929859-22-3Relevant academic research and scientific papers
Amine substitution of quinazolinones leads to selective nanomolar AChE inhibitors with 'inverted' binding mode
Darras, Fouad H.,Wehle, Sarah,Huang, Guozheng,Sotriffer, Christoph A.,Decker, Michael
, p. 4867 - 4881 (2014/11/08)
Selective and nanomolar acetylcholinesterase inhibitors were obtained by connecting tri- and tetracyclic quinazolinones - previously described as moderately active and unselective cholinesterase (ChE) inhibitors - via a hydroxyl group in para position to an anilinic nitrogen with different amines linked via a three carbon atom spacer. These tri- and tetracyclic quinazolinones containing different alicyclic ring sizes and connected to tertiary amines were docked to a high-resolution hAChE crystal structure to investigate the preferred binding mode in relation to results obtained by experimental structure-activity relationships. While the 'classical orientation' locating the heterocycle in the active site was rarely found, an alternative binding mode with the basic aliphatic amine in the active center ('inverted' orientation) was obtained for most compounds. Analyses of extended SARs based on this inverted binding mode are able to explain the compounds' binding affinities at AChE.
Synthesis, biological evaluation, and computational studies of Tri- and tetracyclic nitrogen-bridgehead compounds as potent dual-acting AChE inhibitors and h H3 receptor antagonists
Darras, Fouad H.,Pockes, Steffen,Huang, Guozheng,Wehle, Sarah,Strasser, Andrea,Wittmann, Hans-Joachim,Nimczick, Martin,Sotriffer, Christoph A.,Decker, Michael
, p. 225 - 242 (2014/04/03)
Combination of AChE inhibiting and histamine H3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits in Alzheimer's disease, since both pharmacological actions are able to enhance ch
Neuroprotective tri- and tetracyclic BChE inhibitors releasing reversible inhibitors upon carbamate transfer
Darras, Fouad H.,Kling, Beata,Heilmann, J?rg,Decker, Michael
, p. 914 - 919 (2013/01/15)
Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.
