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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

Synthesis and Antimycobacterial Activity of Isoniazid Derivatives Tethered with Aliphatic Amines

Author(s): Václav Pflégr, Jiřina Stolaříková, Jarmila Vinšová and Martin Krátký*

Volume 22, Issue 32, 2022

Published on: 27 August, 2022

Page: [2695 - 2706] Pages: 12

DOI: 10.2174/1568026622666220805152811

Price: $65

Abstract

Background: There is an urgent need for new antitubercular compounds. Modification of antimycobacterial isonicotinohydrazide at hydrazide N2 provided antimycobacterial active compounds.

Objective: Combining this scaffold with various aliphatic amines that are also frequently present in antitubercular compounds, we have designed, synthesized, and evaluated twenty-three N- (cyclo)alkyl-2-(2-isonicotinoylhydrazineylidene)propanamides and their analogues as potential antimycobacterial compounds. By increasing lipophilicity, we intended to facilitate the penetration of mycobacteria's highly impermeable cell wall.

Methods: The target amides were prepared via condensation of isoniazid and pyruvic acid, followed by carbodiimide-mediated coupling with yields from 35 to 98 %. The compounds were screened against Mycobacterium tuberculosis H37Rv and two nontuberculous mycobacteria (M. avium, M. kansasii).

Results: All the derivatives exhibited low minimum inhibitory concentrations (MIC) from ≤0.125 and 2 μM against M. tuberculosis and nontuberculous mycobacteria, respectively. The most active molecules were substituted by a longer n-alkyl from C8 to C14. Importantly, the compounds showed comparable or even several-fold lower MIC than parent isonicotinohydrazide. Based on in silico predictions, a vast majority of the derivatives share suitable physicochemical properties and structural features for drug-likeness.

Conclusion: Presented amides are promising antimycobacterial agents.

Keywords: Amides, Antimycobacterial activity, Hydrazides, Hydrazones, Isoniazid, Pyruvic acid, Tuberculosis.

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[1]
WHO. Global Tuberculosis Report 2020. Geneva:, 2020. Available from: https://www.who.int/publications/i/item/9789240013131
[2]
Pinheiro, D.O.; Pessoa, M.S.L.; Lima, C.F.C.; Holanda, J.L.B. Tuberculosis and coronavirus disease 2019 coinfection. Rev. Soc. Bras. Med. Trop., 2020, 53, e20200671.
[http://dx.doi.org/10.1590/0037-8682-0671-2020] [PMID: 33174965]
[3]
Seung, K.J.; Keshavjee, S.; Rich, M.L. Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Cold Spring Harb. Perspect. Med., 2015, 5(9), a017863.
[http://dx.doi.org/10.1101/cshperspect.a017863] [PMID: 25918181]
[4]
Rychtarčíková, Z.; Krátký, M.; Gazvoda, M.; Komlóová, M.; Polanc, S.; Kočevar, M.; Stolaříková, J.; Vinšová, J. N-substituted 2-isonicotinoylhydrazinecarboxamides new antimycobacterial active molecules. Molecules, 2014, 19(4), 3851-3868.
[http://dx.doi.org/10.3390/molecules19043851] [PMID: 24686575]
[5]
Vosátka, R.; Krátký, M.; Švarcová, M.; Janoušek, J. Stolaříková, J.; Madacki, J.; Huszár, S.; Mikušová, K.; Korduláková, J.; Trejtnar, F.; Vinšová, J. New lipophilic isoniazid derivatives and their 1,3,4-oxadiazole analogues: Synthesis, antimycobacterial activity and investigation of their mechanism of action. Eur. J. Med. Chem., 2018, 151, 824-835.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.017] [PMID: 29679902]
[6]
Rodrigues, M.O.; Cantos, J.B.; D’Oca, C.R.M.; Soares, K.L.; Coelho, T.S.; Piovesan, L.A.; Russowsky, D.; da Silva, P.A.; D’Oca, M.G.M. Synthesis and antimycobacterial activity of isoniazid derivatives from renewable fatty acids. Bioorg. Med. Chem., 2013, 21(22), 6910-6914.
[http://dx.doi.org/10.1016/j.bmc.2013.09.034] [PMID: 24103427]
[7]
Pflégr, V.; Horváth, L.; Stolaříková, J.; Pál, A.; Korduláková, J.; Bősze, S.; Vinšová, J.; Krátký, M. Design and synthesis of 2-(2-isonicotinoylhydrazineylidene)propanamides as InhA inhibitors with high antitubercular activity. Eur. J. Med. Chem., 2021, 223, 113668.
[http://dx.doi.org/10.1016/j.ejmech.2021.113668] [PMID: 34198149]
[8]
Pflégr, V.; Maixnerová, J.; Stolaříková, J.; Pál, A.; Korduláková, J.; Trejtnar, F.; Vinšová, J.; Krátký, M. Design and synthesis of highly active antimycobacterial mutual esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid. Pharmaceuticals (Basel), 2021, 14(12), 1302.
[http://dx.doi.org/10.3390/ph14121302] [PMID: 34959704]
[9]
Sacksteder, K.A.; Protopopova, M.; Barry, C.E., III; Andries, K.; Nacy, C.A. Discovery and development of SQ109: A new antitubercular drug with a novel mechanism of action. Future Microbiol., 2012, 7(7), 823-837.
[http://dx.doi.org/10.2217/fmb.12.56] [PMID: 22827305]
[10]
Kryukova, L.M.; Zelenin, K.N.; Értevtsian, L.N.; Dobrego, V.A. Synthesis and bacteriostatic activity of thiosemicarbazones and isonicotinoylhydrazones of pyruvic acid. Pharm. Chem. J., 1977, 11, 1609-1611.
[http://dx.doi.org/10.1007/BF00778278]
[11]
Vila-Viçosa, D.; Victor, B.L.; Ramos, J.; Machado, D.; Viveiros, M.; Switala, J.; Loewen, P.C.; Leitão, R.; Martins, F.; Machuqueiro, M. Insights on the mechanism of action of INH-C10 as an antitubercular prodrug. Mol. Pharm., 2017, 14(12), 4597-4605.
[http://dx.doi.org/10.1021/acs.molpharmaceut.7b00719] [PMID: 29091448]
[12]
Ventura, C.; Latino, D.A.R.S.; Martins, F. Comparison of multiple linear regressions and neural networks based QSAR models for the design of new antitubercular compounds. Eur. J. Med. Chem., 2013, 70, 831-845.
[http://dx.doi.org/10.1016/j.ejmech.2013.10.029] [PMID: 24246731]
[13]
Martins, F.; Santos, S.; Ventura, C.; Elvas-Leitão, R.; Santos, L.; Vitorino, S.; Reis, M.; Miranda, V.; Correia, H.F.; Aires-de-Sousa, J.; Kovalishyn, V.; Latino, D.A.R.S.; Ramos, J.; Viveiros, M. Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity. Eur. J. Med. Chem., 2014, 81, 119-138.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.077] [PMID: 24836065]
[14]
Baldi, A. Computational approaches for drug design and discovery: An overview. Sys. Rev. Pharm, 2010, 1, 99-105.
[http://dx.doi.org/10.4103/0975-8453.59519]
[15]
Mohan, S.B.; Dinda, S.C.; Kumar, R.B.; Panda, J.R. Computational approaches for drug design and discovery process. J. Curr. Pharm. Res., 2012, 2, 600-611.
[http://dx.doi.org/10.33786/JCPR.2012.v02i03.015]
[16]
Hung, C.L.; Chen, C.C. Computational approaches for drug discovery. Drug Dev. Res., 2014, 75(6), 412-418.
[http://dx.doi.org/10.1002/ddr.21222] [PMID: 25195585]
[17]
Brogi, S. Computational approaches for drug discovery. Molecules, 2019, 24(17), 3061.
[http://dx.doi.org/10.3390/molecules24173061] [PMID: 31443558]
[18]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[19]
Delaney, J.S. ESOL: Estimating aqueous solubility directly from molecular structure. J. Chem. Inf. Comput. Sci., 2004, 44(3), 1000-1005.
[http://dx.doi.org/10.1021/ci034243x] [PMID: 15154768]
[20]
Daina, A.; Zoete, V. A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem, 2016, 11(11), 1117-1121.
[http://dx.doi.org/10.1002/cmdc.201600182] [PMID: 27218427]
[21]
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[22]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1999, 1(1), 55-68.
[http://dx.doi.org/10.1021/cc9800071] [PMID: 10746014]
[23]
Baell, J.B.; Holloway, G.A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem., 2010, 53(7), 2719-2740.
[http://dx.doi.org/10.1021/jm901137j] [PMID: 20131845]
[24]
Baell, J.B.; Nissink, J.W.M. Seven year itch: Pan-assay interference compounds (PAINS) in 2017-utility and limitations. ACS Chem. Biol., 2018, 13(1), 36-44.
[http://dx.doi.org/10.1021/acschembio.7b00903] [PMID: 29202222]

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