Novel inhibitors of acetyl- and butyrylcholinesterase derived from the alkaloids dehydroevodiamine and rutaecarpine.
Derived from the structures of the alkaloids rutaecarpine and dehydroevodiamine (DHED), and the long-known acetylcholinesterase (AChE) inhibitor tacrine, respectively, novel compounds were synthesised, including: 13-methyl-5,8-dihydro-6H-isoquino[1,2-b]quinazolin-13-ium chloride (12), (8Z)-5,6-dihydro-8H-isoquino[1,2-b]quinazolin-8-imine (13), 5,8-dihydro-6H-isoquino[1,2-b]quinazoline (15a), 13-methyl-5,8-dihydro-6H-isoquino[1,2-b]quinazolin-13-ium chloride (16), 5,7,8,13-tetrahydroindolo [2',3':3,4]pyrido[2,1-b]quinazoline (17), and N-(2-phenylethyl)-N-[(12Z)-7,8,9,10-tetrahydroazepino [2,1-b]quinazolin-12(6H)-ylidene]amine (20), respectively. In a first step to evaluate their possible applicability for antiamnesic therapy, the inhibition of AChE and butyrylcholinesterase (BChE) were determined: compounds 13, 15a, 17, and 20 are moderate or strong inhibitors of ChE, the latter two compounds show a 10-fold higher affinity to BChE. Compound 12 is a moderate inhibitor of AChE showing selectivity towards this enzyme.
Decker
Michael
M
Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, D-07743 Jena, Germany. m.decker@uni-jena.de
D000110:Acetylcholinesterase; D000470:Alkaloids / Q000737:chemistry*; D000818:Animals; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D026121:Indole Alkaloids; D011799:Quinazolines; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000494:pharmacology; D052999:Quinazolinones
D000110:Acetylcholinesterase; D000470:Alkaloids; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors; D026121:Indole Alkaloids; D011799:Quinazolines; D013619:Tacrine; C028633:dehydroevodiamine; C028632:rutecarpine; D052999:Quinazolinones