Dual inhibitors of p38α mitogen-activated protein kinase and butyrylcholinesterase for the modulation of neuroinflammation and cognitive dysfunction

Knez, Damijan (author), Meden, Anže (author), Ferjančič Benetik, Svit (author), Pišlar, Anja (author), Musílek, Kamil (author), Gobec, Stanislav (author)

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.

• Language: English
• Keywords: inflammation, inhibitors, peptides and proteins, nervous system diseases, rodent models
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: Str. 19891-19917
• Numbering: Vol. 69, iss. 16
• PID: 20.500.12556/RUL-189714
• UDC: 615.2-021.321:616.894
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.6c01461
• COBISS.SI-ID: 289183747
• Publication date in RUL: 13.10.2026

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: zaviralci vnetja, peptidi in beljakovine, bolezni živčnega sistema, modeli glodalcev, Alzheimerjeva bolezen, tarčna zdravila