Synthesis of 1,2,3-triazole-1,3,4-thiadiazole hybrids as novel α-glucosidase inhibitors by in situ azidation/click assembly.

α-Glucosidase inhibition is widely used in the oral management of diabetes mellitus (DM), a disease characterized by high blood sugar levels (hyperglycemia) and abnormal carbohydrate metabolism. In this respect, a series of 1,2,3-triazole-1,3,4-thiadiazole hybrids 7a-j were synthesized, inspired by a copper-catalyzed one-pot azidation/click assembly approach. All the synthesized hybrids were screened for inhibition of the α-glucosidase enzyme, displaying IC50 values ranging from 63.35 ± 0.72 to 613.57 ± 1.98 μM, as compared to acarbose (reference) with IC50 of 844.81 ± 0.53 μM. The hybrids 7h and 7e with 3-nitro and 4-methoxy substituents at the phenyl ring of the thiadiazole moiety were the best active hybrids of this series with IC50 values of 63.35 ± 0.72 μM, and 67.61 ± 0.64 μM, respectively. Enzyme kinetics analysis of these compounds revealed a mixed mode of inhibition. Moreover, molecular docking studies were also performed to gain insights into the structure-activity-relationships of the potent compounds and their corresponding analogs.