85654-22-4Relevant articles and documents
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.
Neuroprotective tri- and tetracyclic BChE inhibitors releasing reversible inhibitors upon carbamate transfer
Darras, Fouad H.,Kling, Beata,Heilmann, J?rg,Decker, Michael
supporting information, 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.
SYNTHETIC ANALOGS OF Peganum ALKALOIDS. I. SYNTHESIS OF METHOXY- AND HYDROXY-SUBSTITUTED DEOXYVASICINONES AND DEOXYPEGANINES
Karimov, A.,Telezhenetskaya, M. V.,Yunusov, S. Yu.
, p. 466 - 472 (2007/10/02)
6-Methoxy-, 7-methoxy-, and 8-methoxydeoxyvasicinones have been synthesized by the reaction of substituted (3-methoxy-, 4-methoxy-, and 5-methoxy-) anthranilic acids with α-pyrrolidone.The demethylation of these compounds has given the corresponding hydroxy-substituted analogs of deoxyvasicinone, and the reduction of the products obtained with zinc in hydrochloric acid has given the hydroxy- and methoxy- analogs of deoxypeganine. 8-Hydrooxydeoxypeganine dimethyl-, ethyl-, and butylcarbamates have been obtained by the carbamoylation of 8-hydroxydeoxypeganine.
