Benzimidazole-phenoxy-1,2,3-triazole-benzyl Derivatives as the New Potent α-glucosidase Inhibitors: Design, Synthesis, In Vitro, and In Silico Biological Evaluations
Arash Soltani, Hadi Shirzad, Mohammad Panji, Elahe Motevaseli, Seyyed Amin Mousavinezhad, Saeed KalbasiBackground::
α-Glucosidase inhibitors play an important role in the treatment of type 2 diabetes mellitus. Inhibitors of the latter enzyme that are available on the market creat-ed gastrointestinal side effects and achieve to a high potent and low side effect potent α-glucosidase inhibitors is a valuable target for medicinal chemists. Objective: In this study, de-rivatives of benzimidazole-phenoxy-1,2,3-triazole-benzyl skeleton were introduced as new α-glucosidase inhibitors.
Methods::
Twelve derivatives 8a-l of target scaffold were synthesized via simple chemical re-actions with a yield between 65 and 88%. The in vitro α-glucosidase inhibition activities of these compounds was evaluated against yeast form of this enzyme. After the determination of most potent compound, the interaction of this compound with α-glucosidase was evaluated in vitro by kinetic study and in silico by docking study. Drug-likeness, pharmacokinetics, and toxicity profiles of the most potent compound were predicted by an online software.
Results::
Anti-α-glucosidase assay demonstrated that all synthesized derivatives 8a-l were more potent that standard inhibitor acarbose. Representatively, 2-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole (compound 8a) as the most potent deriv-ative was 150-times more potent than positive control. Kinetic study of compound 8a re-vealed that this compound is an uncompetitive inhibitor against α-glucosidase. Furthermore, molecular docking study showed that compound 8a with favorable binding energy attached to important residues in the α-glucosidase active site. This compound also can be an oral drug with favorable toxicity profile.
Conclusion::
Benzimidazole-phenoxy-1,2,3-triazole-benzyl derivatives 8a-l synthesized and evaluated for anti-α-glucosidase activity. All these compounds were excellent α-glucosidase inhibitor, and compound 8a demonstrated the most significant inhibition effect when com-pared with positive control.