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Targeting the molecular mechanisms underlying therapeutic resistance is crucial for the development of innovative treatment strategies to improve clinical outcomes. Herein, the in vitro antiproliferative activity of novel sulfonamide derivatives, which exhibited significant low micromolar cytotoxicity against H69 human lung carcinoma cells and anthracycline\u2010resistant H69AR cells compared to untreated controls (<jats:italic>p<\/jats:italic> &lt; 0.05), is synthesized and characterized. The most promising compounds (<jats:bold>11e, 11g, 11h, 12<\/jats:bold>) also demonstrate cytotoxic activity against A549 human lung adenocarcinoma cells. Molecular docking studies predict that compound <jats:bold>11e<\/jats:bold> interacts with tropomyosin receptor kinase A (TRKA) and mesenchymal\u2010epithelial transition factor (c\u2010MET) at conserved binding sites also targeted by FDA\u2010approved inhibitors. These findings suggest that the novel sulfonamide derivatives, particularly compound <jats:bold>11e<\/jats:bold>, may serve as promising antiproliferative candidates targeting TRKA and c\u2010MET, potentially contributing to strategies aimed at overcoming drug resistance. Moreover, compound <jats:bold>11e<\/jats:bold> can serve as a structural scaffold for future hit\u2010to\u2010lead optimization efforts.<\/jats:p>","DOI":"10.1002\/cmdc.202500260","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T11:29:38Z","timestamp":1750937378000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis and Characterization of Sulfonamide\u2010Imidazole Hybrids with In Vitro Antiproliferative Activity against Anthracycline\u2010Sensitive and Resistant H69 Small Cell Lung Cancer Cells"],"prefix":"10.1002","volume":"20","author":[{"given":"Valdas","family":"Vainauskas","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry Kaunas University of Technology  Radvil\u0117n\u0173 Rd. 19 LT\u201050254 Kaunas 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