Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction.
Overview
and 7 other authors
Joseph S Brunzelle6, Ludmilla Shuvalova6, Kinga Sałat5, Saktimayee Mitra Roy6, Daniel Martin Watterson6, Kamil Musílek2,3, Stanislav Gobec1- University of Ljubljana, Faculty of Pharmacy, 1000 Ljubljana, Slovenia
- University Hospital in Hradec Kralove, Biomedical Research Centre, 500 05 Hradec Kralove, Czech Republic
- University of Hradec Kralove, Faculty of Science, Department of Chemistry, 500 03 Hradec Kralove, Czech Republic
- Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge 91220, France
- Department of Pharmacodynamics, Chair of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow 30-688, Poland
- Department of Pharmacology, Northwestern University, Chicago, Illinois 60611, United States
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-induc
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Data
Datasets cited
- rcsb.org/
structure/ , at PDB; found in the text, “p38α MAPK Crystallography”4ewq - rcsb.org/
structure/ , at PDB; found in the text, “Introduction”4r3c - rcsb.org/
structure/ , at PDB; found in the text, “Introduction”5nn0 - rcsb.org/
structure/ , at PDB; found in the text, “p38α MAPK Crystallography”9d6p - rcsb.org/
structure/ , at PDB; found in the text, “p38α MAPK Crystallography”9d8g - rcsb.org/
structure/ , at PDB; found in the text, “hBChE Crystallography”9gcq - rcsb.org/
structure/ , at PDB; found in the text, “hBChE Crystallography”9gcr
Versions
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Version 3, 28 September 2026
- Publisher: n/a → American Chemical Society
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 27 authors, 18 MeSH terms, 13 funders, 102 references.
Cite
This paper
Knez, D., Malinak, D., Meden, A., Ferjančič Benetik, S., Pišlar, A., Kohoutova, Z., Vondrackova, I., Psotka, M., Lycka, A., Pulkrabkova, L., Soukup, O., Skarka, A., Andrys, R., Brazzolotto, X., Igert, A., Dias, J., Nachon, F., Detka, J., Targosiński, F., . . . Gobec, S. (2026). Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction. Journal of medicinal chemistry, 69(16), 19891-19917. https://
BibTeX
@article{knez2026dual,
author = {Knez, Damijan and Malinak, David and Meden, Anže and Ferjančič Benetik, Svit and Pišlar, Anja and Kohoutova, Zuzana and Vondrackova, Iveta and Psotka, Miroslav and Lycka, Antonin and Pulkrabkova, Lenka and Soukup, Ondrej and Skarka, Adam and Andrys, Rudolf and Brazzolotto, Xavier and Igert, Alexandre and Dias, José and Nachon, Florian and Detka, Jan and Targosiński, Filip and Hliabovich, Dziyana and Brunzelle, Joseph S and Shuvalova, Ludmilla and Sałat, Kinga and Roy, Saktimayee Mitra and Watterson, Daniel Martin and Musílek, Kamil and Gobec, Stanislav},
title = {{Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction}},
journal = {Journal of medicinal chemistry},
year = {2026},
month = aug,
volume = {69},
number = {16},
pages = {19891--19917},
publisher = {American Chemical Society},
issn = {0022-2623},
doi = {10.1021/
url = {https://
pmid = {42679157},
pmcid = {PMC13528200}
}
RIS
TY - JOUR
AU - Knez, Damijan
AU - Malinak, David
AU - Meden, Anže
AU - Ferjančič Benetik, Svit
AU - Pišlar, Anja
AU - Kohoutova, Zuzana
AU - Vondrackova, Iveta
AU - Psotka, Miroslav
AU - Lycka, Antonin
AU - Pulkrabkova, Lenka
AU - Soukup, Ondrej
AU - Skarka, Adam
AU - Andrys, Rudolf
AU - Brazzolotto, Xavier
AU - Igert, Alexandre
AU - Dias, José
AU - Nachon, Florian
AU - Detka, Jan
AU - Targosiński, Filip
AU - Hliabovich, Dziyana
AU - Brunzelle, Joseph S
AU - Shuvalova, Ludmilla
AU - Sałat, Kinga
AU - Roy, Saktimayee Mitra
AU - Watterson, Daniel Martin
AU - Musílek, Kamil
AU - Gobec, Stanislav
TI - Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction
T2 - Journal of medicinal chemistry
J2 - J Med Chem
PY - 2026
DA - 2026/
VL - 69
IS - 16
SP - 19891
EP - 19917
SN - 0022-2623
PB - American Chemical Society
DO - 10.1021/
UR - https://
LA - en
ER -
CSL-JSON
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