{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T17:31:58Z","timestamp":1791653518905,"version":"4.3.4"},"reference-count":43,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Multitarget-directed ligands offer a promising strategy for overcoming tumor complexity through simultaneous modulation of complementary oncogenic pathways. In this work, a novel (E)-6-(3-(4-methyl-2-thioxo-2,3-dihydrothiazol-5-yl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (compound 6) was synthesized and evaluated as a dual inhibitor of tubulin polymerization and tumor-associated carbonic anhydrases (CAs) IX and XII. Compound 6 displayed potent antiproliferative activity, particularly against MDA-MB-231 triple-negative breast cancer cells (IC50 = 0.37 \u00b5M), with excellent selectivity toward non-tumorigenic cells. Mechanistic studies demonstrated strong tubulin polymerization inhibition (IC50 = 3.40 \u00b1 0.09 \u00b5M) and submicromolar inhibition of CA IX (IC50 = 0.102 \u00b1 0.005 \u00b5M) and CA XII (IC50 = 0.213 \u00b1 0.004 \u00b5M), accompanied by downregulation of CA-IX and CA-XII protein expression. Cellular investigations revealed pronounced G2\/M phase arrest and apoptosis induction via mitochondrial signaling and caspase activation. Anti-angiogenic activity was supported by inhibition of endothelial migration and concentration-dependent suppression of VEGFR-2 (Tyr1175) phosphorylation in HUVEC cells. Human liver microsomal assays indicated measurable metabolic stability, while molecular docking and in silico ADMET predictions supported target engagement and drug-like properties. Collectively, these findings identify compound 6 as a promising multitarget anticancer lead integrating antimitotic, metabolic, and anti-angiogenic mechanisms.<\/jats:p>","DOI":"10.3390\/molecules31060917","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T09:55:38Z","timestamp":1773136538000},"page":"917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Discovery of a Novel Coumarin\/Thiazole Chalcone Hybrid as a Potent Dual Inhibitor of Tubulin and Carbonic Anhydrases IX &amp; XII with Promising Anti-Proliferative Activity"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5947-701X","authenticated-orcid":false,"given":"Basima A. A.","family":"Saleem","sequence":"first","affiliation":[{"name":"Department of Chemistry, College of Science, University of Mosul, Mosul 41001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7627-6105","authenticated-orcid":false,"given":"Ashraf A.","family":"Qurtam","sequence":"additional","affiliation":[{"name":"Biology Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1943-8419","authenticated-orcid":false,"given":"Mohamed","family":"Ahmed","sequence":"additional","affiliation":[{"name":"College of Medicine, Dhofar University, Salalah 122, Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7543-4020","authenticated-orcid":false,"given":"Raed Fanoukh Aboqader","family":"Al-Aouadi","sequence":"additional","affiliation":[{"name":"College of Medicine, Al-Ayen Iraqi University (AUIQ), An Nasiriyah 64001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali Abdulrazzaq Abdulhussein","family":"Alrikabi","sequence":"additional","affiliation":[{"name":"College of Medicine, University of Thi-Qar, Nasiriyah 64001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2810-8246","authenticated-orcid":false,"given":"Helal F.","family":"Hetta","sequence":"additional","affiliation":[{"name":"Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-3191","authenticated-orcid":false,"given":"Stefan","family":"Br\u00e4se","sequence":"additional","affiliation":[{"name":"Institute of Biological and Chemical Systems\u2014Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghallab","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Al-Dawadmi Campus, Shaqra University, Shaqra 11961, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2000-2620","authenticated-orcid":false,"given":"Abdullah","family":"Alkhammash","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Al-Dawadmi Campus, Shaqra University, Shaqra 11961, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7857-2020","authenticated-orcid":false,"given":"Sara Mahmoud","family":"Farhan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, New Minia 61768, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6523","DOI":"10.1021\/jm058225d","article-title":"Designed multiple ligands. 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