2. Academic Validation
  3. Design, synthesis, and biological evaluation of 2-(benzylthio)-5-(indol-3-yl)-1,3,4-oxadiazole derivatives as tubulin polymerization inhibitors with potential anti-cancer effects

Design, synthesis, and biological evaluation of 2-(benzylthio)-5-(indol-3-yl)-1,3,4-oxadiazole derivatives as tubulin polymerization inhibitors with potential anti-cancer effects

  • Eur J Med Chem. 2026 Feb 5:303:118405. doi: 10.1016/j.ejmech.2025.118405.
Bing Yang 1,  Ruo-Jun Man 2,  Qing Xie 3,  Jie You 3,  Jing-Yi Shi 4,  Hong Dai 1,  Hai-Liang Zhu 5
Affiliations

Affiliations

  • 1 School of Chemistry and Chemical Engineering, Nantong University, Nantong, 226019, China.
  • 2 School of Chemistry and Chemical Engineering, Guangxi Minzu University, Guangxi Key Laboratory for Polysaccharide Materials and Modification, Key Laboratory of Universities in Guangxi for Excavation and Development of Ancient Ethnomedicinal Recipes, Nanning, 530006, China. Electronic address: [email protected].
  • 3 School of Chemistry and Chemical Engineering, Guangxi Minzu University, Guangxi Key Laboratory for Polysaccharide Materials and Modification, Key Laboratory of Universities in Guangxi for Excavation and Development of Ancient Ethnomedicinal Recipes, Nanning, 530006, China.
  • 4 Jinhua Advanced Research Institute, Jinhua, 321019, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China. Electronic address: [email protected].
PMID: 41330155 DOI: 10.1016/j.ejmech.2025.118405
Abstract

Thirty new 2-(benzylthio)-5-(indol-3-yl)-1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated as tubulin inhibitors against cancers. Some target compounds showed relatively strong anti-proliferative activity against HepG2, HeLa, MCF-7, and A549 cells. Among them, the top hit, compound C21, yielded an IC50 value of 0.08 μM against HeLa cells, exhibiting lower cytotoxicity compared to 293T cells. Tubulin polymerization inhibition assay indicated that the inhibitory activity of compound C21 (IC50: 1.59 ± 0.66 μM) was stronger than that of Colchicine (IC50: 2.52 ± 0.23 μM). Mechanism studies demonstrated that compound C21 could arrest cell cycle at the G2/M phase and induce tumor cell Apoptosis in a dose- and time-dependent manner. The confocal imaging further demonstrated that compound C21 could inhibit tubulin polymerization, similar to Colchicine. Moreover, compound C21 showed excellent in vivo anti-tumor potency in a human cervical Cancer xenograft mouse model with an inhibitory rate of 80.51 %, which was better than the CA-4P group (49.22 %) and the lower dose group (69.52 %). Furthermore, the docking simulation visualized the possible binding pattern of compound C21 into tubulin. Finally, the information provided in this study will be helpful for the future development of tubulin-related anti-cancer drugs.

Keywords

2-(benzylthio)-5-(indol-3-yl)-1,3,4-oxadiazole derivatives; Anti-cancer agents; Antiproliferative activity; Colchicine-binding site; Tubulin polymerization inhibitors.

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