title: Design, synthesis and evaluation of novel ferulic acid-O-alkylamine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.
abstract: A series of novel ferulic acid-O-alkylamines derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. In vitro studies displayed that all the synthesized target compounds showed impressive inhibitory activity against butyrylcholinesterase (BuChE), significant inhibition/disaggregation of self-induced β-amyloid (Aβ) aggregation and acted as potential antioxidants. Particularly, compound 7f, one of the most potent BuChE inhibitor (IC50value of 0.021 μM for equine serum BuChE, 8.63 μM for ratBuChE and 0.07 μM for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC50= 2.13 μM for electric eel AChE, 1.8 μM for ratAChE and 3.82 μM for human erythrocytes AChE), and the result of molecular docking provided an explanation for its selective BuChE inhibitory activity. Compound 7f also had noteworthy inhibitory effects on self-induced Aβ1-42aggregation (50.8 ± 0.82%) and was found to disaggregate self-induced Aβ1-42aggregation (38.7 ± 0.65%), which was further elucidated by the transmission electron microscopy. Meanwhile, compound 7f showed the modest antioxidant activity (0.55 eq of Trolox), good protective effect against H2O2-induced PC12 cell injury, with low toxicity. Moreover, compound 7f could cross the blood-brain barrier (BBB) in vitro. Significantly, compound 7f did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Taken together, the results indicated that compound 7f is a very promising multifunctional agent in the treatment of Alzheimer's disease, particularly the advanced stages of AD.
authors.affiliation: College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China. Electronic address: sangzhipei@126.com.
authors.forename: Zhipei
authors.initials: Z
authors.lastname: Sang
authors.affiliation: College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
authors.forename: Wanli
authors.initials: W
authors.lastname: Pan
authors.affiliation: Nanyang Normal University Hospital, Nanyang Normal University, Nanyang, 473061, China.
authors.forename: Keren
authors.initials: K
authors.lastname: Wang
authors.affiliation: College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
authors.forename: Qinge
authors.initials: Q
authors.lastname: Ma
authors.affiliation: College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
authors.forename: Lintao
authors.initials: L
authors.lastname: Yu
authors.affiliation: College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Bai
authors.affiliation: Henan Key Laboratory of Insect Biology in Funiu Mountain, China-UK-NYNU-RRes Joint Laboratory of Insect Biology, Nanyang Normal University, Nanyang 473061, China.
authors.forename: Chaoliang
authors.initials: C
authors.lastname: Leng
authors.affiliation: Henan Key Laboratory of Insect Biology in Funiu Mountain, China-UK-NYNU-RRes Joint Laboratory of Insect Biology, Nanyang Normal University, Nanyang 473061, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China.
authors.forename: Zhenghuai
authors.initials: Z
authors.lastname: Tan
authors.affiliation: College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China. Electronic address: liuwm1969@163.com.
authors.forename: Wenmin
authors.initials: W
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000187:drug effects; D000818:Animals; D000975:Antioxidants; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004524:Eels; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D016716:PC12 Cells; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D003373:Coumaric Acids; C004999:ferulic acid; D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; Antioxidant activity; Aβ aggregation; Butyrylcholinesterase inhibition; Ferulic acid-O-alkylamines derivatives; Multifunctional agents; Neuroprotective effects