Synthesis of novel 2-mercapto-1,3,4-oxadiazole derivatives as potent urease inhibitors: In vitro and in silico investigations

•A series of 2-mercapto-1,3,4-oxadiazole has been successfully synthesized.•All compounds underwent characterization using IR, NMR and Mass spectrometry.•These compounds were evaluated as urease inhibitors.•DFT used to predict the electronic, structural and spectroscopic properties.•The docking study contributed to the analysis of urease protein binding. In the present work seven derivatives (5a-5d and 6a-6c) of 2-mercapto-1,3,4-oxadiazole were synthesized by multistep reactions. After characterization through IR, EI-MS, 1H-, and 13C NMR spectroscopy, the synthesized compounds were screened in vitro against urease enzyme. Among the series, five derivatives 6c (IC50 = 9.90 ± 1.92 µM), 6a (IC50 = 10.65 ± 1.80 µM), 6b (IC50 = 12.30 ± 0.99 µM), 5c (IC50 = 12.57 ± 0.41 µM), and 5d (IC50 = 16.96 ± 0.64 µM) attributed excellent inhibition effect excellent than the standard thiourea (IC50 = 22.80 ± 2.20 µM). In addition, the remaining four compounds 5a, 5b, 4, and 3 were found good inhibitors against the urease enzyme with IC50 values of 23.23 ± 0.17, 25.20 ± 0.90, 31.40 ± 1.18, and 36.77 ± 1.03 µM respectively. The cytotoxicity assay revealed that the synthetic derivatives did not show any cytotoxic effect. DFT used to calculate frontier molecular orbital including; HOMO and LUMO to indicate the charge transfer from molecule to biological media, and MEP map to indicate the chemically reactive zone suitable for drug action. The results of docking and MD simulation indicate that most active mercapto-1,3,4-oxadiazoles have high binding efficiency to urease. The In silico ADMET indicated that 5a-d and 6a-c compounds did not exhibit carcinogenicity, mutagenicity or tumorigenicity. [Display omitted]