Synthesis and Antimycobacterial Activity of Isoniazid Derivatives Tetheredwith Aliphatic Amines

Background: There is an urgent need for new antitubercular compounds. Modification of antimycobacterial isonicotinohydrazide at hydrazide N2 provided antimycobacterial active com-pounds. 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 an-timycobacterial 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 struc-tural features for drug-likeness. Conclusion: Presented amides are promising antimycobacterial agents.