title: Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca²⁺ overload.
abstract: In this study, a series of multipotent phenylthiazole-tacrine hybrids (7a-7e, 8, and 9a-9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole-tacrine hybrids were potent cholinesterase inhibitors with pIC(50) (-logIC(50)) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole-tacrine hybrids (9a-9m) could efficiently prevent Aβ(1-42) self-aggregation. The structure-activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4'-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca(2+) overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer's disease.
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Yu
authors.forename: Feng-Chao
authors.initials: FC
authors.lastname: Jiang
authors.forename: Xin-Lei
authors.initials: XL
authors.lastname: Guan
authors.forename: Can-Ming
authors.initials: CM
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.forename: Ming-Xing
authors.initials: MX
authors.lastname: Li
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D013619:Tacrine; D002802:Cholinesterases; D002118:Calcium