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
| Autor: | Xia Jiang, Chengyao Wu, Zai-Wei Zhang, Huanhuan Li, Guijuan Zhang, Wen-Jian Tang, Hua-Li Qin, Ziwen Zhang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Amyloid Compound a Cell Survival RM1-950 Pharmacology Inhibitory postsynaptic potential Nervous System Structure-Activity Relationship chemistry.chemical_compound Alzheimer Disease Morris Water Maze Test In vivo Drug Discovery medicine Animals Cholinesterases Humans Dementia Structure–activity relationship Butyrylcholinesterase Mice Inbred ICR Behavior Animal Molecular Structure Chemistry anti-amyloid Brief Report alzheimer’s disease General Medicine acetylcholinesterase Sulfinic Acids medicine.disease Acetylcholinesterase sulphonyl fluoride In vitro Molecular Docking Simulation Neuroprotective Agents Liver Blood-Brain Barrier Alkynes Drug Design butyrylcholinesterase Cholinesterase Inhibitors Therapeutics. Pharmacology |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1860-1873 (2021) Journal of Enzyme Inhibition and Medicinal Chemistry article-version (VoR) Version of Record |
| DOI: | 10.6084/m9.figshare.16418732 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|