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In this study, aspirin was employed as the parent compound, and N\u2010acylation of aspirin chloride with piperazine\u2010sulfonamide hybrids was utilized to efficiently synthesize promising anticancer agents <jats:bold>3<\/jats:bold>. Biological assays and structure\u2013activity relationship analysis demonstrated that the incorporation of thiophene groups significantly enhanced the anticancer activity of aspirin. Among all eight human cancer cells treated, hybrid <jats:bold>3k<\/jats:bold>, containing a bromothiophene structure, was the most effective against human non\u2010small\u2010cell lung cancer (A549) cells (IC<jats:sub>50<\/jats:sub>\u2009=\u200936\u2009\u03bcM), exhibiting over 33\u2010fold greater toxicity than parent aspirin (IC<jats:sub>50<\/jats:sub>\u2009&gt;\u20091200\u2009\u03bcM) and a higher selectivity index (SI\u2009=\u20096). Mechanistic studies revealed that hybrid <jats:bold>3k<\/jats:bold> induced apoptosis in A549 cells and arrested the cell cycle at the G0\/G1 phase. Molecular docking analysis and COX\u20102 inhibition assay indicated that hybrid <jats:bold>3k<\/jats:bold> likely exerts its anticancer effects through the inhibition of COX\u20102 protein. These findings underscore the potential of hybrid <jats:bold>3k<\/jats:bold> as a novel therapeutic agent for non\u2010small\u2010cell lung cancer and its contribution to expanding the antitumor scope of aspirin.<\/jats:p>","DOI":"10.1002\/ardp.70001","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T10:51:55Z","timestamp":1746787915000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, Synthesis, Biological Evaluation, and In Silico Study of Aspirin\u2013Sulfonamide Hybrids as Potential Anticancer Agents"],"prefix":"10.1002","volume":"358","author":[{"given":"Xusheng","family":"Duan","sequence":"first","affiliation":[{"name":"Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals and College of Pharmaceutical Science Zhejiang University of Technology Hangzhou 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Science Zhejiang University of Technology Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5414-9300","authenticated-orcid":false,"given":"Xuanrong","family":"Sun","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals and College of Pharmaceutical Science Zhejiang University of Technology Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxue","family":"Wei","sequence":"additional","affiliation":[{"name":"Ningxia Research Center for Natural Medicine Engineering and Technology, College of Chemistry and Chemical Engineering Ningxia University Yinchuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoze","family":"Bao","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals and College of Pharmaceutical Science 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