Novel thiosemicarbazide-based β-carboline derivatives as α-glucosidase inhibitors: Synthesis and biological evaluation.

Autor: Liang B; School of Pharmacy and Food Engineering & Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen, 529020, China., Xiao D; School of Pharmacy and Food Engineering & Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen, 529020, China., Wang SH; School of Pharmacy & State Key Laboratory of Applied Organic Chemistry & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou, 730000, China. Electronic address: wangshh@lzu.edu.cn., Xu X; School of Pharmacy and Food Engineering & Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Wuyi University, Jiangmen, 529020, China. Electronic address: wyuchemxxt@126.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116595. Date of Electronic Publication: 2024 Jun 12.
DOI: 10.1016/j.ejmech.2024.116595
Abstrakt: In the quest for potent α-glucosidase inhibitors to combat diabetes, a series of novel thiosemicarbazide-based β-carboline derivatives (CTL1∼36) were synthesized and evaluated. CTL1∼36 exhibited remarkable inhibitory effects against α-glucosidase, with IC 50 values ranging from 2.81 to 12.40 μM, significantly surpassing the positive control acarbose (IC 50  = 564.28 μM). Notably, CTL26 demonstrated the most potent inhibition (IC 50  = 2.81 μM) and was characterized as a non-competitive inhibitor. Through a combination assay with fluorescence quenching, 3D fluorescence spectra, CD spectra, and molecular docking, we elucidated that CTL26 formed a complex with α-glucosidase via hydrogen bondings and hydrophobic interactions, leading to α-glucosidase conformation changes that impaired enzymatic activity. In vivo studies revealed that oral administration of CTL26 (25 and 50 mg/kg/d) reduced fasting blood glucose levels, enhanced glucose tolerance, and ameliorated lipid abnormalities in diabetic mice. These findings positioned CTL26 as a promising candidate for the development of α-glucosidase inhibitors with anti-diabetic potential.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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