Synthesis, Mycobacterium tuberculosis H₃₇Rv inhibitory activity, and molecular docking study of pyrazinamide analogs

Pyrazinamide analogs 5a-h have been successfully synthesized by the Yamaguchi esterification method with yields ranging from 6% to 86%. Among pyrazinamides 5a-h, pyrazinamides 5d,g showed the best antituberculosis activity with MIC values <6.25 µg/ml. Based on the molecular docking studies, all the synthesized pyrazinamide had lower binding energy than pyrazinamide itself (-5.21 kcal/mol), except 5e with a value of -2.83 kcal/mol. Pyrazinamides 5d and 5g showed lower binding energy (-6.36 and -5.91 kcal/mol, respectively) than the native ligand (-5.83 kcal/mol) and pyrazinamide (-5.21 kcal/mol). The lower binding energy of 5d than that of 5g because it interacted strongly with Arg54* via hydrogen bonding, while 5g only interacted via π-cation interaction. However, 5g formed two hydrogen bonds with Tyr90* and Thr57 residues. These findings suggest that the most active compounds 5d, g could be regarded as promising candidates for discovering new antitubercular drugs.