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Synthesis, Biological Evaluation and Molecular Modeling Studies of Propargyl‐Containing 2,4,6‐Trisubstituted Pyrimidine Derivatives as Potential Anti‐Parkinson Agents
ChemMedChem ( IF 3.4 ) Pub Date : 2018-03-13 , DOI: 10.1002/cmdc.201700589
Bhupinder Kumar 1 , Mohit Kumar 1 , Ashish Ranjan Dwivedi 1 , Vinod Kumar 1
Affiliation  

Monoamine oxidase B (MAO‐B) inhibitors are potential drug candidates for the treatment of various neurological disorders including Parkinson's disease. A total of 20 new propargyl‐containing 2,4,6‐trisubstituted pyrimidine derivatives were synthesized and screened for MAO inhibition using Amplex Red assays. All the synthesized compounds were found to be reversible and selective inhibitors of the MAO‐B isoform at sub‐micromolar concentrations. MVB3 was the most potent MAO‐B inhibitor with an IC50 value of 0.38±0.02 μμ, whereas MVB6 (IC50=0.51±0.04 μμ) and MVB16 (IC50=0.48±0.06 μμ) were the most selective for MAO‐B with a selectivity index of more than 100‐fold. In cytotoxic studies, these compounds were found to be nontoxic to human neuroblastoma SH‐SY5Y cells at concentrations of 25 μm. MVB6 was found to decrease the intracellular level of reactive oxygen species to 68 % at 10 μm concentration, whereas other compounds did not produce significant changes in reactive oxygen species levels. In molecular modeling studies, MVB3 displayed strong binding affinity for the MAO‐B isoform with a dock score of −10.45, in agreement with the observed activity. All the compounds fitted well in the hydrophobic cavity of MAO‐B. Thus, propargyl‐substituted pyrimidine derivatives can be promising leads in the development of potent, selective and reversible MAO‐B inhibitors for the treatment of Parkinson's disease.

中文翻译:

含炔丙基2,4,6-三取代嘧啶衍生物作为潜在抗帕金森剂的合成,生物学评估和分子建模研究

单胺氧化酶B(MAO-B)抑制剂是潜在的候选药物,可用于治疗包括帕金森氏症在内的各种神经系统疾病。总共合成了20种新的含炔丙基的2,4,6-三取代嘧啶衍生物,并使用Amplex Red分析筛选了MAO抑制作用。发现所有合成的化合物都是亚微摩尔浓度的MAO-B亚型的可逆和选择性抑制剂。MVB3是最有效的MAO-B抑制剂,其IC 50为0.38±0.02μ值μ,而MVB6(IC 50 = 0.51±0.04μ μ)和MVB16(IC 50 = 0.48±0.06μ μ)对MAO-B的选择性最高,选择性指数超过100倍。在细胞毒性研究中,发现这些化合物是无毒的,以人神经母SH-SY5Y细胞在25μ浓度MVB6被发现在10μ活性氧物种的细胞内水平降低至68%浓度,而其他的化合物不产生活性氧水平显著变化。在分子建模研究中,MVB3对MAO-B同工型显示出很强的结合亲和力,对接得分为−10.45,与观察到的活性一致。所有化合物均能很好地适合MAO-B的疏水腔。因此,炔丙基取代的嘧啶衍生物可以成为开发有效,选择性和可逆的MAO-B抑制剂以治疗帕金森氏病的有前途的先导。
更新日期:2018-03-13
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