Synthesis of novel oxadiazole derivatives: DFT calculations, molecular docking studies, and in vitro, in vivo evaluation of antidiabetic activity using Drosophila melanogaster model

Current antidiabetic medications have a plethora of harmful side effects, and most of the drugs do not contain 1,3,4-oxadiazole moiety. Therefore, research into the development of novel drugs which contain 1,3,4-oxadiazole moiety with fewer side effects is necessary. Novel fluorine-incorporated 1,3,4-oxadiazole derivatives (1c–1n) were synthesized, characterized, and evaluated for α-amylase and α-glucosidase enzyme inhibitor activity. An in vivo Drosophila melanogaster model and an in vitro system were used to investigate its antidiabetic properties, further, which were characterized by ¹HNMR, MASS, and FT-IR. Spectroscopic techniques and DFT are used to calculate more geometrically optimized molecule structures using the B3LYP technique. The compounds were tested against the α-glucosidase and α-amylase enzymes. Among different compounds tested, compounds 1i (IC₅₀ = 54.83 µg/ml), 1k (IC₅₀ = 64.95 µg/ml), 1m (IC₅₀ = 64.78 µg/ml), and 1n (IC₅₀ = 66.30 µg/ml) showed significant α-amylase inhibitor efficacy compared to the acarbose (IC₅₀ = 35.17 µg/ml); compounds 1m (IC₅₀ = 74.64 µg/ml) and 1i (IC₅₀ = 60.35 µg/ml) exhibited significant α-glucosidase inhibitory action compared to acarbose (IC₅₀ = 46.06 µg/ml). The docking study exhibited that compound 1i creates six hydrogen bonds and compound 1m forms three hydrogen bonding contacts at the active site of the enzyme (PDBID:4w93). The obtained results are demonstrated that compounds 1i, 1m, 1n, and 1k had greater antidiabetic activities and can be further taken into consideration for antidiabetic therapeutic interventions.

Graphical abstract