title: Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease.
abstract: All approved drugs for Alzheimer disease (AD) in clinical practice ameliorate the symptoms of the disease. Among them, acetylcholinesterase inhibitors (AChEIs) are used to increase the cholinergic activity. Among new AChEI, tacrine compounds were found to be more toxic compared to 7-MEOTA (9-amino-7-methoxy-1,2,3,4-tetrahydroacridine). In this Letter, series of 7-MEOTA analogues (N-alkyl-7-methoxytacrine) were synthesized. Their inhibitory ability was evaluated on recombinant human acetylcholinesterase (AChE) and plasmatic human butyrylcholinesterase (BChE). Three novel compounds showed promising results towards hAChE better to THA or 7-MEOTA. Three compounds resulted as potent inhibitors of hBChE. The SAR findings highlighted the C(6)-C(7)N-alkyl chains for cholinesterase inhibition.
authors.affiliation: Charles University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry and Drug Control, Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Ondrej
authors.initials: O
authors.lastname: Holas
authors.forename: Jiri
authors.initials: J
authors.lastname: Binder
authors.forename: Filip
authors.initials: F
authors.lastname: Zemek
authors.forename: Jan
authors.initials: J
authors.lastname: Marek
authors.forename: Miroslav
authors.initials: M
authors.lastname: Pohanka
authors.forename: Veronika
authors.initials: V
authors.lastname: Opletalova
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Dohnal
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D011994:Recombinant Proteins; D013619:Tacrine; C016222:7-methoxytacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase