Synthesis of tacrine analogues and their structure-activity relationships.
Three man synthetic routes to analogues of tacrine are described: reaction of anthranilonitriles with cyclohexanone and other ketones, reaction of various anilines with alpha-cyanoketones, and reactions involving anilines and cyclic beta-ketoesters. Although tacrine has a wide range of pharmacological effects, it is best known as an inhibitor of cholinesterase enzymes. Many of the analogues that have been made have not been tested against acetylcholinesterase or butyrylcholinesterase activity. Consequently, there is limited information from which a detailed understanding of structure-activity relationships can be derived. However, some halogenated derivatives are not only more potent acetylcholinesterase inhibitors than tacrine, they are also more selective for acetylcholinesterase than for butyrylcholinesterase.
Proctor
G R
GR
Department of Pure and Applied Chemistry and Strathclyde Institute for Drug Research, University of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, UK.
Harvey
A L
AL
D000110:Acetylcholinesterase / Q000737:chemistry; D000814:Aniline Compounds / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D003489:Cyanoketone / Q000737:chemistry; D003512:Cyclohexanones / Q000737:chemistry; D004952:Esters / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
D000814:Aniline Compounds; D002800:Cholinesterase Inhibitors; D003512:Cyclohexanones; D004952:Esters; D009570:Nitriles; D003489:Cyanoketone; D013619:Tacrine; C036468:cyclohexanone; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C023650:aniline