Design, Synthesis and Mechanistic Studies of Novel Isatin-Pyrazole Hydrazone Conjugates as Selective and Potent Bacterial MetAP Inhibitors.

Methionine aminopeptidases (MetAPs) are attractive drug targets due to their essential role in eukaryotes as well as prokaryotic cells. In this study, biochemical assays were performed on newly synthesized Isatin-pyrazole hydrazones () to identify potent and selective bacterial MetAP inhibitors. Compound inhibited prokaryotic MetAP, i.e., MetAP1c, MetAP1a and MetAP1a with values of 0.31, 6.93 and 0.37 µM, respectively. Interestingly, inhibited the human analogue MetAP1b with i (631.7 µM) about ten thousand-fold higher than the bacterial MetAPs. The in vitro screening against Gram-positive ( and ) and Gram-negative ( and ) bacterial strains also exhibited their antibacterial potential supported by minimum bactericidal concentration (MBC), disk diffusion assay, growth curve and time-kill curve experiments. Additionally, and had synergistic effects when combined with ampicillin (AMP) and ciprofloxacin (CIP) against selective bacterial strains. showed no significant cytotoxic effect on human RBCs, HEK293 cells and larvae in vivo. inhibited the growth of multidrug-resistant environmental isolates as it showed the MIC lower than the standard drugs used against selective bacterial strains. Overall, the study suggested could be a useful candidate for the development of antibacterial alternatives.