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

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

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.

• Language: English
• Keywords: butyrylcholinesterase, p38α mitogen-activated protein kinase, dual inhibitors, carbamate, pseudo-irreversible inhibition
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 1-27
• Numbering: Vol. 165, [article. no.] ǂ108998
• PID: 20.500.12556/RUL-175860
• UDC: 616.894:616-085
• ISSN on article: 0045-2068
• DOI: 10.1016/j.bioorg.2025.108998
• COBISS.SI-ID: 250793731
• Publication date in RUL: 11.11.2025

Record is a part of a journal

• Title: Bioorganic chemistry
• Shortened title: Bioorg. chem.
• Publisher: Academic Press
• ISSN: 0045-2068
• COBISS.SI-ID: 25099008

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: butirilholinesteraza, p38α mitogenom aktivirana proteinska kinaza, dvojni zaviralci, karbamat, psevdo-ireverzibilna inhibicija, Alzheimerjeva bolezen, zdravljenje