Design of novel benzimidazole-propane hydrazide derivatives as α-glucosidase and α-amylase inhibitors: in vitro and in silico studies

A new series of benzimidazole-propane hydrazide derivatives 9a-k were designed, synthesized, and evaluated for their inhibition ability against α-glucosidase and α-amylase. The results of the in vitro evaluations showed that all the tested compounds exhibited significant inhibition against α-glucosidase and α-amylase. Title compounds 9a-k exhibited varying degrees of inhibitory ability against α-glucosidase, with IC50 values in the range of 73.86–151.54 nM, in comparison to the standard acarbose drug with IC50 value of 174.50 nM. Similarly, these compounds demonstrated varying degrees of α-amylase inhibitory ability (the IC50 values ranged from 42.50 to 78.58 nM in comparison to acarbose with IC50 of 79.05 nM). Among the synthesized compounds, compound 9 h demonstrated the highest α-glucosidase inhibitory activity and compound 9 f demonstrated the highest anti-α-amylase activity. To further investigation on the potential of these derivatives as α-glucosidase and α-amylase inhibitors, molecular docking were conducted on all the synthesized compounds 9a-k. Docking results were in agreement with in vitro results. Molecular dynamics of compound 9 h showed that complex compound 9h-α-glucosidase had acceptable stability and flexibility. Calculations of physicochemical properties of compound 9a-k showed that these compounds fallowed of the main drug-likeness rules. Furthermore, the prediction of pharmacokinetics and toxicity profiles of compound 9 h showed that this compound can be considered as a lead drug structure. (Figure presented.)