2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2023 Nov 3:262:115920. doi: 10.1016/j.ejmech.2023.115920.
Qianqian Feng 1,  Jinfeng Zhang 1,  Shuang Luo 1,  Yong Huang 2,  Zhiyun Peng 3,  Guangcheng Wang 4
Affiliations

Affiliations

  • 1 Clinical Trails Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, China.
  • 2 Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang, China.
  • 3 Clinical Trails Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, China. Electronic address: [email protected].
PMID: 37939444 DOI: 10.1016/j.ejmech.2023.115920
Abstract

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.

Keywords

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

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