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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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