20.500.12556/RUL-175860 Transforming ureas into carbamates from allosteric p38α MAPK ligands to dual BChE/p38α MAPK inhibitors 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. butyrylcholinesterase p38α mitogen-activated protein kinase dual inhibitors carbamate pseudo-irreversible inhibition butirilholinesteraza z mitogenom aktivirana proteinska kinaza p38α dvojni zaviralci karbamat psevdoireverzibilna inhibicija Alzheimerjeva bolezen zdravljenje true false true Angleški jezik Slovenski jezik Članek v reviji 2025-11-11 11:19:36 2025-11-11 11:19:43 2026-06-18 10:16:54 0000-00-00 00:00:00 2025 0 0 27 str. art. 108998 Vol. 165 Oct. 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.894:616-085 0045-2068 10.1016/j.bioorg.2025.108998 250793731 1-s2.0-S0045206825008788-main.pdf 1-s2.0-S0045206825008788-main.pdf 1 B8A0CC930E5CC593C0553EE1F1118ADF d4525f2cc5ef2819f30abad9f19265bf4e9debf790840098d3cee930e15b1bd2 bdd6d5ad-bee8-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=221772 https://www.sciencedirect.com/science/article/pii/S0045206825008788 1 9f300e0b-bee7-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=221771 Fakulteta za farmacijo 0 0 0