Novel benzimidazole derivatives; synthesis, bioactivity and molecular docking study as potent urease inhibitors.

Background: Benzimidazole derivatives are widely used to design and synthesize novel bioactive compounds. There are several approved benzimidazole-based drugs on the market.

Objectives: In this study, we aimed to design and synthesize a series of novel benzimidazole derivatives 8a-n that are urease inhibitors.

Methods: All 8a-n were synthesized in a multistep. To determine the urease inhibitory effect of 8a-n, the urease inhibition kit was used. The cytotoxicity assay of 8a-n was determined using MTT method. Molecular modelling was determined using autodock software.

Results: All 8a-n were synthesized in high yield, and their structures were determined using ¹H-NMR, ¹³C-NMR, MS, and elemental analyses. In compared to thiourea and hydroxyurea as standards (IC50: 22 and 100 µM, respectively), all 8a-n had stronger urease inhibition activity (IC50: 3.36-10.81 µM). With an IC50 value of 3.36 µM, 8e had the best enzyme inhibitory activity. On two evaluated cell lines, the MTT cytotoxicity experiment revealed that all 8a-n have IC50 values greater than 50 µM. Finally, a docking investigation revealed a plausible way of interaction between the 8e and 8d and the enzyme's active site's key residues.

Conclusion: The synthesized benzimidazole derivatives exhibit high activity, suggesting that further research on this family of compounds would be beneficial to finding a potent urease inhibitor.