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The cytotoxic activity of the synthesized derivatives was assessed against HepG2 and Huh7 liver cancer cell lines, where compound\n                    <jats:bold>7a<\/jats:bold>\n                    exhibited the most potent activity with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 17.89\u2009\u03bcM and 25.07\u2009\u03bcM, respectively. The kinase inhibition assay revealed that\n                    <jats:bold>7a<\/jats:bold>\n                    strongly inhibited both B\u2010Raf (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.11\u2009\u03bcM) and VEGFR\u20102 (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.15\u2009\u03bcM), surpassing sorafenib in B\u2010Raf inhibition. Further mechanistic studies revealed that\n                    <jats:bold>7a<\/jats:bold>\n                    induced G2\/M phase arrest, with a significant increase in late apoptotic cells (57.08%) compared to the control group (0.15%), confirming its pro\u2010apoptotic effect. The apoptotic pathway was further validated by caspase\u20103 activation, Bax upregulation, and Bcl\u20102 downregulation. Computational analyses verified the effective binding of compound\n                    <jats:bold>7a<\/jats:bold>\n                    to VEGFR\u20102. These analyses included molecular docking, molecular dynamic (MD) simulations, molecular mechanics with generalized Born and surface area solvation (MM\u2010GBSA), protein\u2010ligand interaction fingerprints (ProLIF), principal component analysis (PCAT), and free energy landscape (FEL) studies. Additionally, DFT studies indicated\n                    <jats:bold>7a<\/jats:bold>\n                    's stability and reactivity.\n                    <jats:italic>In silico<\/jats:italic>\n                    ADMET predictions indicated that the derivatives had good absorption, were non\u2010mutagenic, non\u2010carcinogenic, and exhibited low toxicity risks compared to sorafenib. These findings suggest that the synthesized thiadiazole\u2010benzenesulfonamide hybrids, particularly\n                    <jats:bold>7a<\/jats:bold>\n                    , represent promising dual BRAF\/VEGFR\u20102 inhibitors with potent anti\u2010cancer activity, warranting further optimization and preclinical evaluation.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70156","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T06:44:57Z","timestamp":1753080297000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["New Thiadiazole\u2010Benzenesulfonamide Hybrids as Dual B\u2010Raf\/\n                    <scp>VEGFR<\/scp>\n                    \u20102 Inhibitors With Promising Anti\u2010Hepatic Cancer Activity"],"prefix":"10.1111","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4497-5013","authenticated-orcid":false,"given":"Aisha 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Chemistry, Faculty of Science Al\u2010Azhar University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazem A.","family":"Mahdy","sequence":"additional","affiliation":[{"name":"Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys) Al\u2010Azhar University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalal Z.","family":"Husein","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science New Valley University  El\u2010Kharja Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma G.","family":"Amin","sequence":"additional","affiliation":[{"name":"Physics Department, Faculty of Science Alexandria University  Alexandria 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