Expanding the reactive chemistry toolbox – warhead screening for covalent butyrylcholinesterase inhibitors

Meden, Anže (avtor), Brazzolotto, Xavier (avtor), Dias, José (avtor), Stojan, Jure (avtor), Knez, Damijan (avtor), Gobec, Stanislav (avtor)

Many covalent inhibitors of butyryl- and acetylcholinesterase, typically featuring electrophilic carbamoyl, phosphonyl, and sulfonyl groups, were reported in the literature. In this study, we screened these and several other electrophilic moieties for covalent cholinesterase inhibition. The electrophilic warheads were either installed at different positions on a reversible, selective human butyrylcholinesterase inhibitor scaffold or featured as small molecular weight, fragment-sized compounds. Time-dependency of the enzyme inhibition served as an indicator of covalent binding. The 7-indolyl substitution pattern proved optimal for generating time-dependent inhibitors, and carbamate chemotype produced most of the time-dependent hit compounds. Interestingly, the carbamates' reactivity was strongly influenced by their leaving groups’ nucleofugality and not by steric hindrance, as sufficiently acidic leaving groups (pKa <10) enabled carbamoylation of the catalytic serine. Notably, an exception to this rule of a thumb was found in a series of chalcogen carbachol analogues. The gathered insights highlight some key structure–reactivity relationships for covalent hBChE inhibitors and may assist in development of novel serine hydrolase inhibitors.

• Jezik: Angleški jezik
• Ključne besede: cholinesterase inhibitors, warhead, irreversible inhibition, butyrylcholinesterase, carbamate
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: 26 str.
• Številčenje: Vol. 423, art. 111841
• PID: 20.500.12556/RUL-179045
• UDK: 615.4:54:616.894
• ISSN pri članku: 1872-7786
• DOI: 10.1016/j.cbi.2025.111841
• COBISS.SI-ID: 260611587
• Datum objave v RUL: 04.02.2026

Gradivo je del revije

• Naslov: Chemico-biological interactions
• Založnik: Elsevier
• ISSN: 1872-7786
• COBISS.SI-ID: 23211013

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: zaviralci holinesteraze, bojna glava, ireverzibilna inhibicija, butirilholinesteraza, karbamat, farmacevtska kemija, analizna kemija