抑制单胺氧化酶和神经保护作用:查尔酮与色酮。

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED
Reshma Ipe, Jong Min Oh, Sunil Kumar, Iqrar Ahmad, Lekshmi R Nath, Sandeep Bindra, Harun Patel, Krishna Yallappa Kolachi, Prabitha Prabhakaran, Prashant Gahtori, Asad Syed, Abdallah M Elgorbanh, Hoon Kim, Bijo Mathew
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引用次数: 0

摘要

研究人员合成了两个子系列(HC1-HC9)和(HF1-HF9)的 18 种化合物,并评估了它们对单胺氧化酶(MAO)的抑制活性。HC(查尔酮)系列对 MAO-B 的抑制活性高于对 MAO-A 的抑制活性,而 HF(色酮)系列则表现出相反的抑制活性。化合物 HC4 对 MAO-B 的抑制作用最强,IC50 值为 0.040 μM,其次是 HC3(IC50 = 0.049 μM),而化合物 HF4 对 MAO-A 的抑制作用最强(IC50 = 0.046 μM),其次是 HF2(IC50 = 0.075 μM)。HC4 和 HF4 的选择性指数(SI)值分别为 50.40 和 0.59。从结构上看,HC4(B环中有4-OC2H5)对MAO-B的抑制率高于其他衍生物,表明B环中4位的-OC2H5取代有助于提高MAO-B的抑制率,尤其是-OC2H5(HC4)>-OCH3(HC3)>-F(HC7)>-CH3(HC2)>-Br(HC8)>-H(HC1)的顺序。在 MAO-A 抑制作用中,HF4 B 环上的取代基 4-OC2H5 有助于提高抑制活性,其次是 -CH3 (HF2)、-F (HF7)、-Br (HF8)、-OCH3 (HF3) 和-H (HF1)。在酶动力学和可逆性研究中,HC4对MAO-B的Ki值为0.035±0.005 μM,HF4对MAO-A的Ki值为0.035±0.005 μM,两者均为可逆性竞争抑制剂。通过活性氧和超氧化物歧化酶检测,我们证实 HC4 和 HF4 能显著改善鱼藤酮诱导的神经毒性。这项研究还证实了 HC4 和 HF4 对鱼藤酮诱导的毒性中线粒体膜电位的重要影响。研究人员利用一个先导分子进行了分子对接和动态模拟研究。这些结果表明,HC4 是一种强效的选择性 MAO-B 抑制剂,HF4 是一种强效的 MAO-A 抑制剂,表明这两种化合物可用作神经系统疾病的治疗药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Inhibition of monoamine oxidases and neuroprotective effects: chalcones vs. chromones.

Inhibition of monoamine oxidases and neuroprotective effects: chalcones vs. chromones.

Eighteen compounds derived from two sub-series, (HC1-HC9) and (HF1-HF9), were synthesized and evaluated for their inhibitory activities against monoamine oxidase (MAO). HC (chalcone) series showed higher inhibitory activity against MAO-B than against MAO-A, whereas the HF (chromone) series showed reversed inhibitory activity. Compound HC4 most potently inhibited MAO-B with an IC50 value of 0.040 μM, followed by HC3 (IC50 = 0.049 μM), while compound HF4 most potently inhibited MAO-A (IC50 = 0.046 μM), followed by HF2 (IC50 = 0.075 μM). The selectivity index (SI) values of HC4 and HF4 were 50.40 and 0.59, respectively. Structurally, HC4 (4-OC2H5 in B-ring) showed higher MAO-B inhibition than other derivatives, suggesting that the -OC2H5 substitution of the 4-position in the B-ring contributes to the increase of MAO-B inhibition, especially -OC2H5 (HC4) > -OCH3 (HC3) > -F (HC7) > -CH3 (HC2) > -Br (HC8) > -H (HC1) in order. In MAO-A inhibition, the substituent 4-OC2H5 in the B-ring of HF4 contributed to an increase in inhibitory activity, followed by -CH3 (HF2), -F (HF7), -Br (HF8), -OCH3 (HF3), and-H (HF1). In the enzyme kinetics and reversibility study, the Ki value of HC4 for MAO-B was 0.035 ± 0.005 μM, and that of HF4 for MAO-A was 0.035 ± 0.005 μM, and both were reversible competitive inhibitors. We confirmed that HC4 and HF4 significantly ameliorated rotenone-induced neurotoxicity, as evidenced by the reactive oxygen species and superoxide dismutase assays. This study also supports the significant effect of HC4 and HF4 on mitochondrial membrane potential in rotenone-induced toxicity. A lead molecule was used for molecular docking and dynamic simulation studies. These results show that HC4 is a potent selective MAO-B inhibitor and HF4 is a potent MAO-A inhibitor, suggesting that both compounds can be used as treatment agents for neurological disorders.

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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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