Inhibition of monoamine oxidases by heterocyclic derived conjugated dienones: synthesis and in vitro and in silico investigations.

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sunil Kumar, Bishnu Prasad Pandey, Mohamed A Abdelgawad, Mohammed M Ghoneim, Rania B Bakr, Hoon Kim, Bijo Mathew
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引用次数: 0

Abstract

A total of 18 heterocyclic derived conjugated dienones (CD1-CD18) were evaluated for their potential monoamine oxidase (MAO)-A/-B inhibitory activity. Among the analyzed molecules, CD11 and CD14 showed notable inhibitory potentials against MAO-B, with half-maximal inhibitory concentration (IC50) values of 0.063 ± 0.001 μM and 0.036 ± 0.008 μM, respectively. In contrast, CD1, CD2 and CD3 showed comparable inhibitory activities toward MAO-A, with IC50 values of 3.45 ± 0.07, 3.23 ± 0.24, and 3.15 ± 0.10 μM, respectively. Derivatives of thiophene (CD13-CD17) exhibited selectivity indices greater than 250 for MAO-B. Both lead compounds exhibited similar potencies to safinamide and were more potent than pargyline. According to kinetic analysis, CD11 and CD14 exhibited competitive inhibition of MAO-B activity, with K i values of 12.67 ± 3.85 nM and 4.5 ± 0.62 nM, respectively. Furthermore, the reversibility test results indicated that the inhibitions were reversible. Molecular docking and molecular dynamics simulation studies can provide insights into the probable binding interactions of CD11 and CD14 with MAO-B. CD11 demonstrated a bipartite contact with Tyr326 and Phe343, whereas CD14 showed contact with Pro102 and Tyr435 via aromatic hydrogen bonds. These results indicated that both compounds have high-affinity binding interactions ( -10.13 and -9.90 kcal mol-1, respectively) at the active site of MAO-B. Furthermore, we used SwissADME to estimate ADME, and both lead compounds demonstrated blood-brain barrier penetration. The study results indicated that all the compounds evaluated demonstrated potent inhibition of MAO-B activity, which was comparable to the efficacy of reference medications. It is necessary to do further investigations on the lead molecules to see whether they may be used to treat different neurodegenerative illnesses.

杂环衍生共轭二烯酮对单胺氧化酶的抑制作用:合成、体外和硅学研究。
对总共 18 种杂环衍生共轭二烯酮(CD1-CD18)潜在的单胺氧化酶(MAO)-A/-B 抑制活性进行了评估。在分析的分子中,CD11 和 CD14 对 MAO-B 具有显著的抑制潜力,其半最大抑制浓度 (IC50) 值分别为 0.063 ± 0.001 μM 和 0.036 ± 0.008 μM。相比之下,CD1、CD2 和 CD3 对 MAO-A 的抑制活性相当,IC50 值分别为 3.45 ± 0.07、3.23 ± 0.24 和 3.15 ± 0.10 μM。噻吩的衍生物(CD13-CD17)对 MAO-B 的选择性指数大于 250。这两种先导化合物的药效与沙芬酰胺相似,但比帕吉林更强。根据动力学分析,CD11 和 CD14 对 MAO-B 的活性具有竞争性抑制作用,K i 值分别为 12.67 ± 3.85 nM 和 4.5 ± 0.62 nM。此外,可逆性测试结果表明抑制作用是可逆的。分子对接和分子动力学模拟研究可以揭示 CD11 和 CD14 与 MAO-B 的可能结合相互作用。CD11与Tyr326和Phe343呈双键接触,而CD14则通过芳香氢键与Pro102和Tyr435接触。这些结果表明,这两种化合物在 MAO-B 的活性位点具有高亲和力的结合相互作用(分别为 -10.13 和 -9.90 kcal mol-1)。此外,我们还利用 SwissADME 对 ADME 进行了估算,结果显示这两种先导化合物都具有血脑屏障穿透性。研究结果表明,所有评估的化合物都对 MAO-B 的活性有很强的抑制作用,与参考药物的疗效相当。有必要对先导分子进行进一步研究,以确定它们是否可用于治疗不同的神经退行性疾病。
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
CiteScore
5.80
自引率
2.40%
发文量
129
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