20.500.12556/RUL-189714 Dual inhibitors of p38α mitogen-activated protein kinase and butyrylcholinesterase for the modulation of neuroinflammation and cognitive dysfunction Chronic neuroinflammation and cholinergic dysfunction are major contributors to cognitive decline in Alzheimer’s disease. Here, we report a series of pyridazine-based multitarget-directed ligands that simultaneously inhibit human butyrylcholinesterase (hBChE) and p38α mitogen-activated protein kinase (p38α MAPK). Pyridazines 8 and 21 were identified as potent dual inhibitors with submicromolar inhibitory potencies against target enzymes and high selectivity over acetylcholinesterase. X-ray crystallographic analyses revealed the experimental binding modes of 8 and 21 in hBChE and p38α MAPK, and identified conserved π–π, π–cation, and hinge region interactions that rationalize dual-target engagement. Both compounds were blood-brain barrier permeable, exhibited low cytotoxicity, and significantly attenuated lipopolysaccharide-induced proinflammatory responses and apoptosis in BV2 microglia. In vivo, compound 21 enhanced cognitive performance in mouse models of scopolamine-induced amnesia and LPS-stimulated neuroinflammatory cognitive impairment. Collectively, these results document the potential of structure-assisted design to achieve selective dual-target pharmacology within a single molecular entity. inflammation inhibitors peptides and proteins nervous system diseases rodent models zaviralci vnetja peptidi in beljakovine bolezni živčnega sistema modeli glodalcev Alzheimerjeva bolezen tarčna zdravila true false true Angleški jezik Slovenski jezik Članek v reviji 2026-10-13 13:37:02 2026-10-13 13:37:09 2026-10-14 04:14:05 0000-00-00 00:00:00 2026 0 0 Str. 19891-19917 iss. 16 Vol. 69 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.2-021.321:616.894 1520-4804 10.1021/acs.jmedchem.6c01461 289183747 acs.jmedchem.6c01461.pdf acs.jmedchem.6c01461.pdf 1 5EEE376E13134C1AE0F8B5E0B9DD7AB6 799eb400b33e379b0a9fb9f7185b6971f842e668d5d05180d2162b3b1238d69e 0906018c-c6fc-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=250466 https://pubs.acs.org/jmcmar/article/69/16/19891/5251523/Dual-Inhibitors-of-p38-Mitogen-Activated-Protein 1 44448483-c6fa-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=250465 Fakulteta za farmacijo 0 0 0