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

Abstract

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-α-glucosidase activity, focusing on the fact that α-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 μM when compared to the standard drug acarbose (IC₅₀ = 754.1 ± 0.5 μM). The kinetic binding study indicated that the most active derivatives 9b (IC₅₀ = 1.50 ± 0.01 μM) and 9e (IC₅₀ = 1.00 ± 0.01 μM) behaved as the uncompetitive inhibitors of α-glucosidase with K_i = 0.43 and 0.24 μM, 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 (ΔH_m°) and entropy (ΔS_m°) 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.