Discovery a novel of thiazolo[3,2-a]pyridine and pyrazolo[3,4-d]thiazole derivatives as DNA gyrase inhibitors; design, synthesis, antimicrobial activity, and some in-silico ADMET with molecular docking study

Abstract

In our continuous efforts to develop novel and effectual antimicrobial agents, we herein synthesized a novel thiazolo[3,2-a]pyridine and pyrazolo[3,4-d]thiazole derivatives hybrid with pyrazole scaffold. The structure of seventeen synthesized derivatives was confirmed using IR, NMR, Mass spectra, and elemental analysis. The desired compounds have undergone an appraisal for their antimicrobial activity in vitro against six clinical MDR bacterial and fungal isolates through the agar well-diffusion, demonstrating promising results. Additionally, five thiazolo[3,2-a]pyridine derivatives 2a, 2e, 2g, 3c, and 3d revealed significant potent activity against the tested pathogens, with compound 2e as the most active compound with values ranging MIC = 0.125–0.25 µg/mL and MBC = 0.0625–0.125 µg/mL against bacterial isolate and MIC = 0.25 µg/mL and MFC = 0.125 µg/mL against two fungal isolates. In the MBC, MFC, and time-kill, the active target compounds showed -cidal activities towards the pathogenic isolates at different concentrations, and the isolates were not recovered from the treated groups with 1XMIC after 6-24 h of bacterial incubation and after 12 h of fungal incubation, confirming -cidal activity. Moreover, compound 2e exhibited DNA gyrase inhibitor with IC50 = 7.35 µM compared with Ciprofloxacin (IC50 = 47.68 µM). Finally, the docking simulation was performed to determine the mode of molecular interaction. The results exhibited that compound 2e revealed the lowest binding energy S = - 20.84 Kcal/mol compared with Ciprofloxacin S = -13.67 Kcal/mol. In silico, ADMET displayed that compound 2e obeys the Lipinski rule and, therefore, is predicted to be oral bioavailability with a non-toxic and skin sensitization profile.