Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction

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Abstract
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.
Funding Information
  • National Institute on Aging (AG043415)
  • National Institute on Aging (AG062095)
  • Uniwersytet Jagielloński Collegium Medicum (N42/DBS/000454)
  • Univerzita Hradec Králové (2206/2025-2026)
  • Grantová Agentura České Republiky (GF23-42701L)
  • Ministerstvo Zdravotnictví Ceské Republiky (UHHK, 00179906)
  • Narodowe Centrum Nauki (DEC-2021/43/I/NZ7/00342)
  • The Slovenian Research and Innovation Agency (N1-0277)
  • The Slovenian Research and Innovation Agency (P1-0208)
  • The Slovenian Research and Innovation Agency (P4-0127)
  • Univerza v Ljubljani (NA)
  • European Regional Development Fund (NA)
  • Ministère des Armées (NBC-5-C-2316)
  • Graduate Program in Physics at UNIFAL-MG (BI-FR/23-24-PROTEUS-002)
  • Graduate Program in Physics at UNIFAL-MG (NA)

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