Structure–activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease
Copyright policy )Structure–activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease
To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; –OCH3 > –CH3 > –Cl (–Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aβ1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aβ1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.
- Anhui Medical University China (People's Republic of)
- Wuhan University of Technology China (People's Republic of)
- Wuhan University of Technology China (People's Republic of)
- Anhui University China (People's Republic of)
- Wuhan Polytechnic University China (People's Republic of)
Male, Amyloid, Cell Survival, RM1-950, Nervous System, Structure-Activity Relationship, Alzheimer Disease, Morris Water Maze Test, Animals, Cholinesterases, Humans, Mice, Inbred ICR, Behavior, Animal, Molecular Structure, anti-amyloid, Brief Report, alzheimer’s disease, acetylcholinesterase, sulphonyl fluoride, Molecular Docking Simulation, Neuroprotective Agents, Liver, Blood-Brain Barrier, Alkynes, Drug Design, butyrylcholinesterase, Therapeutics. Pharmacology, Cholinesterase Inhibitors
Male, Amyloid, Cell Survival, RM1-950, Nervous System, Structure-Activity Relationship, Alzheimer Disease, Morris Water Maze Test, Animals, Cholinesterases, Humans, Mice, Inbred ICR, Behavior, Animal, Molecular Structure, anti-amyloid, Brief Report, alzheimer’s disease, acetylcholinesterase, sulphonyl fluoride, Molecular Docking Simulation, Neuroprotective Agents, Liver, Blood-Brain Barrier, Alkynes, Drug Design, butyrylcholinesterase, Therapeutics. Pharmacology, Cholinesterase Inhibitors
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).8 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!