Design, synthesis, in-vitro and in-silico studies of novel N-heterocycle based hydrazones as α-glucosidase inhibitors.

Diabetes mellitus has dominated the globe as a chronic health condition and has become a major global health concern. The inhibition of the key metabolic enzymes of carbohydrates digestion including α-amylase and α-glucosidase are the promising targets for the treatment of diabetes via delaying glucose absorption. Therefore, nitrogen containing saturated heterocycle (pyrrolidinyl, piperidinyl and N-methylpiperazinyl) based hydrazones derivatives 5-23 were synthesized through two step reactions and evaluated for their anti-diabetic potential. All compounds exhibited potent α-glucosidase inhibitory capability ranging (IC = 10.26-47.35 µM), as compared to acarbose (IC 871.40 ± 1.24 µM). Interestingly these derivatives also exhibited significant inhibitory capability against α-amylase with IC values in the range 25.81-76.05 µM. Mechanistic study on the most potent compound indicated a competitive type of inhibition with a K value of 8.30 ± 0.0076 µM. Molecular docking was performed to predict binding interactions between receptor proteins and moiety. In QSAR analysis, through use of QSARINS different 1D and 2D descriptors were used to generate different models that enabled further identification of structural requirements that contributed to activity. pIC values were also predicted by QSAR model. Furthermore, in-silico ADMET and BOILED-egg model analysis showed that all analogues exhibited passive GI absorption, and all showed BBB penetration.