Synthesis, biological evaluation and action mechanism of 7H-[1,2,4] triazolo [3,4-b] [1,3,4] thiadiazine-phenylhydrazone derivatives as α-glucosidase inhibitors

In our work, several 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-phenylhydrazone derivatives as α-glucosidase inhibitors (α-GIs) were synthesized and characterized by ¹H NMR, ¹³C NMR, and HRMS spectrum. Then, their bio-activity against the α-glucosidase (α-Glu) was further evaluated. Among them, almost all compounds displayed better bio-activity with IC₅₀ from 31.23 ± 0.89 to 213.50 ± 4.19 μM than acarbose (IC₅₀ = 700.20 ± 10.55 μM). In particular, compound 5o showed the best potency to inhibit α-Glu in a mixed manner. Moreover, the action mechanisms of 5o were further clarified including fluorescence quenching, circular dichroism spectra, three-dimensional fluorescence spectra, molecular docking, etc. All mechanism studies revealed that 5o could arouse the changed secondary structure of α-Glu to hinder Enzyme catalytic activity. It was observed from an in vivo study that 5o of 20 mg/kg could significantly decrease by 24.45 % postprandial blood glucose in mice vs. the control. Meanwhile, 5o had low drug-drug interaction potential and was likely to be an orally active compound. Moreover, 5o was observed to be no obvious cytotoxicity to HEK-293 cells. In summary, compound 5o exhibited one potential to be further applied as an antidiabetic drug.

Diabetes mellitus; Inhibition mechanism; Postprandial blood glucose; α-Glucosidase.