Cyanoacetohydrazide linked to 1,2,3-triazole derivatives: a new class of α-glucosidase inhibitors

In this work, a novel series of cyanoacetohydrazide linked to 1,2,3-triazoles (9a-n) were designed and synthesized to be evaluated for their anti-alpha-glucosidase activity, focusing on the fact that alpha-glucosidase inhibitors have played a significant role in the management of type 2 diabetes mellitus. All synthesized compounds except 9a exhibited excellent inhibitory potential, with IC50 values ranging from 1.00 +/- 0.01 to 271.17 +/- 0.30 mu M when compared to the standard drug acarbose (IC50 = 754.1 +/- 0.5 mu M). The kinetic binding study indicated that the most active derivatives 9b (IC50 = 1.50 +/- 0.01 mu M) and 9e (IC50 = 1.00 +/- 0.01 mu M) behaved as the uncompetitive inhibitors of alpha-glucosidase with K-i = 0.43 and 0.24 mu M, respectively. Moreover, fluorescence measurements were conducted to show conformational changes of the enzyme after binding of the most potent inhibitor (9e). Calculation of standard enthalpy (Delta H-m degrees) and entropy (Delta S-m degrees) values confirmed the construction of hydrophobic interactions between 9e and the enzyme. Also, docking studies indicated desired interactions with important residues of the enzyme which rationalized the in vitro results.