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

Povzetek

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.

Ključne besede

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

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 615.4:54:616.894
COBISS: 100613379 Povezava se bo odprla v novem oknu
ISSN: 0223-5234
Št. ogledov: 66
Št. prenosov: 13
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: Alzheimerjeva bolezen;Farmacevtska kemija;
Vrsta dela (COBISS): Članek v reviji
Strani: 39 str.
Zvezek: ǂVol. ǂ234
Čas izdaje: 2022
DOI: 10.1016/j.ejmech.2022.114248
ID: 16411112