Rational Design and Synthesis of Novel Benzimidazole Derivatives as Potential β-Glucosidase Inhibitors

Background: β-Glucosidase has a variety of biological functions. A structural model for a potential β-glucosidase inhibitor has been proposed in the studies. Objective: A series f new diaryl derivatives linked through benzimidazole have been randomly and rationally designed, synthesized, and evaluated for their inhibitory activities against β-glucosidase (al-mond). The proposed structural model provides a new strategy for the design of potent β-glucosidase inhibitors. Methods: According to the model, a series of benzimidazole derivatives were designed and synthesized, and their inhibitory activity, Ki value, inhibitory type, and binding mode analysis (PDB ID: 2J7C) on β-glucosidase (almond) were evaluated. Results: Two compounds 7b and 7d were the best inhibitors with IC₅₀ values of 7.86 µM and 3.52 µM, respectively. Their K_i values were calculated to be 9.91 µM and 5.81 µM, respectively. Conclusion: The SAR analysis suggested that such benzimidazole derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds on o-trihydroxyphenol; the additional phenyl ring on the other side towards the solvent-exposed region played a very important role in improving their in-hibitory activity against β-glucosidase.