Thiadiazole based β-carboline derivatives as potential α-glucosidase inhibitors: design, synthesis, and bioactivity evaluation.

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-10-05 DOI:10.1007/s11030-025-11369-2

Huan Zhou, Yaxin Wen, Shao-Hua Wang, Yan Liu, Baoqiong Li, Xuetao Xu

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引用次数: 0

Abstract

α-Glucosidase has always been one essential target for clinical prevention and treatment of diabetes. To develop effective α-glucosidase inhibitors, twenty-seven thiadiazole based β-carboline derivatives (TC1-TC27) were designed and synthesized by pharmacophore hybridization strategy, and systematically evaluated their inhibitory activity and binding characteristics against α-glucosidase. All synthesized derivatives (TC1-TC27) displayed significant inhibitory activity against α-glucosidase, with TC16 emerging as the most potent compound (IC₅₀ = 2.62 ± 0.21 μM), far surpassing the reference inhibitor acarbose (IC₅₀ = 210.75 ± 9.52 μM). Furthermore, fluorescence spectra and CD spectra results illustrated the binding of TC16 onto α-glucosidase, which caused the enzyme conformation transition to induce activity decrease. Finally, molecular docking elucidated hydrogen bonds and hydrophobic interactions kept the binding of TC16 onto α-glucosidase. In summary, this work provides a class of thiadiazole based β-carboline derivatives as potential α-glucosidase inhibitors.

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基于噻二唑的β-碳碱衍生物作为潜在的α-葡萄糖苷酶抑制剂：设计、合成和生物活性评价。

α-葡萄糖苷酶一直是临床防治糖尿病的重要靶点之一。为了开发有效的α-葡萄糖苷酶抑制剂，采用药效团杂交策略设计合成了27个噻二唑基β-卡波林衍生物（TC1-TC27），并系统评价了它们对α-葡萄糖苷酶的抑制活性和结合特性。所有合成的衍生物（TC1-TC27）均显示出明显的α-葡萄糖苷酶抑制活性，其中TC16的抑制活性最强（IC50 = 2.62±0.21 μM），远远超过对照抑制剂阿卡波糖（IC50 = 210.75±9.52 μM）。荧光光谱和CD光谱结果表明，TC16与α-葡萄糖苷酶结合，引起酶的构象转变，导致活性降低。最后，分子对接阐明了氢键，疏水相互作用保持了TC16与α-葡萄糖苷酶的结合。综上所述，本研究提供了一类基于噻二唑的β-碳碱衍生物作为潜在的α-葡萄糖苷酶抑制剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;