Research Paper on Novel Isatin-Pyrazole Hydrazone Conjugates as Selective and Potent Bacterial MetAP Inhibitors: Design, Synthesis, and Mechanistic Studies

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

Abstract: Methionine aminopeptidases (MetAPs) play a crucial role in both eukaryotic and prokaryotic cells, making them desirable drug targets. In this study, potent and specific bacterial MetAPs inhibitors were found using biochemical assays on freshly synthesized isatin-pyrazole hydrazones (PS1-14). Prokaryotic MetAPs, i.e., MtMetAP1c, EfMetAP1a, and SpMetAP1a, were inhibited by compound PS9 with Ki values of 0.31, 6.93, and 0.37 M, respectively. It’s interesting to note that PS9 inhibited the human analogue HsMetAP1b with a Ki (631.7 M) value that was 10,000 times higher than that of the bacterial MetAPs. As demonstrated by minimum bactericidal concentration (MBC), disk diffusion assay, growth curve, and time-kill curve experiments, in vitro screening against Gram-positive (Enterococcus faecalis, Bacillus subtilis, and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumonia, and Escherichia coli) bacterial strains also demonstrated its antibacterial potential Additionally, PS6 and PS9 combined with ciprofloxacin (CIP) and ampicillin (AMP) had synergistic effects against specific bacterial strains. In vivo testing on human RBCs, HEK293 cells, and Galleria mellonella larvae revealed no detectable cytotoxic effects of PS9. PS9 demonstrated a lower MIC than the common medications used to treat specific bacterial strains, which prevented the growth of multidrug-resistant environmental isolates. Overall, the research indicated that PS9 might be a good candidate for the creation of antibacterial substitutes.

Keywords: Isatin-pyrazole hydrazone; ESKAPE; antibacterial; MDR; cytotoxicity; MetAP

Paper Quality: SCOPUS / Web of Science Level Research Paper

Subject: Antibiotics

Writer Experience: 20+ Years

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