Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan.
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
Bioorg Chem. 2015 Dec;63:58-63. doi: 10.1016/j.bioorg.2015.09.009. Epub 2015 Sep 30.
Alzheimer's disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC50 value of 0.04±0.01μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC50 value of 0.06±0.02μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.
阿尔茨海默病是最常见的神经退行性疾病之一。胆碱酯酶（ChE）在控制胆碱能传递中起着不可或缺的作用，因此通过抑制 ChE 可以提高大脑中的乙酰胆碱水平。为了确定它们对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的抑制活性，设计、合成并进行了生物评估了香豆素连接硫脲衍生物。香豆素连接硫脲化合物的合成衍生物显示出对 AChE 和 BChE 的潜在抑制活性。在所合成的化合物中，1-(2-氧代-2H-色烯-3-羰基)-3-(3-氯苯基)硫脲（2e）对 AChE 的抑制活性最强，IC50 值为 0.04±0.01μM，而 1-(2-氧代-2H-色烯-3-羰基)-3-(2-甲氧基苯基)硫脲（2b）对 BChE 的抑制活性最强，IC50 值为 0.06±0.02μM。使用两种胆碱酯酶的同源模型进行了分子对接模拟，以探索抑制剂的可能结合模式。结果表明，新型合成的香豆素连接硫脲衍生物是开发有效和有效的乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）抑制剂的潜在候选物。
