{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:01:06Z","timestamp":1790776866259,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Given their critical roles in tumor progression and hypoxia adaptation, concurrent inhibition of carbonic anhydrase IX (hCA IX) and vascular endothelial growth factor receptor\u20102 (VEGFR\u20102) is a viable therapeutic approach. This study rationally developed, synthesized, and biologically assessed a novel class of thiazolidinedione\u2010benzenesulfonamide hybrids as possible dual hCA IX\/VEGFR\u20102 inhibitors. A number of agents, including\n                    <jats:bold>4a<\/jats:bold>\n                    ,\n                    <jats:bold>4b<\/jats:bold>\n                    ,\n                    <jats:bold>4e<\/jats:bold>\n                    ,\n                    <jats:bold>4g<\/jats:bold>\n                    ,\n                    <jats:bold>6a<\/jats:bold>\n                    , and\n                    <jats:bold>6b<\/jats:bold>\n                    , showed strong hCA IX inhibition (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>I<\/jats:sub>\n                    \u2009=\u200915.0\u201337.9\u2009nM), outperforming the reference inhibitor acetazolamide (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>I<\/jats:sub>\n                    \u2009=\u200925\u2009nM) and displaying better selectivity indices. Moreover, these substances efficiently suppressed VEGFR\u20102, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values ranging from 0.055 to 1.080\u2009\u00b5M. Under both normoxic and hypoxic conditions, biological evaluation demonstrated strong anti\u2010proliferative activity against colorectal cancer cell lines (HT\u201029 and HCT\u2010116). Compound\n                    <jats:bold>4g<\/jats:bold>\n                    stood out as the most promising candidate among the investigated derivatives, showing greater activity to 5\u2010fluorouracil during hypoxia and comparable potency under normoxia (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20095.89 vs. 26.66\u2009\u00b5M). In hypoxic conditions,\n                    <jats:bold>4g<\/jats:bold>\n                    significantly enhanced the cytotoxicity of 5\u2010fluorouracil, increasing its activity by more than sevenfold.\n                    <jats:bold>4g<\/jats:bold>\n                    caused cell\u2010cycle arrest at the G\n                    <jats:sub>1<\/jats:sub>\n                    \/G\n                    <jats:sub>2<\/jats:sub>\n                    \/M phases, raised pro\u2010apoptotic markers (caspase\u20103, caspase\u20109, and BAX), downregulated the anti\u2010apoptotic protein Bcl\u20102, and dramatically enhanced apoptotic cell death (total apoptosis: 37.78%), according to mechanistic studies. The persistent binding of\n                    <jats:bold>4g<\/jats:bold>\n                    inside the zinc\u2010containing active site of hCA IX and the ATP\u2010binding pocket of VEGFR\u20102 was validated by molecular docking and molecular dynamics simulations. Additionally, favorable pharmacokinetic and drug\u2010likeness features were shown by in silico ADME research. All of these results point to compound\n                    <jats:bold>4g<\/jats:bold>\n                    as a promising mechanism\u2010based dual VEGFR\u20102\/hCA IX inhibitor with strong anti\u2010colorectal cancer action, especially in hypoxic tumor microenvironment circumstances.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70333","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T06:02:26Z","timestamp":1782108146000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of Sulfonamide\u2010Based Thiazolidine\u20102,4\u2010Dione Derivatives as VEGFR\u20102 and Tumor\u2010Associated hCA IX Inhibitors With Hypoxia\u2010Targeted Anti\u2010Colorectal Cancer Activity"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6455-5716","authenticated-orcid":false,"given":"Haytham O.","family":"Tawfik","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Tanta University Tanta Egypt"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Alsalam University Tanta Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2016-0728","authenticated-orcid":false,"given":"Mohammed A.","family":"Dahab","sequence":"additional","affiliation":[{"name":"Pharmaceutical Medicinal Chemistry &amp; Drug Design Department, Faculty of Pharmacy (Boys) Al\u2010Azhar University 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":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Al\u2010Azhar University Cairo Egypt"},{"name":"Department of Pharmacology, College of Pharmacy The Islamic 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