Discovering the Cholinesterase Inhibitory Potential of Thiosemicarbazone Derivatives through In vitro, Molecular Docking, Kinetics, and Dynamics Studies.

IF 1.9 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Pub Date : 2025-05-12 DOI:10.2174/0115734064375028250427171931

Manel Essid, Aftab Alam, Ghulam Fareed, Sudais Rahman, Imtiaz Ahmad, Imen Zghab, Zainab Hassan Alnakhli, Abid Ali, Masroor Kamal, Momin Khan

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引用次数: 0

Abstract

Background: The current study explored the cholinesterase inhibitory activities of some thiosemicarbazone derivatives bearing 2,4-dichloro phenylacetic acid scaffold.

Objective: This study aimed to screen the synthesized derivatives for their in vitro acetylcholine and butyrylcholinesterase inhibition.

Methods: These compounds were synthesized by refluxing 2,4-dichloro phenylacetic acid with sulfuric acid in ethanol to get the ester, which was further refluxed with thiosemicarbazide in ethanol to get the desired compound (2). Different benzaldehydes were treated with compound (2) in ethanol having a catalytic amount of acetic acid to get thiosemicarbazones.

Results: In the series, seven compounds, including compounds 2c, 2a, 2b, 2d, 2g, 2e, and 2f, displayed excellent acetylcholinesterase inhibition activities in the range of IC₅₀ values from 41.51 ± 3.88 to 95.48 ± 0.70 μM, surpassing than the standard galantamine (IC₅₀ = 104.5 ± 1.20 μM). Also, compounds 2a, 2g, 2h, 2f, 2b, and 2d with IC₅₀ values ranging from 64.47 ± 2.74 to 80.62 ± 0.73 μM exhibited potent inhibition against butyrylcholinesterase enzyme, being similar to the standard galantamine (IC₅₀ = 156.8 ± 1.50 μM). The molecular docking investigation was performed to assess the binding affinity of the compounds with the active site of the enzyme. These compounds, along with the docked complexes, specifically AChE-compound 2a and BuChE-compound 2g, were chosen and subjected to 100-nanosecond molecular dynamics simulations. The simulations demonstrated strong stability of the ligands within the active pockets of AChE and BuChE enzymes.

Conclusion: These derivatives exhibited superior acetylcholinesterase and butyrylcholinesterase inhibitory activities compared to galantamine, with molecular docking and dynamic simulations confirming their strong binding affinity with the active sites of the enzymes.

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通过体外、分子对接、动力学和动力学研究发现硫代氨基脲衍生物的胆碱酯酶抑制潜力。

背景：本研究探讨了以2,4-二氯苯乙酸为支架的某些硫代氨基脲衍生物的胆碱酯酶抑制活性。目的：筛选合成的乙酰胆碱和丁基胆碱酯酶衍生物的体外抑制作用。方法：以2,4-二氯苯乙酸为原料，用硫酸在乙醇中回流制得酯，再用氨基硫脲在乙醇中回流制得所需化合物(2)。用化合物(2)在乙酸催化量的乙醇中处理不同的苯甲醛，得到硫代氨基脲。结果：化合物2c、2a、2b、2d、2g、2e、2f 7个化合物对乙酰胆碱酯酶的抑制活性较好，IC50范围为41.51±3.88 ~ 95.48±0.70 μM，优于标准品加兰他明（IC50 = 104.5±1.20 μM）。化合物2a、2g、2h、2f、2b和2d的IC50值在64.47±2.74 ~ 80.62±0.73 μM范围内，与标准加兰他明的IC50值（156.8±1.50 μM）相似，对丁基胆碱酯酶的抑制作用较强。通过分子对接研究来评估化合物与酶活性位点的结合亲和力。选择这些化合物，以及对接的配合物，特别是ache -化合物2a和buch -化合物2g，并进行100纳秒的分子动力学模拟。模拟结果表明，这些配体在AChE和BuChE酶的活性口袋内具有很强的稳定性。结论：与加兰他敏相比，这些衍生物具有更强的乙酰胆碱酯酶和丁基胆碱酯酶抑制活性，分子对接和动态模拟证实了它们与酶活性位点的强结合亲和力。

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

Medicinal Chemistry 医学-医药化学

CiteScore

4.30

自引率

4.30%

发文量

109

审稿时长

12 months

期刊介绍： Aims & Scope Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.