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ORIGINAL RESEARCH article

Front. Chem.

Sec. Medicinal and Pharmaceutical Chemistry

Volume 13 - 2025 | doi: 10.3389/fchem.2025.1565699

Design, synthesis, in silico studies, and apoptotic antiproliferative activity of novel thiazole-2-acetamide derivatives as tubulin polymerization inhibitors

Provisionally accepted
  • 1 Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
  • 2 Deraya University, New Minia, Egypt
  • 3 Minia University, Minya, Minya, Egypt
  • 4 Assiut University, Assiut, Egypt
  • 5 Karlsruhe Institute of Technology (KIT), Karlsruhe, Baden-Württemberg, Germany

The final, formatted version of the article will be published soon.

    Tubulin polymerization inhibitors have emerged as interesting anticancer therapies. We present the design, synthesis, and structural elucidation of novel thiazole-based derivatives to identify novel tubulin inhibitors with potent antiproliferative efficacy and strong inhibition of tubulin polymerization. The novel compounds consist of two scaffolds. Scaffold A compounds 10a-e and scaffold B compounds 13a-e. The most effective antitubulin derivative was 10a, exhibiting an IC50 value of 2.69 µM. Subsequently, 10o and 13d exhibited IC50 values of 3.62 µM and 3.68 µM, respectively. These compounds exhibited more potency than the reference combretastatin A-4, which displayed an IC50 value of 8.33 µM. These compounds had no cytotoxic effects on normal cells, preserving over 85% cell viability at 50 µM. The antiproliferative experiment demonstrated that compounds 10a, 10o, and 13d displayed significant activity against four cancer cell lines, with average GI50 values of 6, 7, and 8 µM, equivalent to the reference's doxorubicin and sorafenib.Compounds 10a, 10o, and 13d were demonstrated to activate caspases 3, 9, and Bax, while downregulating the anti-apoptotic protein Bcl2. Molecular docking studies demonstrated superior binding affinities for 10a (-7.3 kcal/mol) at the colchicine binding site of tubulin, forming key hydrophobic and hydrogen bonding interactions that enhance its activity. ADMET analysis confirmed favorable drug-like properties, establishing these compounds as promising candidates for further development as anticancer agents targeting tubulin polymerization.

    Keywords: Tubulin, Colchicine, CA-4, Antiproliferative, Cell viability, Docking

    Received: 23 Jan 2025; Accepted: 01 Apr 2025.

    Copyright: © 2025 Al-Wahaibi, Elshamsy, Ali, Youssif, Bräse, Abdel-Aziz and El-koussi. 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:
    Bahaa G. M. Youssif, Assiut University, Assiut, Egypt
    Stefan Bräse, Karlsruhe Institute of Technology (KIT), Karlsruhe, 76344, Baden-Württemberg, Germany

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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