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Two oxindole\u2010coumarin hybrids <jats:bold>6c<\/jats:bold> and <jats:bold>6e<\/jats:bold> showed broad spectrum of anticancer activity with NCI full panel MG\u2010MIDs of 5.01 and 6.31\u2009\u00b5M, respectively. They revealed GI<jats:sub>50<\/jats:sub> of a single digit micromolar concentration against 46 and 39 cell lines, respectively. An apoptosis dependent mechanism is suggested for the potent anticancer activity of compounds <jats:bold>6c<\/jats:bold> and <jats:bold>6e<\/jats:bold> via the increase in the BAX\/BCL\u20102 ratio and enhancement of the expression levels of caspase\u20109 and the tumor suppressor p53. While this structure hybridization resulted in enhanced antitumor activity, it resulted in moderate CA IX and XII inhibitory activity. The potent anticancer compound <jats:bold>6e<\/jats:bold> was among the most active inhibitors of the tumor associated CA IX and CA XII in this study (K<jats:sub>I<\/jats:sub>\u2009=\u20091.8 and 2.1\u2009\u03bcM, respectively). As a result, even compound <jats:bold>6e<\/jats:bold>'s moderate CA IX\/XII inhibitory activity may have synergistic effects contributing to its increased tumor growth suppression and proapoptotic activity. Moreover, compound <jats:bold>6e<\/jats:bold> revealed a nonsignificant cytotoxicity toward the normal kidney epithelial Vero cell line and was totally inactive against the cytosolic isoforms CA I and CA II (K<jats:sub>I<\/jats:sub>\u2009=\u2009&gt;\u2009100\u2009\u03bcM) which mitigate its side effect as chemotherapeutic agent and enforce its safety profile.<\/jats:p>","DOI":"10.1002\/ddr.70116","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T05:55:38Z","timestamp":1749534938000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Oxindole\u2013Coumarin Hybrids With Broad\u2010Spectrum Anticancer Activity: Apoptosis Induction and Selective CA IX\/XII Targeting"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9196-6315","authenticated-orcid":false,"given":"Hend I.","family":"Abdelaal","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Egyptian Russian University Badr City, Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0585-0712","authenticated-orcid":false,"given":"Abdalla R.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Egyptian Russian University Badr City, Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-2369","authenticated-orcid":false,"given":"Mohamed R.","family":"Elnagar","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Department, Faculty of Pharmacy Al\u2010Azhar University Cairo Egypt"},{"name":"Department of Pharmacology, College of Pharmacy The Islamic University Najaf Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0669-7481","authenticated-orcid":false,"given":"Simone","family":"Giovannuzzi","sequence":"additional","affiliation":[{"name":"Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences University of Florence, Polo Scientifico Sesto Fiorentino, Firenze Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7898-6928","authenticated-orcid":false,"given":"Samar H.","family":"Fahim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatem A.","family":"Abdel\u2010Aziz","sequence":"additional","affiliation":[{"name":"Department of Applied Organic Chemistry National Research Center Dokki, Cairo Egypt"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Pharos University in Alexandria Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences University of Florence, Polo Scientifico Sesto Fiorentino, Firenze Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar M.","family":"Abou\u2010Seri","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2016.06.005"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107759"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.07.054"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111768"},{"key":"e_1_2_8_6_1","unstructured":"Albakri M. 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