Development of 5-phenylnitro bearing furan-based chalcones as a new class of potent MAO-B inhibitors.

IF 3.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Future medicinal chemistry Pub Date : 2025-04-03 DOI:10.1080/17568919.2025.2485671

Kadeeja Thottungal Kalathil, Bishnu Prasad Pandey, Arshida Thottile Peedikayil, Raihan Arikkattel Abdu, Rajasree Raghavan Sreekumari, Alanoud T Alfagham, Abdallah M Elgorban, Sunil Kumar, Hoon Kim, Sanal Dev, Bijo Mathew

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引用次数: 0

Abstract

Aim: The purpose is to synthesize a new class of furan-based chalcone compounds (KD1-KD14) and to investigate their monoamine oxidase (MAO)-A and -B inhibitory activities.

Material and method: The 14 chalcones were synthesized using an open mortar and pestle. Lead molecules were screened via inhibitory activity, BBB permeability, and computation studies.

Results: Most of the tested compounds showed promising activity for MAO-B over than MAO-A. Among the molecules, KD1 and KD9 revealed the significant inhibitory potentials toward MAO-B with IC₅₀ values of 0.023 ± 0.004 and 0.015 ± 0.001 µM, respectively, and with high selectivity indices of 723.04 and >2666.66, respectively, over MAO-A. Further, kinetics and reversibility test revealed that both KD1 and KD9 were competitive reversible MAO-B inhibitors with K_i values of 13.5 ± 4.95 and 6.15 ± 0.92 nM, respectively. Additionally, the PAMPA test showed that both KD1 and KD9 compounds permeated the central nervous system. Furthermore, molecular docking and dynamics simulations showed that both the chemicals formed pi-cation and hydrogen bonds with the MAO-B pocket and stabilized the MAO-B over the course of a 100 ns simulation.

Conclusion: Our results revealed that KD1 and KD9 are potent selective, reversible, and competitive MAO-B inhibitors.

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5-苯基硝基呋喃查尔酮类新型高效MAO-B抑制剂的研制。

目的：合成一类新的呋喃基查尔酮类化合物KD1-KD14，并研究其抑制单胺氧化酶(MAO)-A和-B的活性。材料与方法：采用开钵和杵法合成了14种查尔酮。铅分子通过抑制活性、血脑屏障通透性和计算研究来筛选。结果：大部分化合物对MAO-B的活性高于对MAO-A的活性。其中，KD1和KD9对MAO-B具有显著的抑制潜力，IC50值分别为0.023±0.004和0.015±0.001µM，对MAO-A的选择性指数分别为723.04和bb0 2666.66。动力学和可逆性实验表明，KD1和KD9均为竞争性可逆MAO-B抑制剂，Ki值分别为13.5±4.95和6.15±0.92 nM。此外，PAMPA测试显示KD1和KD9化合物都渗透到中枢神经系统。此外，分子对接和动力学模拟表明，在100 ns的模拟过程中，这两种化学物质都与MAO-B口袋形成了阳离子和氢键，并稳定了MAO-B。结论：我们的研究结果表明KD1和KD9是有效的选择性、可逆性和竞争性MAO-B抑制剂。

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

Future medicinal chemistry CHEMISTRY, MEDICINAL-

CiteScore

5.80

自引率

2.40%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Future Medicinal Chemistry offers a forum for the rapid publication of original research and critical reviews of the latest milestones in the field. Strong emphasis is placed on ensuring that the journal stimulates awareness of issues that are anticipated to play an increasingly central role in influencing the future direction of pharmaceutical chemistry. Where relevant, contributions are also actively encouraged on areas as diverse as biotechnology, enzymology, green chemistry, genomics, immunology, materials science, neglected diseases and orphan drugs, pharmacogenomics, proteomics and toxicology.