Rational design of new quinoline-benzimidazole scaffold bearing piperazine acetamide derivatives as antidiabetic agents.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-29 DOI:10.1016/j.bioorg.2024.107908

Mehran Ghasemi, Aida Iraji, Maryam Dehghan, Yazdanbakhsh Lotfi Nosood, Cambyz Irajie, Nafiseh Bagherian Khouzani, Somayeh Mojtabavi, Mohammad Ali Faramarzi, Mohammad Mahdavi, Ahmed Al-Harrasi

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Abstract

In this study, a series of fifteen compounds (7a-o) based on a quinoline-benzimidazole scaffold bearing piperazine acetamide derivatives were synthesized and evaluated for their potential as α-glucosidase inhibitors, which are important therapeutic agents in the management of type 2 diabetes mellitus. Among the synthesized compounds, 7m exhibited the most potent inhibitory activity, demonstrating a 28-fold greater efficacy than the standard clinical inhibitor, acarbose. Molecular docking studies indicated strong binding interactions between 7m and the α-glucosidase active site, including hydrogen bonding, π-π stacking, and π-cation interactions. Furthermore, molecular dynamics simulations revealed that compound 7m formed a highly stable complex with the enzyme. These findings suggest that compound 7m is a promising candidate for further development as an effective antidiabetic agent, offering valuable insights into the design of potent α-glucosidase inhibitors based on the quinoline-benzimidazole framework.

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作为抗糖尿病药物的新型喹啉-苯并咪唑支架哌嗪乙酰胺衍生物的合理设计。

本研究以含有哌嗪乙酰胺衍生物的喹啉-苯并咪唑支架为基础，合成了 15 个系列化合物（7a-o），并评估了它们作为α-葡萄糖苷酶抑制剂的潜力，α-葡萄糖苷酶是治疗 2 型糖尿病的重要药物。在合成的化合物中，7m 的抑制活性最强，其疗效是标准临床抑制剂阿卡波糖的 28 倍。分子对接研究表明，7m 与α-葡萄糖苷酶活性位点之间有很强的结合相互作用，包括氢键、π-π堆积和π-阳离子相互作用。此外，分子动力学模拟显示，化合物 7m 与酶形成了高度稳定的复合物。这些研究结果表明，化合物 7m 有希望进一步发展成为一种有效的抗糖尿病药物，为设计基于喹啉-苯并咪唑框架的强效 α-葡萄糖苷酶抑制剂提供了宝贵的见解。

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

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.