Transforming ureas into carbamatesFerjančič 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) butyrylcholinesterasep38α mitogen-activated protein kinasedual inhibitorscarbamatepseudo-irreversible inhibitionGiven 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.20252025-11-11 11:19:36Članek v reviji175860UDK: 616.894:616-085ISSN pri članku: 0045-2068DOI: 10.1016/j.bioorg.2025.108998COBISS_ID: 250793731sl