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.

Inhibition of α-glucosidase enzyme by 'click'-inspired pharmacophore framework 1,3,4-thiadiazole-1,2,3-triazole hybrids.

Aim: α-Glucosidase inhibitors are important oral antidiabetic drugs that are used alone or in combination therapy. Materials & methods: In this regard, 1,3,4-thiadiazoles-1,2,3-triazoles were designed, synthesized and evaluated for α-glucosidase enzyme inhibition. Results: The applied synthesis protocol involved a 'click' reaction between a novel alkyne derived from a 1,3,4-thiadiazole derivative and phenylacetamide azides. The hybrid (9n) bearing 2-methyl and 4-nitro substituents was the best inhibitor with an IC50 value of 31.91 µM (acarbose IC50 = 844.81 µM). The blind molecular docking study of the best derivative (9n) showed that it interacted with the allosteric site's amino acid residues of α-glucosidase. Conclusion: 'Click'-inspired potential α-glucosidase inhibitors (1,3,4-thiadiazole-1,2,3-triazole hybrids) were identified and structure-activity relationship and kinetic and molecular docking studies accomplished.

Oral antidiabetic drugs such as α-glucosidase inhibitors are used alone or in combination therapy. α-Glucosidase inhibitors are considered important for their localized site of action and limited side effects compared with other antidiabetic medications. In this regard, 1,3,4-thiadiazoles­1,2,3-triazoles were designed and synthesized and their antidiabetic potential (α-glucosidase enzyme inhibition) evaluated. The synthesis involved a 'click', or copper-catalyzed 1,3-dipolar cycloaddition, reaction between a novel alkyne derived from a 1,3,4-thiadiazole derivative and phenylacetamide azides. The synthesis was simple, easy and free of tedious separation processes. All synthesized thiadiazole­triazole hybrids were found to be active toward α-glucosidase (yeast origin). One of the thiadiazole­triazole hybrids showed excellent activity that was approximately 26-times greater than the standard drug acarbose. This study was further supported by computational analysis.

Flavone-1,2,3-triazole derivatives as potential α-glucosidase inhibitors: Synthesis, enzyme inhibition, kinetic analysis and molecular docking study.

α-Glucosidase inhibitors are considered prime therapeutics in the management of type-2 diabetes and are preferred due to their localized action ushered by limited side effects. In this regard, nineteen new flavone-1,2,3-triazole derivatives have been designed and synthesized via utilizing an efficient click reaction protocol, and screened for the inhibition of the α-glucosidase enzyme. The reaction conditions were mild, good yielding and required easy work up. All the synthesized flavone-triazole derivatives were found more active against the yeast α-glucosidase with IC50 values ranging from 24.37 ± 0.55-168.44 ± 0.77 µ M as compared to standard inhibitor acarbose (IC50 = 844.81 ± 0.53 µM). The derivatives with 2,5­dichloro 9k (IC50 = 24.37 ± 0.55 µM) and 4­chloro 9d (IC50 = 24.77 ± 0.30 µM) substituent bearing an amide linkage were the most active. In the kinetic study of most active derivatives 9k and 9d, they were found to be mixed and uncompetitive inhibitors, respectively. In molecular docking studies, blind docking of the most active compounds was accomplished to find the interactions between the compounds and α-glucosidase that further confirms the mixed or uncompetitive nature of the inhibitors.