title: Design, synthesis and evaluation of isaindigotone derivatives as dual inhibitors for acetylcholinesterase and amyloid beta aggregation.
abstract: A series of isaindigotone derivatives and analogues were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced β-amyloid (Aβ) aggregation. The synthetic compounds had IC(50) values at micro or nano molar range for cholinesterase inhibition, and some compounds exhibited strong inhibitory activity for AChE and high selectivity for AChE over BuChE, which were much better than the isaindigotone derivatives previously reported by our group. Most of these compounds showed higher self-induced Aβ aggregation inhibitory activity than a reference compound curcumin. The structure-activity relationship studies revealed that the derivatives with higher inhibition activity on AChE also showed higher selectivity for AChE over BuChE. Compound 6c exhibiting excellent inhibition for both AChE and self-induced Aβ aggregation was further studied using CD, EM, molecular docking and kinetics.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Jin-Wu
authors.initials: JW
authors.lastname: Yan
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Li
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Ye
authors.forename: Shuo-Bin
authors.initials: SB
authors.lastname: Chen
authors.forename: Jin-Qiang
authors.initials: JQ
authors.lastname: Hou
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism*; D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004593:Electrophorus; D006736:Horses; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D011799:Quinazolines; C440668:isaindigotone; D000110:Acetylcholinesterase