Synthesis and Antimycobacterial Activity of Isoniazid Derivatives Tethered with Aliphatic Amines.
Curr Top Med Chem, 2022;22(32):2695-2706.
Pflégr V[1], Stolaříková J[2], Vinšová J[1], Krátký M[1]
Affiliations
PMID: 35929626DOI: 10.2174/1568026622666220805152811
Impact factor: 3.57
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.
MeSH terms
Isoniazid; Antitubercular Agents; Mycobacterium tuberculosis; Amines; Amides; Microbial Sensitivity Tests
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