New cholinesterase inhibitors for Alzheimer's disease: Structure activity for relationship, kinetics and molecular docking studies of 1-butanoyl-3-arylthiourea derivatives

作者：Larik Fayaz Ali; Shah Muhammad Shakil; Saeed Aamer^*; Shah Hamid Saeed; Channar Pervaiz Ali; Bolte Michael; Lqbal Jamshed^*

来源：International Journal of Biological Macromolecules, 2018, 116: 144-150.

DOI：10.1016/j.ijbiomac.2018.05.001

• Thiourea
• Acetylcholinesterase
• Butyrylcholinesterase
• Alzheimer's disease

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 (IC50 +/- SEM = 8.92 +/- 1.03 mu M) and BuChE (IC50 +/- SEM = 6.96 +/- 0.961 mu M) 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.

• 出版日期2018-9