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Among the synthesized compounds,\n                    <jats:bold>7b<\/jats:bold>\n                    emerged as the most potent candidate, exhibiting strong cytotoxicity against the MDA\u2010MB\u2010231 and MCF\u20107 breast cancer cell lines (IC\u2085\u2080\u2009=\u20099.66 and 15.83\u2009\u00b5M, respectively), with minimal toxicity toward normal WI\u201038 and WISH cells, reflected by favorable selectivity indices. Compound\n                    <jats:bold>7b<\/jats:bold>\n                    , featuring a unique structural assembly of a 2,3\u2010dihydro\u20101,3,4\u2010thiadiazole core, a\n                    <jats:italic>para<\/jats:italic>\n                    \u2010methoxyphenyl group, and a sulfonamide\u2010linked methylpiperidine moiety, exhibited superior dual\u2010inhibitory activity. It showed IC\u2085\u2080 values of 0.75\u2009\u00b5M for B\u2010Raf and 58.13\u2009nM for VEGFR\u20102. Flow cytometry and gene expression analysis revealed that\n                    <jats:bold>7b<\/jats:bold>\n                    induces G1\u2010phase cell\u2010cycle arrest and promotes apoptosis through the upregulation of BAX, caspases\u20108\/9, and downregulation of Bcl\u20102. Compound\n                    <jats:bold>7b<\/jats:bold>\n                    also inhibited cell migration in wound\u2010healing assays. Structure\u2013activity relationship (SAR) analysis indicated that\n                    <jats:italic>para<\/jats:italic>\n                    \u2010substituted electron\u2010donating groups enhanced cytotoxic potency. Molecular docking and molecular dynamics simulations confirmed the stable binding of\n                    <jats:bold>7b<\/jats:bold>\n                    to the kinase active sites, supported by favorable Glide scores (\u201325.47\u2009kcal\/mol for VEGFR\u20102 and \u201331.64\u2009kcal\/mol) and MM\u2010GBSA (molecular mechanics with generalized Born and surface area solvation) binding energies. Density functional theory (DFT) calculations further validated the compound's electronic stability and reactivity. These integrated findings suggest that compound\n                    <jats:bold>7b<\/jats:bold>\n                    is a promising lead for further development as a selective dual kinase inhibitor for breast cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70097","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T05:55:56Z","timestamp":1759125356000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["New 1,3,4\u2010Thiadiazole\u2010Based Dual B\u2010Raf\/VEGFR\u20102 Inhibitors With Potential Anti\u2010Breast Activity: Design, Synthesis, In Vitro and In Silico Evaluations"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5982-5635","authenticated-orcid":false,"given":"Walid E.","family":"Elgammal","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Science Al\u2010Azhar University Nasr City Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0893-6703","authenticated-orcid":false,"given":"Hazem","family":"Elkady","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"}]},{"given":"Hazem A.","family":"Mahdy","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\/0000-0001-6489-6035","authenticated-orcid":false,"given":"Bshra A.","family":"Alsfouk","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy Princess Nourah bint Abdulrahman University Riyadh Saudi Arabia"}],"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 Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelrahman A.","family":"Abuelkhir","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, College of Pharmacy (Boys) Al\u2010Azhar University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eslam B.","family":"Elkaeed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy AlMaarefa University Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8566-1980","authenticated-orcid":false,"given":"Ahmed M.","family":"Metwaly","sequence":"additional","affiliation":[{"name":"Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys) Al\u2010Azhar University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6955-2263","authenticated-orcid":false,"given":"Ibrahim H.","family":"Eissa","sequence":"additional","affiliation":[{"name":"Pharmaceutical Medicinal Chemistry &amp; 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