and possessed moderate to poor activity against A. niger and A. clavatus when compared to the standard, Griseofulvin. Sangani et al. [92] reported the synthesis of pyrido[1,2-a]benzimidazole derivatives 219a-219c, via a base-catalyzed microwave-assisted multicomponent cyclocondensation reaction (Scheme 50). Evaluation of antitubercular activity shows that compounds 219b and 219c were found to have better antitubercular activity when compared to standards Isoniazid and Rifampicin, and compound 219a appeared as the promising antimicrobial compound with a significant antitubercular activity. Rathod et al. [93] synthesized a series of INH compounds 220a−220d and 221a−221d using multicomponent reactions in good yields (80-94%), as can be seen in Scheme 51. Electron-withdrawing groups were reported to increase the anti-TB activity [94,95]. Compound 220c (R 1 = H) showed an MIC value of 3.12 µg mL −1 , the minimum inhibitory concentration of 220a (R 1 = Cl) was estimated at 6.25 µg mL −1 , and the MIC value of 221a (R 1 = Cl) was 12.5 µg mL −1 . The other compounds were moderately active (MIC 50 µg mL −1 ) against M. tuberculosis H37Rv in comparison to the standard antitubercular drugs isoniazid (INH), pyrazinamide (PZA), streptomycin (STM), and ciprofloxacin (CPF), as can be seen in Table 14. Rathod et al. [93] synthesized a series of INH compounds 220a−220d and 221a−221d using multicomponent reactions in good yields (80-94%), as can be seen in Scheme 51. Electron-withdrawing groups were reported to increase the anti-TB activity [94,95]. Compound 220c (R 1 = H) showed an MIC value of 3.12 µg mL −1 , the minimum inhibitory concentration of 220a (R 1 = Cl) was estimated at 6.25 µg mL −1 , and the MIC value of 221a (R 1 = Cl) was 12.5 µg mL −1 . The other compounds were moderately active (MIC 50 µg mL −1 ) against M. tuberculosis H37Rv in comparison to the standard antitubercular drugs isoniazid (INH), pyrazinamide (PZA), streptomycin (STM), and ciprofloxacin (CPF), as can be seen in Table 14. Rathod et al. [93] synthesized a series of INH compounds 220a-220d and 221a-221d using multicomponent reactions in good yields (80-94%), as can be seen in Scheme 51. Electron-withdrawing groups were reported to increase the anti-TB activity [94,95]. Compound 220c (R 1 = H) showed an MIC value of 3.12 µg mL −1 , the minimum inhibitory concentration of 220a (R 1 = Cl) was estimated at 6.25 µg mL −1 , and the MIC value of 221a (R 1 = Cl) was 12.5 µg mL −1 . The other compounds were moderately active (MIC 50 µg mL −1 ) against M. tuberculosis H37Rv in comparison to the standard antitubercular drugs isoniazid (INH), pyrazinamide (PZA), streptomycin (STM), and ciprofloxacin (CPF), as can be seen in Table 14.

Synthesis of Antiviral Pyridine Compounds
In recent years, several important viral infections have emerged and antiviral chemotherapeutic agents are not sufficiently effective in clinic, leading to serious human diseases and mortality. Therefore, novel antiviral candidates are urgently desirable, which is undoubtedly essential for the therapy of various fatal viral infections. Pyridine compounds are obtaining importance in the field of medicinal chemistry because of the broad spectrum of their physiological activities. In this part of the review is highlighted antiviral behavior of pyridine compounds [96]. The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment [97].
Balzarini et al. [98] reported the synthesis of pyridine N-oxide derivatives and the inhibitory effect of these compounds on human SARS and feline infectious peritonitis coronavirus in cell culture. Thus, compounds 222 and 223 were the most interesting compounds that had a comparable (potent) activity against both SARS-CoV and feline coronavirus FIPV strain (EC 50 : 1.7-4.2 mg L −1 ), being poorly cytotoxic ( Figure 22). Furthermore, they reported that a lack of the oxide moiety proved detrimental for anti-SARS-CoV and anti-FIPV activity, as none of the tested compounds was antivirally active at subtoxic concentrations [99]. coronavirus in cell culture. Thus, compounds 222 and 223 were the most interesti pounds that had a comparable (potent) activity against both SARS-CoV and feli navirus FIPV strain (EC50: 1.7-4.2 mg L −1 ), being poorly cytotoxic ( Figure 22). Furth they reported that a lack of the oxide moiety proved detrimental for anti-SARS-C anti-FIPV activity, as none of the tested compounds was antivirally active at subto centrations [99]. Continuing their research, the Ghaleb group [100] found the structural co that N-oxides must meet in order to have an increased antiviral activity, which i in Figure 23. In this study, pyridine N-oxide 223 with SARS-CoV inhibitory activ selected for a further 3 D-QSAR studies. From 3D QSAR, molecular docking mod was found that compound 224 is more potent than chloroquine and hydroxychlo against SARS-CoV-2. Moreover, 223 shows an excellent stability to inhibit the m tease 3CLpro of CoV-2 and also has excellent bioavailability and no toxicity result Continuing their research, the Ghaleb group [100] found the structural conditions that N-oxides must meet in order to have an increased antiviral activity, which is shown in Figure 23. In this study, pyridine N-oxide 223 with SARS-CoV inhibitory activity was selected for a further 3 D-QSAR studies. From 3D QSAR, molecular docking modeling, it was found that compound 224 is more potent than chloroquine and hydroxychloroquine against SARS-CoV-2. Moreover, 223 shows an excellent stability to inhibit the main protease 3CLpro of CoV-2 and also has excellent bioavailability and no toxicity results. In this study, Surflex-Dock was used for molecular docking using SYBYL-X.  Ghosh et al. [101] reported synthesis of 5-chloro-4-methylpyridin-3-yl-1H-indole-4 carboxylate 227 from 5-chloro-4-methylpyridin-3-ol 225 and 1H-indole-4-carboxylic acid 226 in the presence of EDC (1-ethyl-3-carbodiimide hydrochloride) and DMAP (4-dime thyl aminopyridine) using dichloromethane as solvent (Scheme 52). Compound 227 ex hibited potent antiviral activity (EC50 ∼ 2.2 µM) against SARS-CoV-2 3CLpro, which wa comparable to antiviral medicine Remdesivir. The authors demonstrate that the antivira activity of a compound is not because of misleading cytostatic effects or cytotoxic effect but due to an apparent destructive "antiviral effect." The determined high-resolution X ray structures of compounds bound to SARS-CoV 3CLpro and SARS-CoV-2 3CLpro en zymes revealed that catalytic Cys145 formed a covalent bond with the indole carbony group. Furthermore, the indole rings of the inhibitor formed π−π stacking interaction with the imidazole ring of His41, a residue that must move substantially before, during and after reaction with the inhibitors (Figure 24). X-ray data of the compounds were in dexed, integrated, and scaled using the HKL2000 software package.  Ghosh et al. [101] reported synthesis of 5-chloro-4-methylpyridin-3-yl-1H-indole-4carboxylate 227 from 5-chloro-4-methylpyridin-3-ol 225 and 1H-indole-4-carboxylic acid 226 in the presence of EDC (1-ethyl-3-carbodiimide hydrochloride) and DMAP (4-dimethyl aminopyridine) using dichloromethane as solvent (Scheme 52). Compound 227 exhibited potent antiviral activity (EC 50 ∼ 2.2 µM) against SARS-CoV-2 3CLpro, which was comparable to antiviral medicine Remdesivir. The authors demonstrate that the antiviral activity of a compound is not because of misleading cytostatic effects or cytotoxic effects but due to an apparent destructive "antiviral effect." The determined high-resolution X-ray structures of compounds bound to SARS-CoV 3CLpro and SARS-CoV-2 3CLpro enzymes revealed that catalytic Cys145 formed a covalent bond with the indole carbonyl group. Furthermore, the indole rings of the inhibitor formed π−π stacking interactions with the imidazole ring of His41, a residue that must move substantially before, during, and after reaction with the inhibitors (Figure 24). X-ray data of the compounds were indexed, integrated, and scaled using the HKL2000 software package. but due to an apparent destructive "antiviral effect." The determined high-resolution Xray structures of compounds bound to SARS-CoV 3CLpro and SARS-CoV-2 3CLpro enzymes revealed that catalytic Cys145 formed a covalent bond with the indole carbonyl group. Furthermore, the indole rings of the inhibitor formed π−π stacking interactions with the imidazole ring of His41, a residue that must move substantially before, during, and after reaction with the inhibitors (Figure 24). X-ray data of the compounds were indexed, integrated, and scaled using the HKL2000 software package.  but due to an apparent destructive "antiviral effect." The determined high-resolution Xray structures of compounds bound to SARS-CoV 3CLpro and SARS-CoV-2 3CLpro enzymes revealed that catalytic Cys145 formed a covalent bond with the indole carbonyl group. Furthermore, the indole rings of the inhibitor formed π−π stacking interactions with the imidazole ring of His41, a residue that must move substantially before, during, and after reaction with the inhibitors (Figure 24). X-ray data of the compounds were indexed, integrated, and scaled using the HKL2000 software package. Scheme 52. Synthesis of pyridine compound 227 [101].  Starčević et al. [102] reported the synthesis of 2-substituted-5-amidino-benzimidazoles 230a-230c from the reaction of 1,2-phenylenediamine 228 and picolinaldehyde 229. All compounds possessed excellent antiviral activity against coxsackievirus B5 and echovirus 7, with EC 50 values of 0.33-56.7 µM (Scheme 53, Table 15). Starčević et al. [102] reported the synthesis of 2-substituted-5-amidino-benzimidazoles 230a−230c from the reaction of 1,2-phenylenediamine 228 and picolinaldehyde 229. All compounds possessed excellent antiviral activity against coxsackievirus B5 and echovirus 7, with EC50 values of 0.33-56.7 µM (Scheme 53, Table 15). Scheme 53. Synthesis of pyridine compounds 230a−230c [102]. Salem et al. [103] reported the synthesis of compound 231 by cyclisation of ethyl 2-(3-cyano-4-(furan-2-yl)-6-(naphthalen-1-yl)pyridin-2-yloxy)acetate in the presence of alcoholic KOH 10% at reflux and compound 232 by refluxing 4-(furan-2-yl)-2-hydrazinyl-6-(naphthalen-1-yl) nicotinonitrile with POCl3 and PCl5, in a water bath ( Figure 25). Compounds 231 and 232 showed antiviral activity against rotavirus Wa strain and adenovirus type 7. Compound 231 showed a 60% and 53.3% reduction in viral titer with rotavirus Wa strain and adenovirus type 7, respectively. Compound 232 showed 53.3% and 50% reduction with rotavirus Wa strain and adenovirus type 7, respectively. Sekhar et al. [84] reported that compounds 202a and 202b (Scheme 44) exhibited the better antiviral activities against Newcastle disease virus (NDV) in embryonated chicken eggs by vanishing of vi-Scheme 53. Synthesis of pyridine compounds 230a-230c [102]. Salem et al. [103] reported the synthesis of compound 231 by cyclisation of ethyl 2-(3-cyano-4-(furan-2-yl)-6-(naphthalen-1-yl)pyridin-2-yloxy)acetate in the presence of alcoholic KOH 10% at reflux and compound 232 by refluxing 4-(furan-2-yl)-2-hydrazinyl-6-(naphthalen-1-yl) nicotinonitrile with POCl 3 and PCl 5 , in a water bath ( Figure 25). Compounds 231 and 232 showed antiviral activity against rotavirus Wa strain and adenovirus type 7. Compound 231 showed a 60% and 53.3% reduction in viral titer with rotavirus Wa strain and adenovirus type 7, respectively. Compound 232 showed 53.3% and 50% reduction with rotavirus Wa strain and adenovirus type 7, respectively. Sekhar et al. [84] reported that compounds 202a and 202b (Scheme 44) exhibited the better antiviral activities against Newcastle disease virus (NDV) in embryonated chicken eggs by vanishing of virus at the sixth titer (1/32). Abu-Hashem et al. [104] reported the synthesis of compounds 234a and 234b by reaction of 233a and 233b, respectively, with triethoxy-methane (Scheme 54). The data revealed that isothio chromeno-triazolopyrimidines 234a and 234b have promising in vitro antiviral activity against herpes simplex virus-1 (HSV-1) and human immunodeficiency virus-1 (HIV-1).

Conclusions
This review summarizes the syntheses of pyridine compounds with the antimicrobial and antiviral properties mentioned in the literature. Bioinformatics analysis plays a central role in finding new antimicrobial and antiviral structures, as is seen in the particular cases shown in the article. From the data presented, it can be concluded that the presence of another heterocycle (pyrazole, imidazole, thiazole, pyrimidine, benzimidazole, indole, etc.) on pyridine compounds improves antimicrobial or antiviral activities. In pyridinium salts it was found that an appropriate balance between hydrophobicity and hydrophilicity or an alkyl chain of C12-C16 improves the antimicrobial activity. Moreover, the presence of certain groups grafted on pyridine nuclei, such as -F, -Cl, -OH, -CF3, OCH3, -N(CH3)2, -NHCO, -COOCH3, -CHO, -NO2, and -CN, increases the antimicrobial and antiviral activity of the compounds. As is shown, the positions of the substituents on the pyridine molecule are also very important for the antimicrobial and antiviral activity of the compounds. Additionally, the binding linker between pyridine and another heterocycle is important for their antimicrobial and antiviral activity. Additionally, the antimicrobial activity is improved if the molecule contains linker groups such as carbonyl (CO), amide (NHCO), thioamide (NHCS), or other heteroatoms. It is also noted that pyridine compounds containing P, Se, and B, generally have an improved antimicrobial activity compared to those with only heterocyclic rings.
From the literature reports presented, we can highlight the following aspects related to the interaction of pyridine compounds, which determine the selectivity of antimicrobial action: a favorable binding interaction with Thymidylate kinase (ID: 4QG), within the binding pocket of TMPK, determines a good antimicrobial activity of bis (1H-indol-3-yl)pyridine 78d, against S. aureus, E. coli, and C. albicans strains; Scheme 54. Synthesis of pyridine compounds 234a and 234b [104].

Conclusions
This review summarizes the syntheses of pyridine compounds with the antimicrobial and antiviral properties mentioned in the literature. Bioinformatics analysis plays a central role in finding new antimicrobial and antiviral structures, as is seen in the particular cases shown in the article. From the data presented, it can be concluded that the presence of another heterocycle (pyrazole, imidazole, thiazole, pyrimidine, benzimidazole, indole, etc.) on pyridine compounds improves antimicrobial or antiviral activities. In pyridinium salts it was found that an appropriate balance between hydrophobicity and hydrophilicity or an alkyl chain of C12-C16 improves the antimicrobial activity. Moreover, the presence of certain groups grafted on pyridine nuclei, such as -F, -Cl, -OH, -CF 3 , OCH 3 , -N(CH 3 ) 2 , -NHCO, -COOCH 3 , -CHO, -NO 2 , and -CN, increases the antimicrobial and antiviral activity of the compounds. As is shown, the positions of the substituents on the pyridine molecule are also very important for the antimicrobial and antiviral activity of the compounds. Additionally, the binding linker between pyridine and another heterocycle is important for their antimicrobial and antiviral activity. Additionally, the antimicrobial activity is improved if the molecule contains linker groups such as carbonyl (CO), amide (NHCO), thioamide (NHCS), or other heteroatoms. It is also noted that pyridine compounds containing P, Se, and B, generally have an improved antimicrobial activity compared to those with only heterocyclic rings.
From the literature reports presented, we can highlight the following aspects related to the interaction of pyridine compounds, which determine the selectivity of antimicrobial action: -a favorable binding interaction with Thymidylate kinase (ID: 4QG), within the binding pocket of TMPK, determines a good antimicrobial activity of bis (1H-indol-3-yl)pyridine 78d, against S. aureus, E. coli, and C. albicans strains; -affinity and activity of thiophene-pyridines 82-84 on the target protein GlcN-6-P synthase is supported by in vitro antimicrobial screenings against almost all tested strains, S. aureus, B. subtilis, E. coli, S. typhimurium, A. flavus, and C. albicans; - The good antimicrobial activity of triazino-oxacalixarenes 150 and 151 against E. coli is due to a good covalent interaction with acyl enzyme PDB: 1PW8; -3D interaction of selenium compound 210c with 1kzn protein, the lower hydrophobicity, higher topological polar surface area, lower dipole moment, high H-bonding acceptor and donor, and in-silico absorption percentage of it explicates its highest antimicrobial activity against all tested strains, S. aureus, S. pyogenes, E. coli, P. aeruginosa, as well as a good antifungal agent, against C. albicans, A. niger, and A. clavatus; -3D QSAR, molecular docking modeling showed that pyridine-N-oxide 223 shows an excellent stability to inhibit the main protease 3CLpro of CoV-2 and also has excellent bioavailability and no toxicity results; -the excellent antiviral activity of compound 227 (EC50∼2.2 µM) against SARS-CoV-2 3CLpro comparable to antiviral medicine Remdesivir is due to binding of the compound to SARS-CoV 3CLpro and SARS-CoV-2 3CLpro enzymes, which revealed that catalytic Cys145 formed a covalent bond with the indole carbonyl group, and also indole rings of inhibitor formed π−π stacking interactions with the imidazole ring of His41. It is once again confirmed that the cleavage of SARS-CoV-2 polyproteins by 3CLpro (3-Chymotrypsin-like protease) is facilitated by a Cys145-His41 catalytic dyad [105].
We hope that this review will be useful for the synthesis of other pyridine compounds with antimicrobial and antiviral properties, in order to help the current situation of the pandemic, with the infection with SARS-CoV-2.