Targeting neuroinflammation and cognitive decline : first-in-class dual butyrylcholinesterase and p38α mitogen-activated protein kinase inhibitors

Ferjančič Benetik, Svit (author), Proj, Matic (author), Knez, Damijan (author), Košak, Urban (author), Meden, Anže (author), Krajšek, Katja (author), Pišlar, Anja (author), Horvat, Selena (author), Obreza, Aleš (author), Gobec, Stanislav (author)

The currently approved drugs for the treatment of Alzheimer’s disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers an innovative dual approach to mitigate two major drivers of neurodegeneration in AD: cholinergic deficit and neuroinflammation. Using structure-based drug design and a library of known p38α MAPK inhibitors, we developed first-in-class, selective dual BChE/p38α MAPK inhibitors with balanced activity against both targets. The X-ray crystal structures of the two most promising molecules bound to both enzymes were solved. Those ligands effectively reduced the production of proinflammatory markers in vitro and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation models. Remarkably, these compounds also significantly improved cognition in scopolamine- and lipopolysaccharide-induced models of cognitive dysfunction in mice. Because our dual-acting inhibitors target both the symptoms and the underlying neuropathology, they offer an innovative and comprehensive strategy to combat AD.

• Language: English
• Keywords: central nervous system, inhibition, inhibitors, peptides and proteins, 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: 2025
• Number of pages: Str. 17378−17411
• Numbering: Vol. 68, iss. 16
• PID: 20.500.12556/RUL-175854
• UDC: 615.4:54:616.894
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.5c00933
• COBISS.SI-ID: 250778371
• Publication date in RUL: 11.11.2025

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: centralni živčni sistem, inhibicija, inhibitorji, peptidi in beljakovine, modeli glodalcev, farmacevtska kemija, Alzheimerjeva bolezen