用于治疗 II 型糖尿病的新型喹喔啉衍生物的合成、分子建模和生物学评价。

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fatmah Ali S Alasmary, Dalal A Abdullah, Vijay H Masand, Abir Ben Bacha, Abdelsattar Mansour Omar Ebeid, Moustafa E El-Araby, Ahmed M Alafeefy
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引用次数: 0

摘要

喹喔啉类是苯并吡嗪衍生物,在制药业具有重要的治疗作用。事实证明,它们可用于治疗炎症、细菌、真菌、病毒感染、糖尿病和其他应用。最近,美国食品及药物管理局于 2024 年 1 月批准了含有喹喔啉的新药厄达非替尼,用于治疗某些癌症。尽管喹喔啉衍生物具有多种生物活性,而且分泌型磷脂酶 A2(sPLA2)在糖尿病相关并发症中扮演着重要角色,但以 sPLA2 为靶点的喹喔啉类抑制剂在有效应对这些并发症方面的潜力仍有待开发。因此,我们设计了新型 sPLA2-和 α-葡萄糖苷酶靶向喹喔啉类杂环抑制剂,以调节与糖尿病相关的心血管并发症患者餐后血糖升高。化合物 5a-d 和 6a-d 是通过喹喔啉酰肼与各种芳基磺酰氯缩合合成的。生物筛选显示,化合物 6a 是一种强效的 sPLA2 抑制剂(IC50 = 0.0475 µM),而化合物 6c 则能最有效地抑制α-葡萄糖苷酶(IC50 = 0.0953 µM),优于阳性对照阿卡波糖。此外,化合物 6a 是这两种酶的最佳抑制剂。分子对接显示了药效学特征,突出了磺酰肼分子在这些化合物结构设计中的重要性,从而开发出了强效的 sPLA2 和 α-葡萄糖苷酶抑制剂。总之,我们的研究结果有助于确定有希望开发出治疗糖尿病的新型治疗剂的候选化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes.

Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC50 = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC50 = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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