Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal-chelation potential. All the synthesized compounds were found to be selective and potent inhibitors of MAO-A and AChE enzymes at nanomolar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 μM, respectively. It also showed potent AChE inhibition with an IC50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with an IC50 value of 9.54 ± 0.07 nM and displayed an IC50 value of 1010 ± 70.42 nM against the MAO-A isoform. In the cytotoxic studies, these compounds were found to be nontoxic to the human neuroblastoma SH-SY5Y cells even at 25 μM concentration. All the compounds were found to be reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA- and H2O2-induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found to be stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual-acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer's disease.

中文翻译：

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4,6-二苯基嘧啶衍生物作为单胺氧化酶和乙酰​​胆碱酯酶的双重抑制剂，可治疗阿尔茨海默氏病。

阿尔茨海默氏病（AD）是一种具有多因素发病机制的神经退行性疾病。单胺氧化酶（MAO）和乙酰胆碱酯酶（AChE）是治疗AD的潜在靶标。总共合成了15种含有4,6-二苯基嘧啶衍生物的新炔丙基，并筛选了其对MAO和AChE的抑制活性以及对ROS产生的抑制作用和金属螯合电位。发现所有合成的化合物都是纳摩尔浓度的MAO-A和AChE酶的选择性抑制剂。发现VB1是最有效的MAO-A和BuChE抑制剂，IC50值分别为18.34±0.38 nM和0.666±0.03μM。它还显示出有效的AChE抑制作用，IC50值为30.46±0.23 nM。发现化合物VB8是最有效的AChE抑制剂，IC50值为9.54±0。07 nM，对MAO-A同工型的IC50值为1010±70.42 nM。在细胞毒性研究中，发现这些化合物即使在25μM浓度下对人神经母细胞瘤SH-SY5Y细胞也无毒。发现所有化合物都是MAO-A和AChE酶的可逆抑制剂。此外，这些化合物还对SH-SY5Y细胞中的6-OHDA-和H2O2诱导的神经毒性表现出良好的神经保护作用。所有的化合物都能很好地适应MAO-A和AChE酶的疏水腔。在分子动力学模拟研究中，发现VB1和VB8在各自的腔体中稳定30 ns。因此，在开发针对MAO-A和AChE酶的双作用抑制剂以治疗阿尔茨海默氏病方面，4,6-二苯基嘧啶衍生物可以作为有前途的先导。