新的苯并咪唑-吲哚-酰胺衍生物作为α-葡萄糖苷酶和乙酰胆碱酯酶抑制剂。

IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL
Narges Naimi, Somaye Karimian, Navid Dastyafteh, Mild Noori, Maryam Mohammadi-Khanaposhtani, Armin Dadgar, Bagher Larijani, Vahid Lotfi, İlhami Çelik, Aydın Aktaş, Nastaran Sadeghian, Parham Taslimi, Mohammad Mahdavi
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引用次数: 0

摘要

以苯并咪唑-吲哚-酰胺为支架,合成了新的衍生物6a-m,并评估了其对α-葡萄糖苷酶和乙酰胆碱酯酶(AChE)的潜在抑制作用。这些化合物是由各种胺衍生物合成的。除2个化合物外,标题衍生物的α-葡萄糖苷酶抑制活性均高于阳性对照阿卡波糖。此外,除1个化合物外,这些化合物的抗乙酰胆碱活性均优于他克林(标准抑制剂)。对α-葡萄糖苷酶活性最强的化合物是3-甲基苯基衍生物6i,对乙酰胆碱酯酶活性最强的化合物是3,4-二甲氧基苯基衍生物6m。通过硅对接方法将合成的化合物分别置于α-葡萄糖苷酶和乙酰胆碱酯酶的活性位点上,得到的结合能与体外观察数据基本一致。最有效的化合物6i和6m的相互作用模式表明,这些化合物与目标酶的重要残基相互作用。针对化合物6i与α-葡萄糖苷酶的配合物进行分子动力学模拟,以更深入地了解该分子的行为。此外,对大多数有效化合物进行的计算机药代动力学和毒性研究预测,这些化合物在口服吸收和毒性方面具有良好的特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

New benzimidazole–indole–amide derivatives as potent α-glucosidase and acetylcholinesterase inhibitors

New benzimidazole–indole–amide derivatives as potent α-glucosidase and acetylcholinesterase inhibitors

New derivatives 6a–m with benzimidazole–indole–amide scaffold were developed, synthesized, and assessed for potential inhibitory effects on α-glucosidase and acetylcholinesterase (AChE). These compounds were synthesized by various amine derivatives. With the exception of two compounds, the α-glucosidase inhibitory activities of the title derivatives were more than that of the positive control acarbose. Moreover, the anti-AChE activity of these compounds, with the exception of one compound, was better than that of tacrine (standard inhibitor). The most potent compound against α-glucosidase was 3-methylphenyl derivative 6i and the most potent compound against AChE was 3,4-dimethoxyphenethyl derivative 6m. All the synthesized compounds were placed in the active sites of α-glucosidase and AChE by in silico docking method and the obtained binding energies were approximately in agreement with the in vitro observed data. Interaction modes of the most potent compounds 6i and 6m demonstrated that these compounds interacted with important residues of their target enzymes. Molecular dynamics simulation was conducted specifically on compound 6i in complex with α-glucosidase to obtain deeper insights into the behavior of this molecule. Furthermore, in silico pharmacokinetic and toxicity studies on the most potent compound predicted that these compounds have good profiles in terms of oral absorption and toxicity.

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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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