title: Design, synthesis and evaluation of tacrine-flurbiprofen-nitrate trihybrids as novel anti-Alzheimer's disease agents.
abstract: To search for multifunctional anti-Alzheimer's disease (AD) agents with good safety, the previously synthesized tacrine-flurbiprofen hybrids 1a and 1b were modified into tacrine-flurbiprofen-nitrate trihybrids 3a-h. These compounds displayed comparable or higher cholinesterase inhibitory activity relative to the bivalent hybrids. Compound 3a was the most potent, which released moderate NO, exerted blood vessel relaxative activity, and showed significant Aβ inhibitory effects whereas tacrine and flurbiprofen did not exhibit any Aβ inhibitory activity at the same dose. In addition, 3a was active in improving memory impairment in vivo. More importantly, the hepatotoxicity study showed that 3a was much safer than tacrine, suggesting it might be a promising anti-AD agent for further investigation.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Jianfei
authors.initials: J
authors.lastname: Sun
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D005480:Flurbiprofen / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D009566:Nitrates; D013619:Tacrine; D005480:Flurbiprofen; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase