Homobivalent quinazolinimines as novel nanomolar inhibitors of cholinesterases with dirigible selectivity toward butyrylcholinesterase.
Homobivalent dimers of quinazolinimines, which bridge the imine nitrogen atoms via a hepta- and an octamethylene spacer, with different ring sizes of the alicycles were synthesized from the corresponding quinazolinethiones. The resulting compounds show >100-fold increase of inhibitory activities compared to related monomeric compounds yielding low-nanomolar inhibitors. For heptamethylene dimers, mixed inhibition profiles were obtained, whereas for the octamethylene compounds selectivity toward butyrylcholinesterase (>180) can be achieved with an eight-membered alicycle.
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 / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D019281:Dimerization; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry
D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007097:Imines; D008024:Ligands; D011799:Quinazolines; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase