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Nepflamapimod (<jats:bold>1<\/jats:bold>) is a brain\u2010penetrant selective inhibitor of the alpha isoform of the mitogen\u2010activated serine\/threonine protein kinase (MAPK) p38\u03b1, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of <jats:bold>1<\/jats:bold> and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6\u2010dichlorophenyl ring of <jats:bold>1<\/jats:bold>, generating neflamapimod\u2010propargylamine hybrids <jats:bold>3<\/jats:bold> and <jats:bold>4<\/jats:bold>. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:italic>N<\/jats:italic>\u2010propargyl derivative <jats:bold>4<\/jats:bold> showed a nanomolar p38\u03b1\u2010MAPK inhibitory activity (IC<jats:sub>50<\/jats:sub>\u2009=\u200998.7\u2009nM), which is only 2.6\u2010fold lower compared to that of the parent compound <jats:bold>1<\/jats:bold>, while displaying no hepato\u2010 and neurotoxicity up to 25\u2009\u03bcM concentration. It also retained a similar immunomodulatory profile against the N9 microglial cell line. Gratifyingly, at 5\u2009\u03bcM concentration, <jats:bold>4<\/jats:bold> demonstrated a neuroprotective effect against dexamethasone\u2010induced reactive oxygen species production in neuronal cells that was higher than that of <jats:bold>1<\/jats:bold>.<\/jats:p>","DOI":"10.1002\/ardp.202300525","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T22:06:49Z","timestamp":1709071609000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting Lewy body dementia with neflamapimod\u2010rasagiline hybrids"],"prefix":"10.1002","volume":"357","author":[{"given":"Claudia","family":"Albertini","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Biotechnology Alma Mater Studiorum\u2014University of Bologna Bologna Italy"}]},{"given":"Sabrina","family":"Petralla","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Molecular Biotechnology 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Medicinal Chemistry Eberhard\u2010Karls\u2010Universit\u00e4t T\u00fcbingen T\u00fcbingen Germany"}]},{"given":"Thales","family":"Kronenberger","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Medicinal Chemistry Eberhard\u2010Karls\u2010Universit\u00e4t T\u00fcbingen T\u00fcbingen Germany"},{"name":"School of Pharmacy University of Eastern Finland Kuopio Finland"}]},{"given":"Matthias","family":"Gehringer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Medicinal Chemistry Eberhard\u2010Karls\u2010Universit\u00e4t T\u00fcbingen T\u00fcbingen Germany"}]},{"given":"Stefan","family":"Laufer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Medicinal Chemistry Eberhard\u2010Karls\u2010Universit\u00e4t T\u00fcbingen T\u00fcbingen Germany"}]},{"given":"Maria L.","family":"Bolognesi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology Alma Mater 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