Substituted D-Galactose-Conjugated Thiazole-Thioureas Derivatives as Promising Antidiabetic Agents: Synthesis, In Vitro Inhibition, and Molecular Simulation for α-Amylase, α-Glucosidase, Protein Glycation, and Oxidative Stress

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Nguyen Dinh Thanh, Vu Ngoc Toan, Duong Ngoc Toan, Vu Minh Trang
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引用次数: 0

Abstract

A thiourea series (7a–l) containing 4-arylthiazoles and the d-galactose moiety were synthesized and explored for their multi-target inhibition against α-amylase from porcine pancreas and α-glucosidase from Saccharomyces cerevisiae. Among these thioureas, 7h was the most potent inhibitor for α-amylase (IC50 of 7.84 ± 0.14 μM) and 7c was the most potent inhibitor for α-glucosidase (IC50 of 7.15 ± 0.12 μM). These thioureas also exhibited anti-glycation and antioxidant activity. They were noncytotoxic for NIH-3T3 cells. Induced-fit molecular docking study was applied to the two most potential inhibitors 7c and 7h. Their active interactions with residues in the catalytic pockets of the corresponding studied enzymes, 1OSE and 3TOP, were suitable to their inhibitory potentials against each tested enzyme. The molecular dynamics simulations validated the in vitro data for these compounds whereas the pharmacokinetics profile (ADMET) revealed the druglike properties of potent inhibitors.

Abstract Image

取代d -半乳糖偶联噻唑-硫脲衍生物作为有前景的降糖药:α-淀粉酶、α-葡萄糖苷酶、蛋白糖化和氧化应激的合成、体外抑制和分子模拟
合成了含有4-芳基噻唑和d-半乳糖的硫脲系列(7a-l),并探索了其对猪胰腺α-淀粉酶和酿酒酵母α-葡萄糖苷酶的多靶点抑制作用。其中7h对α-淀粉酶的抑制作用最强(IC50为7.84±0.14 μM), 7c对α-葡萄糖苷酶的抑制作用最强(IC50为7.15±0.12 μM)。这些硫脲还具有抗糖基化和抗氧化活性。它们对NIH-3T3细胞无细胞毒性。对两种最有潜力的抑制剂7c和7h进行了诱导匹配分子对接研究。它们与所研究的酶(1OSE和3TOP)的催化口袋中的残基的活性相互作用与它们对每种酶的抑制电位相适应。分子动力学模拟验证了这些化合物的体外数据,而药代动力学谱(ADMET)揭示了有效抑制剂的药物样特性。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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