Synthesis and Antimycobacterial Activity of Isoniazid Derivatives Tethered with Aliphatic Amines

Background: There is an urgent need for new antitubercular compounds. Modification of antimycobacterial isonicotinohydrazide at hydrazide N-2 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 H(37)Rv and two nontuberculous mycobacteria (M. avium, M. kansasii). Results: All the derivatives exhibited low minimum inhibitory concentrations (MIC) from <= 0.125 and 2 mu M against M. tuberculosis and nontuberculous mycobacteria, respectively. The most active molecules were substituted by a longer n-alkyl from C-8 to C-14. 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.

Automated summary

A total of 23 N-(cyclo)alkyl-2-(2-isonicotinoylhydrazineylidene)propanamides and their analogues were designed, synthesized, and evaluated as potential antimycobacterial compounds. These compounds showed low minimum inhibitory concentrations (MIC) against both Mycobacterium tuberculosis and nontuberculous mycobacteria, and exhibited even lower MIC values compared to parent isonicotinohydrazide.