{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T13:18:34Z","timestamp":1784726314220,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T00:00:00Z","timestamp":1704672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.<\/jats:p>","DOI":"10.3390\/ijms25020799","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T04:38:51Z","timestamp":1704775131000},"page":"799","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6284-4546","authenticated-orcid":false,"given":"Silvia","family":"P\u00e9rez-Silanes","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Martisova","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7670-3237","authenticated-orcid":false,"given":"Maite","family":"Solas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8266-0445","authenticated-orcid":false,"given":"Daniel","family":"Plano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3431-7826","authenticated-orcid":false,"given":"Carmen","family":"Sanmartin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3488-9579","authenticated-orcid":false,"given":"Mar\u00eda Javier","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s11357-022-00707-z","article-title":"The Potential of Hyperbaric Oxygen as a Therapy for Neurodegenerative Diseases","volume":"45","author":"Sumien","year":"2023","journal-title":"Geroscience"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1002\/alz.12362","article-title":"Population Estimate of People with Clinical Alzheimer\u2019s Disease and Mild Cognitive Impairment in the United States (2020\u20132060)","volume":"17","author":"Rajan","year":"2021","journal-title":"Alzheimers Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S527","DOI":"10.3233\/JAD-2010-100501","article-title":"Why Women Have More Alzheimer\u2019s Disease than Men: Gender and Mitochondrial Toxicity of Amyloid-Beta Peptide","volume":"20","author":"Lloret","year":"2010","journal-title":"J. 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