title: Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones.
abstract: 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 IC50of 0.16 ± 0.008 μM and 2m in 2-pyrazoline chalcones with IC50of 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.
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad-22060, Abbottabad, Pakistan; Division of Analytical Chemistry, Institute of Chemical Science, Bahauddin Zakariya University, 60800, Multan, Pakistan.
authors.forename: Muhammad Shakil
authors.initials: MS
authors.lastname: Shah
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad-22060, Abbottabad, Pakistan.
authors.forename: Shafi Ullah
authors.initials: SU
authors.lastname: Khan
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad-22060, Abbottabad, Pakistan.
authors.forename: Syeda Abida
authors.initials: SA
authors.lastname: Ejaz
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad-22060, Abbottabad, Pakistan.
authors.forename: Saifullah
authors.initials: S
authors.lastname: Afridi
authors.affiliation: Institute of Chemistry, University of the Punjab, Lahore, Pakistan.
authors.forename: Syed Umar Farooq
authors.initials: SUF
authors.lastname: Rizvi
authors.affiliation: Division of Analytical Chemistry, Institute of Chemical Science, Bahauddin Zakariya University, 60800, Multan, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Najam-Ul-Haq
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad-22060, Abbottabad, Pakistan. Electronic address: drjamshed@ciit.net.pk.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004593:Electrophorus; D006801:Humans; D062105:Molecular Docking Simulation; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047188:Chalcones; D002800:Cholinesterase Inhibitors; D011720:Pyrazoles; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: 2-Pyrazoline derivatives of chalcones; Alzheimer's disease; Cholinesterases inhibitors; Molecular docking; Piperidyl-thienyl derivatives