Darras, Fouad H. and Wehle, Sarah and Huang, Guozheng and Sotriffer, Christoph A. and Decker, Michael (2014) Amine substitution of quinazolinones leads to selective nanomolar AChE inhibitors with 'inverted' binding mode. BIOORGANIC & MEDICINAL CHEMISTRY, 22 (17). pp. 4867-4881. ISSN 0968-0896, 1464-3391
Full text not available from this repository. (Request a copy)Abstract
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. (C) 2014 Elsevier Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NITROGEN-BRIDGEHEAD COMPOUNDS; EMPIRICAL SCORING FUNCTIONS; ACETYLCHOLINESTERASE INHIBITORS; CHOLINESTERASE-INHIBITORS; ALZHEIMERS-DISEASE; GENETIC ALGORITHM; IDENTIFICATION; ALKALOIDS; COGNITION; DOCKING; Alzheimer's disease; Cholinesterase inhibitors; Computational study; Heterocycles; Quinazolinones |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Aug 2019 11:27 |
| Last Modified: | 29 Aug 2019 11:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9678 |
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