optimization of a butyrylcholinesterase inhibitor series
Anže Meden (Author), Damijan Knez (Author), Xavier Brazzolotto (Author), Florian Nachon (Author), Jose Dias (Author), Jurij Svete (Author), Jure Stojan (Author), Uroš Grošelj (Author), Stanislav Gobec (Author)

Abstract

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.

Keywords

zaviralci holinesteraze;butirilholinesteraza;karbamat;psevdoireverzibilna inhibicija;cholinesterase inhibitors;Alzheimer's disease;butyrylcholinesterase;carbamate;pseudoirreversible inhibition;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.4:54:616.894
COBISS: 100613379 Link will open in a new window
ISSN: 0223-5234
Views: 66
Downloads: 13
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Other data

Secondary language: Slovenian
Secondary keywords: Alzheimerjeva bolezen;Farmacevtska kemija;
Type (COBISS): Article
Pages: 39 str.
Issue: ǂVol. ǂ234
Chronology: 2022
DOI: 10.1016/j.ejmech.2022.114248
ID: 16411112