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

Aim: alpha-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 a-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 mu M (acarbose IC50 = 844.81 mu M). The blind molecular docking study of the best derivative (9n) showed that it interacted with the allosteric site's amino acid residues of a-glucosidase. Conclusion: 'Click'-inspired potential a-glucosidase inhibitors (1,3,4-thiadiazole-1,2,3-triazole hybrids) were identified and structure-activity relationship and kinetic and molecular docking studies accomplished. Plain language summary: Oral antidiabetic drugs such as a-glucosidase inhibitors are used alone or in combination therapy. a-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 (a-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 a-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.