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Structural activity relationship (SAR) studies in medicinal chemistry are crucial for lead optimization, where a subtle change in the substituent can significantly alter its binding affinity with the biological target. Herein, a highly efficient single\u2010atom substitution (SAS) approach has been developed, where sulfur for oxygen strategy is utilized as a powerful molecular editing technique to identify N\u2010vinyl Indole\u2010thiobarbituric acid (<jats:bold>6\u2009a<\/jats:bold>) as a novel small molecule\u2010based scaffold with tunable photophysical and antiproliferative activities. A series of NIR\u2010emitting indole\u2010barbituric\/thiobarbituric acid conjugates exhibiting aggregation\u2010induced emission (AIE) were prepared, where the replacement of oxygen for sulfur strategy emerged as a magic bullet. On the evaluation of photophysical properties and chemopreventive efficacies, a significant improvement in the absorption and emission profile, cellular uptake, and antiproliferative activity was noted for sulfur counterparts. From the pool of the molecules, the lead molecule <jats:bold>6\u2009a<\/jats:bold> unveils a 55\u2005nm emission shift, 142\u2010fold increased anticancer profile, and ~4\u2010fold elevated cellular uptake. Furthermore, the colocalization experiment unravels the nuclear localization of <jats:bold>6\u2009a<\/jats:bold>, where it causes severe DNA damage, arrests the cell cycle in the G2\/M phase, and leads to the activation of p53\u2010mediated apoptosis. Our experimental findings represent <jats:bold>6\u2009a<\/jats:bold> as a potential lead molecule possessing excellent anticancer potency in the HCT 116\u2005cell line and HCT 116\u2010derived 3D spheroid model.<\/jats:p>","DOI":"10.1002\/cmdc.202400849","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T08:48:44Z","timestamp":1736412524000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Harnessing the Sulfur\u2010for\u2010Oxygen Shift: A Magic Bullet for Dynamic Photophysical and Anticancer Activities of Indole\u2010Barbituric Acid Construct"],"prefix":"10.1002","volume":"20","author":[{"given":"Kartikay","family":"Tyagi","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Biology and Medicinal Chemistry Department of Chemistry Indian Institute of Technology Roorkee  Uttarakhand 247667 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reena","family":"Kumari","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Biology and Medicinal Chemistry Department of Chemistry Indian Institute of Technology Roorkee  Uttarakhand 247667 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9520-6842","authenticated-orcid":false,"given":"V.","family":"Venkatesh","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Biology and Medicinal Chemistry Department of Chemistry Indian Institute of Technology Roorkee  Uttarakhand 247667 India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.9b00500"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27640-7"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c12726"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","unstructured":"M. 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