title: Novel oxoisoaporphine-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation.
abstract: A series of novel oxoisoaporphine-based inhibitors (10-aminoalkylamino-1-azabenzanthrone Ar-NH(CH(2))(n)NR(1)R(2)) of acetylcholinesterase (AChE) has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE) and AChE-induced β-amyloid (Aβ) aggregation. The synthetic compounds exhibited high AChE inhibitory activity with IC(50) values in the submicromolar range in most cases. Non-competitive binding mode was found for these derivatives by the graphical analysis of steady-state inhibition data. Moreover, all compounds exhibit significant inhibitory activity on AChE-induced Aβ aggregation with inhibitory potency from 54.5% to 93.5%. Finally, six out of twelve synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. The result encourages us to study this class of compounds thoroughly and systematically.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering of Guangxi Normal University, Guilin, PR China.
authors.forename: Huang
authors.initials: H
authors.lastname: Tang
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhao
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Zhong
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Wang
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D001060:Aporphines / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008567:Membranes, Artificial; D008958:Models, Molecular; D015394:Molecular Structure; D010539:Permeability; D011485:Protein Binding
chemical_list: D016229:Amyloid beta-Peptides; D001060:Aporphines; D002800:Cholinesterase Inhibitors; D008567:Membranes, Artificial; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase