Department of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan.
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan; Division of Analytical Chemistry, Institute of Chemical Science, Bahauddin Zakariya University, 60800 Multan, Pakistan.
Int J Biol Macromol. 2018 Sep;116:144-150. doi: 10.1016/j.ijbiomac.2018.05.001. Epub 2018 May 2.
Highly progressive neurodegenerative disorder generally known as Alzheimer's disease (AD), is a type of dementia, which is very common in elderly. The most common symptoms may include loss of memory along with disturbed behavioral and cognitive functions. Until now, only 4 cholinesterase (ChE) inhibitors are approved by FDA for symptomatic treatment of AD. Aroyl thiourea derivatives are well known bioactive organic molecules containing carbonyl and thiocarbonyl functional groups. Here, total 14 different thiourea derivatives (3a-3n) were synthesized and characterized by NMR, FTIR and X-ray crystallographic techniques. The synthesized compounds displayed varying inhibition activities on both acetylcholineterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Among all compounds, 3b and 3e were potent inhibitors of AChE (IC ± SEM = 8.92 ± 1.03 μM) and BuChE (IC ± SEM = 6.96 ± 0.961 μM) respectively. Enzyme kinetic studies showed that 3b exhibited uncompetitive binding with AChE while 3e demonstrated a mixed inhibition of BuChE. Molecular docking studies on AChE showed that 3b got binding interaction with Trp86 and Tyr337 while 3e showed binding affinity with Trp82 and His438 when docked with BuChE. The obtained results indicated that these thiourea derivatives could be considered as potential candidates to treat AD.
高度进行性神经退行性疾病通常称为阿尔茨海默病（AD），是一种痴呆症，在老年人中非常常见。最常见的症状可能包括记忆丧失以及行为和认知功能障碍。到目前为止，只有 4 种乙酰胆碱酯酶（ChE）抑制剂被 FDA 批准用于 AD 的症状治疗。芳酰基硫脲衍生物是众所周知的含有羰基和硫羰基官能团的生物活性有机分子。在这里，总共合成了 14 种不同的硫脲衍生物（3a-3n），并通过 NMR、FTIR 和 X 射线晶体学技术进行了表征。合成的化合物对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）均显示出不同的抑制活性。在所有化合物中，3b 和 3e 分别是 AChE（IC ± SEM = 8.92 ± 1.03 μM）和 BuChE（IC ± SEM = 6.96 ± 0.961 μM）的有效抑制剂。酶动力学研究表明，3b 对 AChE 表现出非竞争性结合，而 3e 对 BuChE 表现出混合抑制。对 AChE 的分子对接研究表明，3b 与 Trp86 和 Tyr337 有结合相互作用，而 3e 与 Trp82 和 His438 有结合亲和力，当与 BuChE 对接时。所得结果表明，这些硫脲衍生物可用作治疗 AD 的潜在候选物。
