Transforming ureas into carbamates : from allosteric p38α MAPK ligands to dual BChE/p38α MAPK inhibitors

Ferjančič Benetik, Svit (avtor), Meden, Anže (avtor), Knez, Damijan (avtor), Mastnak-Sokolov, Peter (avtor), Košak, Urban (avtor), Horvat, Selena (avtor), Pišlar, Anja (avtor), Obreza, Aleš (avtor), Gobec, Stanislav (avtor)

Given the limited benefits of anticholinergic drugs and the repeated clinical failures of anti-amyloid therapies, the therapeutic focus in Alzheimer's disease (AD) is gradually shifting toward addressing both disease symptoms and its major underlying cause – neuroinflammation. We have developed novel multi-target directed ligands that inhibit butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) to simultaneously target cholinergic deficits and neuroinflammation in AD. Following in silico design, we converted known allosteric pyrazolyl urea p38α MAPK ligands into N,N-disubstituted carbamates that pseudo-irreversibly inhibit hBChE while retaining p38α MAPK inhibitory activity. The lead compound 13a has favourable central nervous system (CNS) drug-like properties in vitro and shows procognitive effects in an in vivo scopolamine-induced amnesia model. Our series demonstrates that targeted structural modifications of selective kinase inhibitors, based on a comprehensive knowledge of cholinesterase structure and function, enable expansion of the effect to the CNS. This approach offers critical insights to pave the way for the development of novel dual-target agents that modulate both cholinergic and neuroinflammatory pathways in neurodegenerative diseases.

• Jezik: Angleški jezik
• Ključne besede: butyrylcholinesterase, p38α mitogen-activated protein kinase, dual inhibitors, carbamate, pseudo-irreversible inhibition
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2025
• Št. strani: 27 str.
• Številčenje: Vol. 165, art. 108998
• PID: 20.500.12556/RUL-175860
• UDK: 616.894:616-085
• ISSN pri članku: 0045-2068
• DOI: 10.1016/j.bioorg.2025.108998
• COBISS.SI-ID: 250793731
• Datum objave v RUL: 11.11.2025

Gradivo je del revije

• Naslov: Bioorganic chemistry
• Skrajšan naslov: Bioorg. chem.
• Založnik: Elsevier
• ISSN: 0045-2068
• COBISS.SI-ID: 25099008

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: butirilholinesteraza, z mitogenom aktivirana proteinska kinaza p38α, dvojni zaviralci, karbamat, psevdoireverzibilna inhibicija, Alzheimerjeva bolezen, zdravljenje