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Synthesis, molecular modelling and biological activity of some pyridazinone derivatives as selective human monoamine oxidase-B inhibitors.
Pharmacological Reports ( IF 4.4 ) Pub Date : 2020-03-06 , DOI: 10.1007/s43440-020-00070-w
Zeynep Özdemir 1 , Mehmet Abdullah Alagöz 1 , Harun Uslu 2 , Arzu Karakurt 1 , Acelya Erikci 3 , Gulberk Ucar 3 , Mehtap Uysal 4
Affiliation  

BACKGROUND Since brain neurotransmitter levels are associated with the pathology of various neurodegenerative diseases like Parkinson and Alzheimer, monoamineoxidase (MAO) plays a critical role in balancing these neurotransmitters in the brain. MAO isoforms appear as promising drug targets for the development of central nervous system agents. Pyridazinones have a broad array of biological activities. Here, six pyridazinone derivatives were synthesized and their human monoamine oxidase inhibitory activities were evaluated by molecular docking studies, in silico ADME prediction and in vitro biological screening tests. METHODS The compounds were synthesized by the reaction of different piperazine derivatives with 3 (2H)-pyridazinone ring and MAO-inhibitory effects were investigated. Docking studies were conducted with Maestro11.8 software. RESULTS Most of the synthesized compounds inhibited hMAO-B selectively except compound 4f. Compounds 4a-4e inhibited hMAO-B selectively and reversibly in a competitive mode. Compound 4b was found as the most potent (ki = 0.022 ± 0.001 µM) and selective (SI (Ki hMAO-A/hMAO-B) = 206.82) hMAO-B inhibitor in this series. The results of docking studies were found to be consistent with the results of the in vivo activity studies. Compounds 4a-4e were found to be non-toxic to HepG2 cells at 25 μM concentration. In silico calculations of ADME properties indicated that the compounds have good pharmacokinetic profiles. CONCLUSION It was concluded that 4b is possibly recommended as a promising nominee for the design and development of new pyridazinones which can be used in the treatment of neurological diseases.

中文翻译:

一些哒嗪酮衍生物作为选择性人单胺氧化酶 B 抑制剂的合成、分子建模和生物活性。

背景技术由于脑神经递质水平与多种神经变性疾病如帕金森和阿尔茨海默病的病理学相关,单胺氧化酶(MAO)在平衡大脑中的这些神经递质方面起着关键作用。MAO 亚型似乎是开发中枢神经系统药物的有希望的药物靶点。哒嗪酮类具有广泛的生物活性。在这里,合成了六种哒嗪酮衍生物,并通过分子对接研究、计算机模拟 ADME 预测和体外生物筛选试验评估了它们的人单胺氧化酶抑制活性。方法通过不同哌嗪衍生物与3(2H)-哒嗪酮环反应合成化合物,并研究其对MAO的抑制作用。对接研究使用 Maestro11.8 软件进行。结果除化合物4f外,大多数合成的化合物选择性抑制hMAO-B。化合物 4a-4e 以竞争模式选择性和可逆地抑制 hMAO-B。发现化合物 4b 是该系列中最有效 (ki = 0.022 ± 0.001 µM) 和选择性 (SI (Ki hMAO-A/hMAO-B) = 206.82) hMAO-B 抑制剂。发现对接研究的结果与体内活性研究的结果一致。发现化合物 4a-4e 在 25 μM 浓度下对 HepG2 细胞无毒。ADME 特性的计算机计算表明这些化合物具有良好的药代动力学特征。结论 得出的结论是,4b 可能被推荐为设计和开发可用于治疗神经系统疾病的新型哒嗪酮类药物的有前途的候选人。
更新日期:2020-03-06
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