<br>新型磺酸盐酯连接的氟化腙衍生物作为多靶点碳酸酐酶和胆碱酯酶抑制剂：设计、合成、生物学评价、分子对接和 ADME 分析,Chemistry & Biodiversity

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新型磺酸盐酯连接的氟化腙衍生物作为多靶点碳酸酐酶和胆碱酯酶抑制剂：设计、合成、生物学评价、分子对接和 ADME 分析
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2024-08-19 , DOI: 10.1002/cbdv.202401849
Reşit Çakmak ₁ , Berna Akış ₂ , Murat Şentürk ₃

Affiliation

在本研究中，设计了一些新的腙衍生物（2a-g），首次合成，并作为 AChE、BChE、hCA I 和 hCA II 的多靶点抑制剂进行评估。新杂化物的化学结构通过元素分析和一些光谱技术得到证实。所有测试化合物均显示出低纳摩尔抑制作用，对 hCA I 的 IC 值在 30.4-264.0 nM、对 hCA II 的 23.2-251.6 nM、对 AChE 的 12.1-114.3 nM 和对 BChE 的 76.4-134.0 ₅₀ nM 的范围内。这些化合物对 hCA I 和 AChE 的抑制作用大于乙酰唑胺（AZA）和新斯的明。其中，具有线性结构的化合物 2c 和 2e 被确定为针对这些选定酶的最活跃的抑制剂候选者。对化合物（2a--g）进行分子对接研究，揭示了它们与 AChE、BChE、hCA I 和 hCA II 活性位点的结合相互作用，从而支持实验结果。此外，使用计算机模拟方法对获得的化合物（2a--g）进行计算机吸收、分布、代谢和排泄（ADME）预测研究，以确定它们的溶解度、它们是否有可能穿过血脑屏障（BBB）、GI 吸收等值和药物相似性原则。

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New Sulfonate Ester-Linked Fluorinated Hydrazone Derivatives as Multitarget Carbonic Anhydrase and Cholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, Molecular Docking and ADME Analysis

In this study, some new hydrazone derivatives (2a–g) was designed, synthesized for first time, and evaluated as multitarget inhibitors of AChE, BChE, hCA I and hCA II. The chemical structures of new hybrids were confirmed by elemental analysis and some spectroscopic techniques. All tested compounds showed low nanomolar inhibition with IC₅₀ values of in the range of 30.4–264.0 nM against hCA I, 23.2–251.6 nM against hCA II, 12.1–114.3 nM against AChE, and 76.4–134.0 nM against BChE. These compounds inhibited hCA I and AChE more than acetazolamide (AZA) and neostigmine. Among them, compounds 2c and 2e, which have a linear structure, were determined to be the most active inhibitor candidates against these selected enzymes. Molecular docking studies were carried out on the compounds (2a--g), revealing their binding interactions with the active site of AChE, BChE, hCA I and hCA II thus supporting the experimental findings. Additionally, in silico absorption, distribution, metabolism, and excretion (ADME) prediction studies of the obtained compounds (2a--g) with in silico approaches were carried out to determine their solubility, whether they have the potential to cross the blood-brain barrier (BBB), values such as GI absorption and drug likeness principles.

更新日期：2024-08-19

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