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Molecules 2017, 22(3), 495; doi:10.3390/molecules22030495

3-Substituted N-Benzylpyrazine-2-carboxamide Derivatives: Synthesis, Antimycobacterial and Antibacterial Evaluation

1
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
2
Department of Clinical Microbiology, University Hospital, Sokolská 581, 500 05 Hradec Králové, Czech Republic
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 6 February 2017 / Revised: 6 March 2017 / Accepted: 17 March 2017 / Published: 21 March 2017
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [1086 KB, uploaded 21 March 2017]   |  

Abstract

A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N-benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N-(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) and N-(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 μg·mL−1. Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) against Staphylococcus aureus with MIC = 7.81 μM, and Staphylococcus epidermidis with MIC = 15.62 μM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis. In some cases, it was capable of H-bond interactions, typical for most of the known inhibitors. View Full-Text
Keywords: pyrazinamide derivatives; benzylamines; antibacterial activity; antimycobacterial activity; cytotoxicity; enoyl-ACP-reductase; molecular docking pyrazinamide derivatives; benzylamines; antibacterial activity; antimycobacterial activity; cytotoxicity; enoyl-ACP-reductase; molecular docking
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Semelková, L.; Janďourek, O.; Konečná, K.; Paterová, P.; Navrátilová, L.; Trejtnar, F.; Kubíček, V.; Kuneš, J.; Doležal, M.; Zitko, J. 3-Substituted N-Benzylpyrazine-2-carboxamide Derivatives: Synthesis, Antimycobacterial and Antibacterial Evaluation. Molecules 2017, 22, 495.

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