Synthesis of new 1,2-disubstituted benzimidazole analogs as potent inhibitors of β-Glucuronidase and in silico study

New benzimidazole analogues (1-18) were synthesized and characterized through different spectroscopic techniques such as H-1 NMR, C-13 NMR and HREI-MS. All analogues were screened for beta-glucuronidase inhibitory potential. All analogues showed varied degree of inhibitory potentials with IC50 values ranging between 1.10 +/- 0.10 to 39.60 +/- 0.70 mu M when compared with standard (D)-saccharic acid -1,4-lactone having IC50 value 48.30 mu M. Analogues 17, 11, 9, 6, 1 and 13 having IC50 values 1.10 +/- 0.10, 1.70 +/- 0.10, 2.30 +/- 0.10, 5.30 +/- 0.20, 6.20 +/- 0.20 and 8.10 +/- 0. 20 mu M respectively, showed excellent beta-glucuronidase inhibitory potential many folds better than the standard. All other analogues also showed good inhibitory potential better as compared to standard. Structure activity relationships (SAR) has been established for all compounds. The results from molecular docking studies supports the established SAR and developed a strong correlation with the results from in to vitro assay. The molecular docking results clearly highlighted how substituents like nitro and chloro affect the binding position of the active compounds in the active site. The docking results were also used to properly establish the effect of bulky substituents of least active compounds on reduced beta-glucuronidase inhibitory activity. Compounds 1-18 were found non-toxic. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.

Automated summary

New benzimidazole analogues (1-18) were synthesized and characterized using various spectroscopic techniques, and were screened for beta-glucuronidase inhibitory potential. The results showed that compounds 17, 11, 9, 6, 1, and 13 exhibited excellent inhibitory activity, with superior potency compared to the standard. Molecular docking studies highlighted the impact of substituents on binding position, and indicated the effect of bulky substituents on reducing inhibitory activity.