Novel heterobivalent tacrine derivatives as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase.
Two series of novel heterobivalent tacrine derivatives were synthesized. A trimethoxy substituted benzene was linked to the tacrine moiety by a hydrazide-based linker. The compounds were evaluated as cholinesterase inhibitors, and trimethoxybenzoic acid derivatives with 11- or 12-atom spacers were the most potent inhibitors of human acetylcholinesterase. The inhibitors showed a surprising selectivity toward human butyrylcholinesterase, where several trimethoxyphenylpropionic acid derivatives had IC(50) values less than 250 pM.
Elsinghorst
Paul W
PW
Pharmazeutisches Institut, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Tanarro
Camino M Gonzalez
CM
Gütschow
Michael
M
D000110:Acetylcholinesterase / Q000737:chemistry; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004593:Electrophorus; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
D001549:Benzamides; D002800:Cholinesterase Inhibitors; D006834:Hydrazines; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase