A series of N-pyridinylbenzamides was designed and prepared to investigate the influence of isosterism and positional isomerism on antimycobacterial activity. Comparison to previously published isosteric N-pyrazinylbenzamides was made as an attempt to draw structure-activity relationships in such type of compounds. In total, we prepared 44 different compounds, out of which fourteen had minimum inhibitory concentration (MIC) values against Mycobacterium tuberculosis H37Ra below 31.25 µg/ml, most promising being N-(5-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (23) and N-(6-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (24) with MIC = 7.81 µg/ml (26 µm). Five compounds showed broad-spectrum antimycobacterial activity against M. tuberculosis H37Ra, M. smegmatis and M. aurum. N-(pyridin-2-yl)benzamides were generally more active than N-(pyridin-3-yl)benzamides, indicating that N-1 in the parental structure of N-pyrazinylbenzamides might be more important for antimycobacterial activity than N-4. Marginal antibacterial and antifungal activity was observed for title compounds. The hepatotoxicity of title compounds was assessed in vitro on hepatocellular carcinoma cell line HepG2, and they may be considered non-toxic (22 compounds with IC50 over 200 µm).

Faculty of Pharmacy in Hradec Králové Charles University Hradec Králové Czech Republic

Zobrazit více v PubMed

Adachi, R., Okada, K., Skene, R., Ogawa, K., Miwa, M., Tsuchinaga, K., Ohkubo, S., Henta, T., & Kawamoto, T. (2017). Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline. Biochemical and Biophysical Research Communications, 488, 393-399. https://doi.org/10.1016/j.bbrc.2017.05.064

Adamek, R. N., Credille, C. V., Dick, B. L., & Cohen, S. M. (2018). Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition. Journal of Biological Inorganic Chemistry, 23, 1129-1138. https://doi.org/10.1007/s00775-018-1593-1

Ambrożkiewicz, W., Kučerová-Chlupáčová, M., Janďourek, O., Konečná, K., Paterová, P., Bárta, P., Vinšová, J., Doležal, M., & Zitko, J. (2020). 5-Alkylamino-N-phenylpyrazine-2-carboxamides: Design, preparation, and antimycobacterial evaluation. Molecules, 25, 1561. https://doi.org/10.3390/molecules25071561

Bates, B. S., Rodriguez, A. L., Felts, A. S., Morrison, R. D., Venable, D. F., Blobaum, A. L., Byers, F. W., Lawson, K. P., Daniels, J. S., Niswender, C. M., Jones, C. K., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2014). Discovery of VU0431316: A negative allosteric modulator of mGlu(5) with activity in a mouse model of anxiety. Bioorganic & Medicinal Chemistry Letters, 24, 3307-3314. https://doi.org/10.1016/j.bmcl.2014.06.003

Begouin, A., & Queiroz, M.-J.-R.-P. (2009). Palladium-Catalysed Multicomponent Aminocarbonylation of Aryl or Heteroaryl Halides with [Mo(CO)6] and Aryl- or ­Heteroarylamines Using Conventional Heating. European Journal of Organic Chemistry, 2009, 2820-2827. https://doi.org/10.1002/ejoc.200900167

Dragovich, P. S., Zhao, G., Baumeister, T., Bravo, B., Giannetti, A. M., Ho, Y.-C., Hua, R., Li, G., Liang, X., Ma, X., O’Brien, T., Oh, A., Skelton, N. J., Wang, C., Wang, W., Wang, Y., Xiao, Y., Yuen, P.-W., Zak, M., … Zheng, X. (2014). Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT). Bioorganic & Medicinal Chemistry Letters, 24, 954-962. https://doi.org/10.1016/j.bmcl.2013.12.062

Elemans, J., Bijsterveld, E. J. A., Rowan, A. E., & Nolte, R. J. M. (2007). Manganese porphyrin hosts as epoxidation catalysts - Activity and stability control by axial ligand effects. European Journal of Organic Chemistry, 2007, 751-757. https://doi.org/10.1002/ejoc.200600648

Franzblau, S. G., Witzig, R. S., McLaughlin, J. C., Torres, P., Madico, G., Hernandez, A., Degnan, M. T., Cook, M. B., Quenzer, V. K., Ferguson, R. M., & Gilman, R. H. (1998). Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay. Journal of Clinical Microbiology, 36, 362-366. https://doi.org/10.1128/JCM.36.2.362-366.1998

Gopal, P., Nartey, W., Ragunathan, P., Sarathy, J., Kaya, F., Yee, M., Setzer, C., Manimekalai, M. S. S., Dartois, V., Grüber, G., & Dick, T. (2017). Pyrazinoic acid inhibits mycobacterial coenzyme A biosynthesis by binding to aspartate decarboxylase PanD. ACS Infectious Diseases, 3, 807-819. https://doi.org/10.1021/acsinfecdis.7b00079

Irikura, T., & Kasuga, K. (1971). New antiulcer agents. 1. Syntheses and biological activities of 1-acyl-2-,-3-, and -4-substituted benzamidopiperidines. Journal of Medicinal Chemistry, 14, 357-361. https://doi.org/10.1021/jm00286a021

Jetter, M. C., McNally, J. J., Youngman, M. A., McDonnell, M. E., Dubin, A. E., Nasser, N., Zhang, S.-P., Codd, E. E., Colburn, R. W., Stone, D. R., Brandt, M. R., Flores, C. M., & Dax, S. L. (2008). N-pyridin-3-yl- and N-quinolin-3-yl-benzamides: Modulators of human vanilloid receptor 1 (TRPV1). Bioorganic & Medicinal Chemistry Letters, 18, 2730-2734. https://doi.org/10.1016/j.bmcl.2008.02.075

Joseph, J., Dixit, S. R., & Pujar, G. V. (2019). Design, synthesis and in-vitro evaluation of aryl amides as potent inhibitors against Mycobacterium tuberculosis. Journal of Pharmaceutical Sciences and Research, 11, 3166-3173.

Juhás, M., & Zitko, J. (2020). Molecular interactions of pyrazine-based compounds to proteins. Journal of Medicinal Chemistry, 63, 8901-8916. https://doi.org/10.1021/acs.jmedchem.9b02021

Katritzky, A. R., El-Gendy Bel, D., Todadze, E., & Abdel-Fattah, A. A. (2008). (Alpha-aminoacyl)amino-substituted heterocycles and related compounds. The Journal of Organic Chemistry, 73, 5442-5445. https://doi.org/10.1021/jo8007379

Luan, F., Cordeiro, M. N. D. S., Alonso, N., García-Mera, X., Caamaño, O., Romero-Duran, F. J., Yañez, M., & González-Díaz, H. (2013). TOPS-MODE model of multiplexing neuroprotective effects of drugs and experimental-theoretic study of new 1,3-rasagiline derivatives potentially useful in neurodegenerative diseases. Bioorganic & Medicinal Chemistry, 21, 1870-1879. https://doi.org/10.1016/j.bmc.2013.01.035

Miletin, M., Kopecký, K., Novakova, V., Zimcik, P., Cidlina, A., & Svec, J. (2015). Preparation and use of pyrazine derivatives and isosteres thereof as compounds binding to DNA minor groove. Czech Republic Patent No. CZ 305332.

Mndzhoyan, A. L., & Afrikyan, V. G. (1957). Amides of the pyridine and thiazole series. Izvest Akad Nauk Armyan SSR, Ser Khim Nauk, 10, 143-156.

Mndzhoyan, A. L., Apoyan, N. A., Zhuruli, L. D., & Ter-Zakharyan, Y. Z. (1962). Effect of organic acids of pyridyl and thiazolylamides on certain members of coli-typhosal, staphylococcal, streptococcal groups and on acid-resistant mycobacteria. Biologicheskie Svoistva Khimicheskikh Soedinenii, 219-233.

Phelan, J., Maitra, A., McNerney, R., Nair, M., Gupta, A., Coll, F., Pain, A., Bhakta, S., & Clark, T. G. (2015). The draft genome of Mycobacterium aurum, a potential model organism for investigating drugs against Mycobacterium tuberculosis and Mycobacterium leprae. International Journal of Mycobacteriology, 4, 207-216. https://doi.org/10.1016/j.ijmyco.2015.05.001

Piccaro, G., Poce, G., Biava, M., Giannoni, F., & Fattorini, L. (2015). Activity of lipophilic and hydrophilic drugs against dormant and replicating Mycobacterium tuberculosis. Journal of Antibiotics, 68, 711-714. https://doi.org/10.1038/ja.2015.52

Russell, C. C., Stevens, A., Young, K. A., Baker, J. R., McCluskey, S. N., Khazandi, M. et al (2019). Discovery of 4,6-bis(2-((E)-benzylidene)hydrazinyl)pyrimidin-2-Amine with Antibiotic Activity. ChemistryOpen, 8, 896-907. https://doi.org/10.1002/open.201800241

Shi, W., Zhang, X., Jiang, X., Yuan, H., Lee, J. S., Barry, C. E., Wang, H., Zhang, W., & Zhang, Y. (2011). Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science, 333, 1630-1632. https://doi.org/10.1126/science.1208813

Sun, Q., Li, X., Perez, L. M., Shi, W., Zhang, Y., & Sacchettini, J. C. (2020). The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD. Nature Communications, 11, 339. https://doi.org/10.1038/s41467-019-14238-3

Szirtes, T., Palosi, E., Ezer, E., Szporny, L., & Kisfaludy, L. (1973). Preparation and pharmacological action of new urethane-type compounds. Acta Pharmaceutica Hungarica, 43, 224-228.

Theodorou, V., Gogou, M., Giannoussi, A., & Skobridis, K. (2014). Insights into the N, N-diacylation reaction of 2-aminopyrimidines and deactivated anilines: An alternative N-monoacylation reaction. Arkivoc, 2014(4), 11-23. https://doi.org/10.3998/ark.5550190.p008.209

Timari, G., Hajos, G., & Messmer, A. (1990). Synthesis, alkylation and ring-opening of 2 differently fused pyridoquinazolones. Journal of Heterocyclic Chemistry, 27, 2005-2009. https://doi.org/10.1002/jhet.5570270730

Ueda, S., & Nagasawa, H. (2009). Copper-catalyzed synthesis of benzoxazoles via a regioselective C-H functionalization/C-O bond formation under an air atmosphere. Journal of Organic Chemistry, 74, 4272-4277. https://doi.org/10.1021/jo900513z

Von der Saal, W., Mertens, A., Zilch, H., Boehm, E., & Martin, U. (1989). Preparation of tertiary-butylphenylcarbamoylpyridines as cardiovascular agents. Patent No. DE3804346A1.

World_Health_Organisation. (2019). Global Tuberculosis Report 2019. WHO/CDS/TB/2019.15. Available online: http://www.who.int/tb/publications/global_report/en/

World_Health_Organisation. (2020). WHO Consolidated Guidelines on Tuberculosis, Module 4: Treatment - Drug-Resistant Tuberculosis Treatment. https://www.who.int/publications/i/item/9789240007048

Yew, W. W., & Leung, C. C. (2006). Antituberculosis drugs and hepatotoxicity. Respirology, 11, 699-707. https://doi.org/10.1111/j.1440-1843.2006.00941.x

Zimmer, C., Hafner, M., Zender, M., Ammann, D., Hartmann, R. W., & Vock, C. A. (2011). N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2). Bioorganic & Medicinal Chemistry Letters, 21, 186-190. https://doi.org/10.1016/j.bmcl.2010.11.040

Zitko, J., Mindlová, A., Valášek, O., Jand’ourek, O., Paterová, P., Janoušek, J., Konečná, K., & Doležal, M. (2018). Design, Synthesis and evaluation of N-pyrazinylbenzamides as potential antimycobacterial agents. Molecules, 23, 2390. https://doi.org/10.3390/molecules23092390

Antimicrobial and Antiproliferative Properties of 2-Phenyl-N-(Pyridin-2-yl)acetamides

Design, Synthesis and Antimicrobial Evaluation of New N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole