Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones

详细信息    查看全文

• 作者：Muhammad Shakil Shah^a ; ^b ; Shafi Ullah Khan^a ; Syeda Abida Ejaz^a ; Saifullah Afridi^a ; Syed Umar Farooq Rizvi^c ; Muhammad Najam-ul-Haq^b ; Jamshed Iqbal^a ; ^{drjamshed@ciit.net.pk} ; ^{jamshediqb@googlemail.com}
• 关键词：Alzheimer's disease ; Cholinesterases inhibitors ; Piperidyl-thienyl derivatives ; 2-Pyrazoline derivatives of chalcones ; Molecular docking
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2017
• 出版时间：22 January 2017
• 年：2017
• 卷：482
• 期：4
• 页码：615-624
• 全文大小：2882 K
• 卷排序：482

文摘

Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various neurological problems most precisely Alzheimer's disease (AD), which leads to senile dementia. Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the treatment of Alzheimer's disease. FDA approved drugs for the treatment of AD, belong to a group of cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential. For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC50 of 0.16 ± 0.008 μM and 2m in 2-pyrazoline chalcones with IC50 of 0.13 ± 0.006 μM, were found to be the most potent inhibitors of AChE, exhibiting ≈142 and ≈ 173-fold greater inhibitory potential compared to the reference inhibitor i.e., Neostigmine (IC50 ± SEM = 22.2 ± 3.2 μM). Molecular docking studies of most potent inhibitors were carried out to investigate the binding interactions inside the active site. Molecular docking study revealed that potent compounds and co-crystalized ligand had same binding orientation within the active site of target enzyme. Most of these compounds are selective inhibitors of AChE with a potential use against progressive neurodegenerative disorder and age related problems.