5(6)-苯甲酰取代苯并咪唑及其苯并咪唑盐:设计、合成、表征、晶体结构和某些代谢酶抑制性能

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Aydın Aktaş, Eda Mehtap Özden, Duygu Barut Celepci, Tugba Taskin-Tok, Funda Sultan Ekti, İlhami Gülçin, Muhittin Aygün, Yetkin Gök, İlhami Çelik
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引用次数: 0

摘要

本文介绍了1-烷基-5(6)-苯甲酰取代苯并咪唑及其1,3-双烷基苯并咪唑卤化物盐的合成,并对其代谢酶抑制作用进行了评价。所有化合物都用各种光谱技术进行了表征。单晶XRD分析确定了两种化合物的分子结构。新合成的化合物对乙酰胆碱酯酶(AChE)和人碳酸酐酶异构体I和II (hCA I和hCA II)酶具有明显的抑制作用。这些化合物对hCA I的Ki值为12.4±5.4 ~ 109.4±49.9 nM,对hCA II的Ki值为23.1±11.2 ~ 115.0±17.9 nM,对AChE的Ki值为0.7±0.3 ~ 4.4±1.0 nM。对照物acetazolamide对hCA I和hCA II同工酶的Ki值分别为30.5±6.7 nM和37.4±7.8 nM。此外,已知的AChE抑制剂tacrine的Ki值为5.1±2.7 nM。CA和AChE的双重抑制是一种有价值的药理学方法,具有广泛的治疗应用。通过分子对接研究对合成的化合物与hCA I、hCA II和AChE酶的相互作用得到的酶抑制数据进行解释和评价。我们特别关注了hCA I的三个化合物(4e、4f和4j);hCA II为3g、4f和4k;和4e、4f、4j和4l(乙酰胆碱酯酶)对每种酶的潜在活性最高。然后预测潜在配体的物理化学,ADME,药物相似性,药物化学和毒性性质,从而揭示其候选药物的进一步研究适用性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

5(6)-Benzoyl-Substituted Benzimidazoles and Their Benzimidazolium Salts: Design, Synthesis, Characterization, Crystal Structure, and Some Metabolic Enzymes Inhibition Properties

5(6)-Benzoyl-Substituted Benzimidazoles and Their Benzimidazolium Salts: Design, Synthesis, Characterization, Crystal Structure, and Some Metabolic Enzymes Inhibition Properties

Herein, the synthesis of 1-alkyl-5(6)-benzoyl-substituted benzimidazoles and their 1,3-bisalkylbenzimidazolium halide salts are presented and evaluated for some metabolic enzyme inhibition. All compounds were characterized using various spectroscopic techniques. Single-crystal XRD analysis was performed to determine the molecular structure of two compounds. The newly synthesized compounds exhibited significant inhibitory effects against acetylcholinesterase (AChE) and human carbonic anhydrase isoforms I and II (hCA I and hCA II) enzymes. These compounds demonstrated promising inhibition profiles, with Ki values ranging from 12.4 ± 5.4 to 109.4 ± 49.9 nM for hCA I, 23.1 ± 11.2 to 115.0 ± 17.9 nM for hCA II, and 0.7 ± 0.3 to 4.4 ± 1.0 nM for AChE. In comparison, the reference compound acetazolamide showed Ki values of 30.5 ± 6.7 nM and 37.4 ± 7.8 nM against hCA I and hCA II isoenzymes, respectively. Additionally, tacrine, a known AChE inhibitor, exhibited a Ki value of 5.1 ± 2.7 nM. The dual inhibition of CA and AChE represents a valuable pharmacological approach with a wide range of therapeutic applications. The explanation and evaluation of the enzyme inhibition data obtained in line with the interactions of the synthesized compounds with hCA I, hCA II, and AChE enzymes were carried out by molecular docking studies. In particular, we focused on the three compounds (4e, 4f, and 4j for hCA I; 3g, 4f, and 4k for hCA II; and 4e, 4f, 4j, and 4l for AChE) with the highest potential activity with each enzyme. The physicochemical, ADME, drug-likeness, medicinal chemistry, and toxicity properties of the potential ligands were then predicted so that their drug candidate suitability for further studies is revealed.

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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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