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From tryptophan-based amides to tertiary amines : optimization of a butyrylcholinesterase inhibitor seriesMeden, Anže ...Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp (Chierrito et al., 2018) [3]-rich analogues ... with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold). Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme). Additionally, N-hydroxyindole was discovered as a novel leaving group chemotype. The covalent mechanism of action was confirmed by time-dependency experiments, progress curve analysis, and indirectly by co-crystallization with the human recombinant enzyme. Two crystal structures of BChE-inhibitor complexes were solved and coupled with the supporting molecular dynamics simulations increased our understanding of the structure-activity relationship, while also providing the neccessary structural infromation for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors.Source: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 234, 2022, 39 str.)Type of material - article, component part ; adult, seriousPublish date - 2022Language - englishCOBISS.SI-ID - 100613379
Author
Meden, Anže |
Knez, Damijan, farmacevt |
Brazzolotto, Xavier |
Nachon, Florian |
Dias, Jose |
Svete, Jurij |
Stojan, Jure, 1956- |
Grošelj, Uroš |
Gobec, Stanislav, 1970-
Topics
Alzheimerjeva bolezen |
Farmacevtska kemija |
zaviralci holinesteraze |
butirilholinesteraza |
karbamat |
psevdoireverzibilna inhibicija |
cholinesterase inhibitors |
Alzheimer's disease |
butyrylcholinesterase |
carbamate |
pseudoirreversible inhibition
Author | Meden, Anže ... |
Title | From tryptophan-based amides to tertiary amines : optimization of a butyrylcholinesterase inhibitor series |
Publication date | 2022-04-15 |
COBISS.SI-ID | 100613379 |
Publication version in repository | Publisher's version |
Publication licence | Creative Commons Attribution 4.0 International |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
---|---|---|---|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Napredna organska sinteza in kataliza | P1-0179-2020 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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https://www.sciencedirect.com/science/article/pii/S0223523422001507 |
https://repozitorij.uni-lj.si/IzpisGradiva.php?id=140000 |
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Meden, Anže | 53584 |
Knez, Damijan, farmacevt | 36438 |
Brazzolotto, Xavier | |
Nachon, Florian | |
Dias, Jose | |
Svete, Jurij | 08284 |
Stojan, Jure, 1956- | 03723 |
Grošelj, Uroš | 22602 |
Gobec, Stanislav, 1970- | 15284 |
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