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Dual targeting of the histamine H<jats:sub>3<\/jats:sub> receptor (H<jats:sub>3<\/jats:sub>R) and acetylcholinesterase (AChE) is a valid strategy for the treatment of AD. In this work, a new series of pyrrolo[2,3\u2010<jats:italic>d<\/jats:italic>]pyrimidines fused to fluorobenzylpiperidine derivatives was designed, synthesized, and pharmacologically evaluated. Among the 16 derivatives reported here, compounds <jats:bold>4a<\/jats:bold> (IC<jats:sub>50<\/jats:sub>\u2009=\u20092.19\u2009\u00b5M for human acetylcholinesterase (hAChE) and <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u2009=\u20091.05\u2009\u00b5M for H<jats:sub>3<\/jats:sub>R) and <jats:bold>4f<\/jats:bold> (IC<jats:sub>50<\/jats:sub>\u2009=\u20094.27\u2009\u00b5M for hAChE and <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u2009=\u20091.31\u2009\u00b5M for H<jats:sub>3<\/jats:sub>R) show the most balanced dual targeting behavior coupled with moderate affinities at both targets. Selected compounds showed medium inhibition of butyrylcholinesterase (BuChE). Moreover, these compounds did not show any toxicity in the SH\u2010SY5Y or HEK\u2010293 cell lines at pharmacologically relevant concentrations. In silico studies allowed the proposition of binding modes and the prediction of favorable absorption, distribution, metabolism and excretion properties. The cumulative results suggest compounds <jats:bold>4a<\/jats:bold> and <jats:bold>4f<\/jats:bold> as lead structures for the further development of novel dual\u2010targeted ligands for AD therapy.<\/jats:p>","DOI":"10.1002\/ardp.202400387","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T04:31:56Z","timestamp":1741753916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["First in class pyrrolo[2,3\u2010<i>d<\/i>]pyrimidine derivatives fused to fluorobenzylpiperidines as dual ligands of acetylcholinesterase and histamine H<sub>3<\/sub> receptor"],"prefix":"10.1002","volume":"358","author":[{"given":"Tito","family":"A\u00f1azco","sequence":"first","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica y de Farmacia Pontificia Universidad Cat\u00f3lica de Chile Santiago 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