Synthesis and In Vitro/In Silico α-Glucosidase Inhibitory Study of Novel Ethanones Containing Naphthalene-Linked 1,2,4-Triazole

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-07-31 DOI:10.1021/acsmedchemlett.5c00387

Cong T. Nguyen, Dung T.K. Hoang, Vu A. Truong, Loan T.K. Nguyen, Phi C. Dinh, Dung H.A. Mai*, Duc T. Le* and Nam N. Pham*,

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Abstract

Type 2 diabetes mellitus is a chronic-metabolic disorder characterized by insulin resistance, resulting in persistent hyperglycemia and severe complications. α-Glucosidase inhibitors (AGIs) effectively control postprandial blood glucose level by delaying carbohydrate digestion. This study reports the synthesis of novel naphthalene-linked 1,2,4-triazole-bearing ethanones (5a–e and 7a–f) as potential AGIs. Enzymatic assay demonstrated significantly superior α-glucosidase inhibitory potency of aryl-substituted derivatives (7a−f) compared to ethyl-substituted analogs (5a−e), highlighting the advance of aromatic substituents. Compounds 7b and 7c exhibited exceptional inhibitory activity (IC₅₀ = 9.23–9.61 μM), conferring 37-fold more potency than voglibose. Molecular docking and dynamics simulations indicated predominant π-π stacking and hydrophobic interactions contributing to their stable enzyme binding. MM/GBSA binding-affinity calculation further supported their enhanced binding affinity, providing mechanistic insights into their potent activity. Collectively, these findings highlight the promise of naphthalene- and 1,2,4-triazole-bearing ethanones for the development of effective antidiabetic therapies.

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新型萘链1,2,4-三唑类乙酮的合成及体外/硅内α-葡萄糖苷酶抑制研究

2型糖尿病是一种以胰岛素抵抗为特征的慢性代谢紊乱，可导致持续高血糖和严重并发症。α-葡萄糖苷酶抑制剂（AGIs）通过延缓碳水化合物消化，有效控制餐后血糖水平。本文报道了一种新型的含萘链1,2,4-三唑的乙酮（5a-e和7a-f）的合成。酶分析表明，芳基取代衍生物（7a−f）的α-葡萄糖苷酶抑制能力明显优于乙基取代类似物（5a−e），突出了芳香取代基的先进性。化合物7b和7c表现出优异的抑制活性（IC50 = 9.23 ~ 9.61 μM），比伏糖糖的抑制活性高37倍。分子对接和动力学模拟表明，主要的π-π堆叠和疏水相互作用有助于它们稳定的酶结合。MM/GBSA结合亲和力计算进一步支持其增强的结合亲和力，为其有效活性提供了机制见解。总的来说，这些发现强调了含萘和1,2,4-三唑的乙酮在开发有效的抗糖尿病疗法方面的前景。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.