Design, Synthesis, In Silico ADME, Toxicity Prediction and Molecular Docking Studies of Benzimidazole-Oxadiazole Derivatives for α-Glucosidase and Aldose Reductase Pathways as Potent Anti-Diabetic Agents

Abstract

In this study, due to the side effect profiles and low efficacy of currently used inhibitors, novel benzimidazole-oxadiazole derivatives (6a–6e, 7a–7e) were synthesized as dual inhibitors of α-GLY and AR. Their structures were elucidated using 13C-NMR and 1H-NMR techniques. Their binding properties were investigated by molecular docking studies, and their ADME properties were screened in silico. AR and α-GLY inhibitory effects of the synthesized compounds were examined. The compounds were observed to exhibit partially similar inhibitory effects to the reference drug epalrestate (IC50: 0.78 nM; KI: 0.74 ± 0.0 nM) on AR inhibition. Among them, compounds 6a, 6b, and 6c showed the highest activity with KI values of 8.6 ± 0.4, 3.5 ± 0.3 and 6.3 ± 0.5 nM, respectively. Compounds 6a and 7e were found to have higher inhibitory activity against the α-GLY enzyme than the reference drug Acarbose (IC50: 128.4 µM; KI: 96.2 ± 5.7 µM) with KI values of 5.8 ± 0.4 and 7.9 ± 0.8 µM, respectively. Overall, the newly synthesized compounds demonstrated pronounced AR inhibitory activity and notable α-GLY inhibition. Nevertheless, further pharmacological and toxicity evaluations are required to confirm their therapeutic potential. Among the tested molecules, compounds 6a and 7e may therefore be considered potential candidates for further investigation as anti-diabetic agents.