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Antagonism of the histamine H\n                    <jats:sub>3<\/jats:sub>\n                    receptor (H\n                    <jats:sub>3<\/jats:sub>\n                    R) represents a promising alternative strategy, exemplified by the clinically approved inverse agonist\/antagonist pitolisant (PIT) for narcolepsy. Herein, we designed a novel series of non\u2010imidazole H\n                    <jats:sub>3<\/jats:sub>\n                    R antagonists by introducing a sulfur atom into the PIT scaffold to modulate lipophilicity, flexibility, and target binding. The synthesis and pharmacological evaluation of 12 target compounds (\n                    <jats:bold>3a\u20133h<\/jats:bold>\n                    ,\n                    <jats:bold>5a\u20135d<\/jats:bold>\n                    ) are reported. Compounds\n                    <jats:bold>3e<\/jats:bold>\n                    and\n                    <jats:bold>3f<\/jats:bold>\n                    showed potent H\n                    <jats:sub>3<\/jats:sub>\n                    R antagonism with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 0.18\u2009\u00b5M and 0.036\u2009\u00b5M, respectively, with the\u00a0latter more active than PIT (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.1\u2009\u00b5M). In the maximal electroshock (MES) model,\n                    <jats:bold>3f<\/jats:bold>\n                    exhibited superior antiseizure activity (ED\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200914.0\u2009mg\/kg) compared to PIT (ED\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200916.3\u2009mg\/kg). What's more, compounds\n                    <jats:bold>3e<\/jats:bold>\n                    and\n                    <jats:bold>3f<\/jats:bold>\n                    showed significant seizure protection in a zebrafish pentylenetetrazol (PTZ) model, and favorable cytotoxicity and neurotoxicity profiles in cell and animal experiments. Compound\n                    <jats:bold>3f<\/jats:bold>\n                    exhibits low hERG toxicity risk with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 1.83\u2009\u00b5M compared to PIT (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20091.51\u2009\u00b5M), and excellent blood\u2010brain barrier penetration with a brain\u2010to\u2010plasma ratio of 4.56. Molecular docking studies revealed stable interactions with key H\n                    <jats:sub>3<\/jats:sub>\n                    R residues, including ASP114, VAL95, and PHE189. Collectively, these results indicate that\n                    <jats:bold>3f<\/jats:bold>\n                    shows considerable promise as a lead candidate in the search for new antiepileptic drugs.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70327","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:09:17Z","timestamp":1790687357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Pharmacological Evaluation of Sulfur\u2010Containing Pitolisant Analogs as Potent H\n                    <sub>3<\/sub>\n                    R Antagonists for Epilepsy Therapy"],"prefix":"10.1002","volume":"359","author":[{"given":"Ying","family":"Zheng","sequence":"first","affiliation":[{"name":"Affiliated Hospital of Jinggangshan University, Key Laboratory for Personalized Drug Therapy in Neuropsychiatric Disorders of Jiangxi Provincial Department of Education, Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center College of Traditional Chinese Medicine and Pharmacy, Jinggangshan University Ji'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guowen","family":"He","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Jinggangshan University, Key Laboratory for Personalized Drug Therapy in Neuropsychiatric Disorders of Jiangxi Provincial Department of Education, Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center College of Traditional Chinese Medicine and Pharmacy, Jinggangshan University Ji'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xia","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Jinggangshan University, Key Laboratory for Personalized Drug Therapy in Neuropsychiatric Disorders of Jiangxi Provincial Department of Education, Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center College of Traditional Chinese Medicine and Pharmacy, Jinggangshan University Ji'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7538-1889","authenticated-orcid":false,"given":"Jiuhong","family":"Kang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Jinggangshan University, Key Laboratory for Personalized Drug Therapy in Neuropsychiatric Disorders of Jiangxi Provincial Department of Education, Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center College of Traditional Chinese Medicine and Pharmacy, Jinggangshan University Ji'an China"},{"name":"Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, National Stem Cell Translational Resource Center School of Life Sciences and Technology, Tongii University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Ji","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Jinggangshan University, Key Laboratory for Personalized Drug Therapy in Neuropsychiatric Disorders of Jiangxi Provincial Department of Education, Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center College of Traditional Chinese Medicine and Pharmacy, Jinggangshan University Ji'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruokun","family":"Wu","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Jinggangshan University, Key Laboratory for Personalized Drug Therapy in Neuropsychiatric Disorders of Jiangxi Provincial Department of Education, Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center College of Traditional Chinese Medicine and Pharmacy, Jinggangshan University Ji'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Qu","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Jinggangshan University, Key Laboratory for Personalized Drug Therapy in Neuropsychiatric Disorders of Jiangxi Provincial Department of Education, Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center College of Traditional Chinese Medicine and Pharmacy, Jinggangshan University Ji'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8337-5191","authenticated-orcid":false,"given":"Mingxia","family":"Song","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Jinggangshan University, Key Laboratory for Personalized Drug Therapy in Neuropsychiatric Disorders of Jiangxi Provincial Department of Education, Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center College 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