{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T17:32:00Z","timestamp":1791653520668,"version":"4.3.4"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Multitargeted anticancer agents can overcome resistance by simultaneously modulating key pathways. This study reports a novel thiazole -chalcone\/sulfonamide hybrid (compound 7) designed to inhibit both tubulin polymerization and carbonic anhydrase IX (CA IX).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Compound 7 was synthesized through a five-step sequence and characterized by NMR and elemental analysis. Its cytotoxicity was assessed against cancer (HT-29, A549, 786-O, MCF-7) and normal (WI-38) cell lines. Tubulin polymerization and CA isoform inhibition (I, II, IX, XII) were evaluated. Apoptosis induction was confirmed by measuring p53, Bax, Bcl-2, and caspases 3 and 9. Molecular docking, ADMET, and DFT studies supported mechanistic insights.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and discussion<\/jats:title>\n                    <jats:p>\n                      Compound 7 showed potent activity against HT-29 cells (IC\n                      <jats:sub>50<\/jats:sub>\n                      = 0.98 \u03bcM) and low toxicity toward WI-38 cells. It inhibited tubulin polymerization (IC\n                      <jats:sub>50<\/jats:sub>\n                      = 2.72 \u03bcM) and selectively targeted CA IX (IC\n                      <jats:sub>50<\/jats:sub>\n                      = 0.021 \u03bcM) and CA XII, while sparing CA I and II. Apoptotic effects were confirmed by increased p53 and Bax, reduced Bcl-2, and activation of caspases. Docking studies revealed key interactions within the colchicine-binding site of tubulin and CA IX\u2019s zinc-binding pocket. ADMET and DFT results supported its drug-like properties and electronic suitability. These findings suggest that compound 7 is a promising lead for dual-targeted anticancer therapy with selective cytotoxicity and mechanistic efficacy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fchem.2025.1606848","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T01:28:48Z","timestamp":1750901328000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["A novel thiazole-sulfonamide hybrid molecule as a promising dual tubulin\/carbonic anhydrase IX inhibitor with anticancer activity"],"prefix":"10.3389","volume":"13","author":[{"given":"Hussam Elddin Nabeih","family":"Khasawneh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elryah I.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranya Mohammed","family":"Elmagzoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raed Fanoukh Aboqader","family":"Al-Aouadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesam Taher","family":"Almagharbeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghallab","family":"Alotaibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Br\u00e4se","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Alkhammash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107154","DOI":"10.1016\/j.bioorg.2024.107154","article-title":"Design, synthesis and in silico insights of novel 1,2,3-triazole benzenesulfonamide derivatives as potential carbonic anhydrase IX and XII inhibitors with promising anticancer activity","volume":"144","author":"Abdelhakeem","year":"2024","journal-title":"Bioorg Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e22197","DOI":"10.1002\/ddr.22197","article-title":"Design and synthesis of novel tetrabromophthalimide derivatives as potential tubulin inhibitors endowed with apoptotic induction for cancer treatment","volume":"85","author":"Abdel-Motaal","year":"2024","journal-title":"Drug Dev. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1016\/j.bioorg.2019.04.002","article-title":"Novel synthesized SLC-0111 thiazole and thiadiazole analogues: determination of their carbonic anhydrase inhibitory activity and molecular modeling studies","volume":"87","author":"Abo-Ashour","year":"2019","journal-title":"Bioorg Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2304625","DOI":"10.1080\/14756366.2024.2304625","article-title":"Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers","volume":"39","author":"Ahmed","year":"2024","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"115805","DOI":"10.1016\/j.ejmech.2023.115805","article-title":"Exploring novel anticancer pyrazole benzenesulfonamides featuring tail approach strategy as carbonic anhydrase inhibitors","volume":"261","author":"Ahmed","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2440","DOI":"10.1039\/d4md00302k","article-title":"Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer","volume":"15","author":"Albelwi","year":"2024","journal-title":"RSC Med. Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1565699","DOI":"10.3389\/fchem.2025.1565699","article-title":"Design, synthesis, in silico studies, and apoptotic antiproliferative activity of novel thiazole-2-acetamide derivatives as tubulin polymerization inhibitors","volume":"13","author":"Al-Wahaibi","year":"2025","journal-title":"Front. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"5780","DOI":"10.3390\/molecules26195780","article-title":"The design, synthesis, and biological activities of pyrrole-based carboxamides: the novel tubulin inhibitors targeting the colchicine-binding site","volume":"26","author":"Boichuk","year":"2021","journal-title":"Molecules"},{"key":"B8","doi-asserted-by":"publisher","first-page":"980141","DOI":"10.3389\/fonc.2022.980141","article-title":"Editorial: multi-target directed ligands for the treatment of cancer","volume":"12","author":"Brindisi","year":"2022","journal-title":"Front. Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.4155\/fmc.14.68","article-title":"Sulfonamides and their isosters as carbonic anhydrase inhibitors","volume":"6","author":"Carta","year":"2014","journal-title":"Future Med. Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3074","DOI":"10.1021\/jo00115a023","article-title":"Synthesis of 3-substituted pentane-2,4-diones: valuable intermediates for liquid crystals","volume":"60","author":"Cativiela","year":"1995","journal-title":"J. Org. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1158\/0008-5472.CAN-08-2470","article-title":"Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH","volume":"69","author":"Chiche","year":"2008","journal-title":"Cancer Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1186\/s12964-024-01607-9","article-title":"Potentials and future perspectives of multi-target drugs in cancer treatment: the next generation anti-cancer agents","volume":"22","author":"Doostmohammadi","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"B14","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1038\/nrd3253","article-title":"Microtubule-binding agents: a dynamic field of cancer therapeutics","volume":"9","author":"Dumontet","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"B15","doi-asserted-by":"publisher","first-page":"33599","DOI":"10.1021\/acsomega.2c05077","article-title":"Synthesis and molecular docking study of new thiazole derivatives as potential tubulin polymerization inhibitors","volume":"7","author":"El-Abd","year":"2022","journal-title":"ACS Omega"},{"key":"B16","doi-asserted-by":"publisher","first-page":"113360","DOI":"10.1016\/j.ejmech.2021.113360","article-title":"Identification of N-phenyl-2-(phenylsulfonyl)acetamides\/propanamides as new SLC-0111 analogues: synthesis and evaluation of the carbonic anhydrase inhibitory activities","volume":"218","author":"Elbadawi","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"140462","DOI":"10.1016\/j.ijbiomac.2025.140462","article-title":"Development of pyrazolo[1,5-a]pyrimidine-grafted coumarins as selective carbonic anhydrase inhibitors and tubulin polymerization inhibitors with potent anticancer activity","volume":"303","author":"Elkotamy","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"114","DOI":"10.21608\/jabps.2023.198467.1183","article-title":"Recent progress in biological activities of dihydropyrimidine derivatives: an updated mini-review","volume":"6","author":"Elshamsy","year":"2023","journal-title":"J. Adv. Biomed. Pharm. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.3390\/ph17091154","article-title":"Synthesis of new thiazole-privileged chalcones as tubulin polymerization inhibitors with potential anticancer activities","volume":"17","author":"Hashem","year":"2024","journal-title":"Pharm. (Basel)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.3390\/biom12121843","article-title":"Recent advances of tubulin inhibitors targeting the colchicine binding site for cancer therapy","volume":"12","author":"Hawash","year":"2022","journal-title":"Biomolecules"},{"key":"B22","doi-asserted-by":"publisher","first-page":"113449","DOI":"10.1016\/j.ejmech.2021.113449","article-title":"Discovery of highly potent tubulin polymerization inhibitors: design, synthesis, and structure-activity relationships of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines","volume":"220","author":"Huo","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/nrc1317","article-title":"Microtubules as a target for anticancer drugs","volume":"4","author":"Jordan","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"13405","DOI":"10.3390\/ijms222413405","article-title":"Carbonic anhydrase IX inhibitors as candidates for combination therapy of solid tumors","volume":"22","author":"Kalinin","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4958","DOI":"10.2174\/0929867329666220318100019","article-title":"Thiazole and related heterocyclic systems as anticancer agents: a review on synthetic strategies, mechanisms of action and SAR studies","volume":"29","author":"Kaur","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/nrc2803","article-title":"Microtubules and resistance to tubulin-binding agents","volume":"10","author":"Kavallaris","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"B27","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s10517-023-05835-w","article-title":"Pharmacological properties of sulfonamide derivatives, new inhibitors of carbonic anhydrase","volume":"175","author":"Khokhlov","year":"2023","journal-title":"Bull. Exp. Biol. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1039\/D0OB02513E","article-title":"Synthesis and application of a thiol-reactive HBED-type chelator for development of easy-to-produce Ga-radiopharmaceutical kits and imaging probes","volume":"19","author":"Klika","year":"2021","journal-title":"Org. Biomol. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"10374","DOI":"10.1021\/acs.jmedchem.4c00838","article-title":"Systematic investigation of dual-target-directed ligands","volume":"67","author":"Lembo","year":"2024","journal-title":"J. Med. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"10581","DOI":"10.1021\/acs.jmedchem.1c00683","article-title":"Rational multitargeted drug design strategy from the perspective of a medicinal chemist","volume":"64","author":"Li","year":"2021","journal-title":"J. Med. Chem."},{"key":"B31","article-title":"Synthesis and biological evaluation of 2\u2032,5\u2032-dimethoxychalcone derivatives as microtubule-targeted anticancer agents","author":"Lin","year":"2011","journal-title":"US2011306775A1"},{"key":"B32","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1080\/14756366.2021.1976772","article-title":"A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors","volume":"37","author":"Liu","year":"2022","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3364","DOI":"10.1158\/0008-5472.CAN-10-4261","article-title":"Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors","volume":"71","author":"Lou","year":"2011","journal-title":"Cancer Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1055\/s-0039-1690194","article-title":"A multifunctional HBED-type chelator with dual conjugation capabilities for radiopharmaceutical development","volume":"30","author":"Makarem","year":"2019","journal-title":"Synlett"},{"key":"B35","doi-asserted-by":"publisher","first-page":"19","DOI":"10.3390\/metabo8010019","article-title":"Carbonic anhydrases: role in pH control and cancer","volume":"8","author":"Mboge","year":"2018","journal-title":"Metabolites"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3297","DOI":"10.3390\/cancers14143297","article-title":"Cancer therapeutic targeting of hypoxia induced carbonic anhydrase IX: from bench to bedside","volume":"14","author":"McDonald","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2552","DOI":"10.3390\/ijms19092552","article-title":"Synthesis, evaluation for cytotoxicity and molecular docking studies of benzo[c]furan-chalcones for potential to inhibit tubulin polymerization and\/or EGFR-tyrosine kinase phosphorylation","volume":"19","author":"Mphahlele","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1038\/nrd3554","article-title":"Interfering with pH regulation in tumours as a therapeutic strategy","volume":"10","author":"Neri","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"B39","doi-asserted-by":"publisher","first-page":"4522","DOI":"10.1021\/jm100326d","article-title":"Synthesis and Structure\u2212Activity relationships of long-acting \u03b22Adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach","volume":"53","author":"Procopiou","year":"2010","journal-title":"J. Med. Chem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s41573-020-0073-9","article-title":"Radiopharmaceutical therapy in cancer: clinical advances and challenges","volume":"19","author":"Sgouros","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"B41","doi-asserted-by":"publisher","first-page":"113283","DOI":"10.1016\/j.ejmech.2021.113283","article-title":"Development of novel benzofuran-based SLC-0111 analogs as selective cancer-associated carbonic anhydrase isoform IX inhibitors","volume":"216","author":"Shaldam","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bioorg.2017.10.019","article-title":"Synthesis of benzo[d]imidazo[2,1-b]thiazole-chalcone conjugates as microtubule targeting and apoptosis inducing agents","volume":"76","author":"Sultana","year":"2018","journal-title":"Bioorg Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1080\/13543784.2018.1548608","article-title":"Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors","volume":"27","author":"Supuran","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"B44","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1007\/s00280-015-2903-8","article-title":"Antimitotic drugs in the treatment of cancer","volume":"76","author":"van Vuuren","year":"2015","journal-title":"Cancer Chemother. Pharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1126\/science.1235122","article-title":"Cancer genome landscapes","volume":"339","author":"Vogelstein","year":"2013","journal-title":"Science"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1080\/14756366.2021.1958213","article-title":"Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors","volume":"36","author":"Wang","year":"2021","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"137343","DOI":"10.1016\/j.molstruc.2023.137343","article-title":"Synthesis, biological evaluation and molecular docking of thiazole hydrazone derivatives grafted with indole as novel tubulin polymerization inhibitors","volume":"1301","author":"Wang","year":"2024","journal-title":"J. Mol. Struct."},{"key":"B49","doi-asserted-by":"publisher","first-page":"128693","DOI":"10.1016\/j.bmcl.2022.128693","article-title":"Design and synthesis of an N-benzyl 5-4-sulfamoylbenzylidene-2-thioxothiazolidin-4-one scaffold as a novel NLRP3 inflammasome inhibitor","volume":"65","author":"Zuo","year":"2022","journal-title":"Bioorg Med. Chem. Lett."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2025.1606848\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T14:10:42Z","timestamp":1752502242000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2025.1606848\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,26]]},"references-count":50,"alternative-id":["10.3389\/fchem.2025.1606848"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2025.1606848","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,26]]},"article-number":"1606848"}}