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.

Department of Pharmacodynamics Chair of Pharmacodynamics Faculty of Pharmacy Jagiellonian University Medical College Krakow 30 688 Poland

University of Hradec Kralove Faculty of Science Department of Chemistry 500 03 Hradec Kralove Czech Republic

University of Hradec Kralove Faculty of Science Department of Chemistry 500 03 Hradec Kralove Czech Republic; University Hospital in Hradec Kralove Biomedical Research Centre 500 05 Hradec Kralove Czech Republic

University of Ljubljana Faculty of Pharmacy Department of Pharmaceutical Chemistry 1000 Ljubljana Slovenia

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