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.

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Králové Charles University Akademika Heyrovského 1203 500 05 Hradec Králové Czech Republic

Laboratory for Mycobacterial Diagnostics and Tuberculosis Regional Institute of Public Health in Ostrava Partyzánské náměstí 7 702 00 Ostrava Czech Republic

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Global Tuberculosis Report 2020 Geneva: WHOAvailable from: 2020

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