Study on the interaction of triaryl-dihydro-1,2,4-oxadiazoles with α-glucosidase

One of the therapeutic approaches in the management of Type 2 diabetes is delaying the absorption of glucose through α-glucosidase enzymes inhibition, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense due to inducing oxidative stress induced pancreatic β-cell destruction through uncontrolled free radicals generation such as ROS, which in turn, leads to various macrovascular and microvascular complications. This study aimed to synthesize 2-aryl-4,6-diarylpyrimidine derivatives, screen their α-glucosidase inhibitory activity, perform kinetic and molecular docking studies.

A series of 3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Compounds 6a-k were synthesized via a two-step reaction with a yield between 65 and 88%. The structural elucidation of the synthesized derivatives was performed by different spectroscopic techniques. α-Glucosidase inhibitory activity of the oxadiazole derivatives 6a-k was evaluated against Saccharomyces cerevisiae α-glucosidase.

Most of the synthesized compounds demonstrated α-glucosidase inhibitory action. Particularly compounds 6c, 6d and 6 k were the most active compounds with IC₅₀ values 215 ± 3, 256 ± 3, and 295 ± 4 μM respectively. A kinetic study performed for compound 6c revealed that the compound is a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with K_i of 122 μM. The docking study also revealed that the two compounds, 6c and 6 k, have important binding interactions with the enzyme active site.

The overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel α-glucosidase inhibitors to manage the postprandial hyperglycemia incidence. Graphical abstract.