Design, synthesis and antimycobacterial activity of hybrid molecules combining pyrazinamide with a 4-phenylthiazol-2-amine scaffold

Abstract

Hybrid compounds based on a combination of the first-line antitubercular pyrazinamide (PZA) and a formerly identified antimycobacterial scaffold of 4-arylthiazol-2-amine were designed. Eighteen compounds were prepared, characterized and tested for <i>in vitro</i> growth inhibition activity against <i>M. tuberculosis</i> H37Rv, <i>M. kansasii</i>, <i>M. avium</i> and <i>M. smegmatis</i> by Microplate Alamar Blue Assay at neutral pH. Active compounds were tested for <i>in vitro</i> cytotoxicity in the human hepatocellular carcinoma cell line (HepG2). The most active 6-chloro-<i>N</i>-[4-(4-fluorophenyl)thiazol-2-yl]pyrazine-2-carboxamide (9b) also had the broadest spectrum of activity and inhibited <i>M. tuberculosis</i>, <i>M.</i> kansasii, and <i>M. avium</i> with MIC = 0.78 μg mL^-1 (2.3 μM) and a selectivity index related to HepG2 cells of SI > 20. Structure-activity relationships within the series are discussed. Based on its structural similarity to known inhibitors and the results of a molecular docking study, we suggest mycobacterial beta-ketoacyl-(acyl-carrier-protein) synthase III (FabH) as a potential target.