From tryptophan-based amides to tertiary amines : optimization of a butyrylcholinesterase inhibitor series

Meden, Anže (avtor), Knez, Damijan (avtor), Brazzolotto, Xavier (avtor), Nachon, Florian (avtor), Dias, Jose (avtor), Svete, Jurij (avtor), Stojan, Jure (avtor), Grošelj, Uroš (avtor), Gobec, Stanislav (avtor)

Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp$^3$-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.

• Jezik: Angleški jezik
• Ključne besede: cholinesterase inhibitors, Alzheimer's disease, butyrylcholinesterase, carbamate, pseudoirreversible inhibition
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; FKKT - Fakulteta za kemijo in kemijsko tehnologijo ; MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2022
• Št. strani: 39 str.
• Številčenje: Vol. 234, art. 114248
• PID: 20.500.12556/RUL-140000
• UDK: 615.4:54:616.894
• ISSN pri članku: 0223-5234
• DOI: 10.1016/j.ejmech.2022.114248
• COBISS.SI-ID: 100613379
• Datum objave v RUL: 09.09.2022

Gradivo je del revije

• Naslov: European journal of medicinal chemistry
• Skrajšan naslov: Eur. j. med. chem.
• Založnik: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: zaviralci holinesteraze, butirilholinesteraza, karbamat, psevdoireverzibilna inhibicija, Alzheimerjeva bolezen, farmacevtska kemija