ORIGINAL RESEARCH article
Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 13 - 2025 | doi: 10.3389/fchem.2025.1606848
This article is part of the Research TopicRecent Advances in Synthetic Organic Chemistry at the Biomedical Interface: Honoring Professor Iwao Ojima on the Occasion of his 80th BirthdayView all 15 articles
A Novel Thiazole-Sulfonamide Hybrid Molecule as a promising Dual Tubulin/Carbonic Anhydrase IX Inhibitor with Anticancer Activity
Provisionally accepted
Hussam Elddin Nabeih Khasawneh1Elryah I. Ali2
Ranya Mohammed Elmagzoub2*Raed Fanoukh Aboqader Al-Aouadi3Wesam Taher Almagharbeh4
Ghallab Alotaibi5
Stefan Bräse6*Abdullah Alkhammash5- 1Chemical Engineering Department, Al-Huson University College, Al-Balqa’ Applied University, Al-Salt P.O. Box 19117, Jordan, IRBID, Jordan
- 2Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia
- 3College of Medicine, Al-Ayen Iraqi University, AUIQ, An Nasiriyah, Iraq
- 4Medical and Surgical Nursing Department, Faculty of Nursing, University of Tabuk, Tabuk, Saudi Arabia
- 5Department of Pharmacology, College of Pharmacy, Al-Dawadmi Campus, Shaqra University, Shaqra, Saudi Arabia
- 66Institute of Biological and Chemical Systems, Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany
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The development of multitargeted anticancer agents represents a promising approach to overcoming resistance and enhancing therapeutic efficacy. In this context, a novel thiazole–chalcone/sulfonamide hybrid (compound 7) was rationally designed, synthesized, and biologically evaluated as a dual inhibitor of tubulin polymerization and carbonic anhydrase IX. Compound 7 was synthesized via a multistep sequence and structurally characterized by NMR and elemental analysis. Biological assays displayed potent and selective cytotoxicity against several cancer cell lines, particularly HT-29 (IC₅₀ = 0.98 μM), with minimal toxicity to normal fibroblasts. Mechanistic studies confirmed its ability to inhibit tubulin polymerization (IC₅₀ = 2.72 μM) and selectively target CA IX (IC₅₀ = 0.021 μM), alongside notable inhibition of CA XII, with weaker off-target effects on CA I and CA II. Apoptosis induction was supported by the upregulation of p53 and Bax, the downregulation of Bcl-2, and the significant activation of caspases 3 and 9. Molecular docking revealed key binding interactions within both the colchicine site of tubulin and the active site of CA IX. At the same time, ADMET and DFT analyses highlighted favorable drug-like properties and electronic stability. Collectively, these findings position compound 7 as a promising lead for the development of dual-targeted anticancer therapeutics.
Keywords: Thiazole, Chalcone, Sulphonamide, Tubulin, carbonic anhydrase, Cytotoxicity, Apoptosis
Received: 06 Apr 2025; Accepted: 09 Jun 2025.
Copyright: © 2025 Khasawneh, Ali, Elmagzoub, Al-Aouadi, Almagharbeh, Alotaibi, Bräse and Alkhammash. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ranya Mohammed Elmagzoub, Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia
Stefan Bräse, 6Institute of Biological and Chemical Systems, Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany
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