Lead optimization for promising monoamine oxidase inhibitor from eugenol for the treatment of neurological disorder: synthesis and in silico based study
Lead optimization for promising monoamine oxidase inhibitor from eugenol for the treatment of neurological disorder: synthesis and in silico based study
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DOI：
10.1186/s13065-019-0552-4
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发表时间：
2019-03-26
期刊：
影响因子：
4.6
通讯作者：
Khatkar, Anurag
中科院分区：
文献类型：
--
作者：
Dhiman, Priyanka;Malik, Neelam;Khatkar, Anurag
单胺氧化酶的天然抑制剂是用于治疗几种神经退行性和神经心理学障碍（包括抑郁症、焦虑症、帕金森病和阿尔茨海默病）的有希望的候选药物。在本研究中，我们设计并合成了基于丁香酚的衍生物，并研究了它们作为神经系统疾病治疗剂的有希望的候选物的人MAO抑制潜力。采用自由基清除法和过氧化氢（H_2O_2）、DPPH自由基清除法对所设计的衍生物进行了活性测定。基于丁香酚的衍生物被设计和合成用于人MAO抑制作用。使用计算机模拟和体外模型评价hMAO抑制。通过分子对接研究，深入了解了化合物与hMAO-A和hMAO-B活性位点之间的分子相互作用。两种分光光度滴定技术被用来评估抗氧化潜力。发现化合物5 b和16是最具活性的hMAO-A抑制剂，其IC 50值分别为5.989 +/- 0.007 μ M和7.348 +/- 0.027 μ M，明显的选择性指数值分别为0.19和0.14。在hMAO-B抑制的情况下，发现化合物13 a和13 b是最有活性的hMAO-B抑制剂，分别具有7.494 +/- 0.014 μ M和9.183 +/- 0.034 μ M的IC 50值，以及分别为5.14和5.72的选择性指数的突出值。自由基清除实验表明，化合物5 b、5a、9 b、9a具有一定的抗氧化活性。本研究的结果表明干实验室和湿实验室hMAO抑制实验之间具有良好的相关性。有趣的是，表现出更好的MAO抑制活性的化合物也被认为是良好的抗氧化剂。
Natural based inhibitors of monoamine oxidase are promising drug candidates for the treatment of several neurodegenerative and neuropsychological disorders including depression, anxiety, Parkinson's disease and Alzheimer's disease. In the present study we designed and synthesized the eugenol based derivatives and investigated them for human MAO inhibitory potential as promising candidates for therapeutics of neurological disorders. Moreover, radical scavenging activity of designed derivatives was tested by and H2O2 and DPPH scavenging methods. Eugenol based derivatives were designed and synthesized for human MAO inhibitory action. The in silico and in vitro models were utilized for the evaluation of hMAO inhibition. The insight into molecular interactions among the compounds and both hMAO-A and hMAO-B active site was achieved by molecular docking studies. The two spectrophotometric titrations techniques were used to evaluate antioxidant potential. Compounds 5b and 16 were found as most active hMAO-A inhibitors with IC50 values of 5.989 +/- 0.007 mu M and 7.348 +/- 0.027 mu M respectively, through an appreciable selectivity index value of 0.19 and 0.14 respectively. In case of hMAO-B inhibition compounds 13a and 13b were found as most active hMAO-B inhibitors with IC50 values of 7.494 +/- 0.014 mu M and 9.183 +/- 0.034 mu M receptively and outstanding value of selectivity index of 5.14 and 5.72 respectively. Radical scavenging assay showed that compounds 5b, 5a, 9b, 9a were active antioxidants. The findings of present study indicated excellent correlation among dry lab and wet lab hMAO inhibitory experiments. Interestingly, the compounds exhibiting better MAO inhibition activity was also appeared as good antioxidant agents.