Title:Synthesis and Antimycobacterial Activity of Isoniazid Derivatives Tethered
with Aliphatic Amines
Volume: 22
Issue: 32
Author(s): Václav Pflégr, Jiřina Stolaříková, Jarmila Vinšová and Martin Krátký*
Affiliation:
- Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University,
Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
Keywords:
Amides, Antimycobacterial activity, Hydrazides, Hydrazones, Isoniazid, Pyruvic acid, Tuberculosis.
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.
