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The primary aim of this work was to develop cost\u2010effective and environmentally friendly synthetic procedures for preparing 2\u2010phenylimidazo[1,2\u2010b]pyridazine derivatives. After optimizing the synthesis of this compound class using efficient and green techniques such as microwaves and ultrasound irradiation, we further evaluated the antiepileptic effects of DM1 and DM2 in two animal models: CD\u20101 ICR mice after pentylenetetrazol administration and DBA\/2 mice with seizures induced by audiogenic stimuli. Their neuroprotective effect against oxidative stress were assessed using C6 rat brain glioma cells. DM1 and DM2 exhibited potent anti\u2010seizure effects in both animal models and demonstrated significant <jats:italic>in\u2005vitro<\/jats:italic> neuroprotective activity by reducing reactive oxygen species release. To lay the groundwork for the future rational optimization of this promising class of compounds, the molecular bases of DM1 and DM2 activity were investigated by modelling their interaction with hCav<jats:sub>3.1<\/jats:sub> channels. The calculated binding modes of DM1 and DM2 to hCav<jats:sub>3.1<\/jats:sub> channels partially mirrored that of the selective Cav<jats:sub>3.1<\/jats:sub> blocker Z944, paving the way for future lead optimization.<\/jats:p>","DOI":"10.1002\/cmdc.202400721","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T12:29:55Z","timestamp":1732019395000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Eco\u2010friendly Synthesis and Molecular Modelling of 2\u2010Phenylimidazo[1,2\u2010b]pyridazine Derivatives: <i>In Vitro<\/i> and <i>In Vivo<\/i> Studies for Lead Optimization"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4456-3003","authenticated-orcid":false,"given":"Marica Erminia","family":"Schiano","sequence":"first","affiliation":[{"name":"Department of Pharmacy \u201cFederico II\u201d University of Napoli  Via Domenico Montesano 49 80131 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