DESIGN, SYNTHESIS, AND PRELIMINARY ANTIPROLIFERATIVE EVALUATION OF BENZIMIDAZOLE-1,3,4-OXADIAZOLE HYBRIDS SHOWING PREFERENTIAL ACTIVITY IN BREAST CANCER CELL LINES

Vollständiger Abstract

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In this study, a new series of benzylthio-substituted benzimidazole-1,3,4-oxadiazole hybrids was designed, synthesized, and evaluated for their biological activity. The title compounds, 2-((2-(benzylthio)-1H-benzimidazol-1-yl)methyl)-5-aryl-1,3,4-oxadiazoles (1-4), were prepared through a multistep synthetic route starting from 2-mercaptobenzimidazole. The synthesis involved S-benzylation, N-alkylation with ethyl chloroacetate, hydrazide formation, and POCl3-mediated cyclodehydration with selected benzoic acid derivatives. The structures of the synthesized compounds were confirmed by FT-IR, 1H NMR, 13C NMR, and HRMS analyses. The antiproliferative activities of compounds 1-4 were investigated against A549 lung adenocarcinoma, MCF-7 estrogen receptor-positive breast cancer, and MDA-MB-468 triple-negative breast cancer cell lines using the MTT assay. Doxorubicin was used as the reference anticancer drug. The synthesized compounds did not show a meaningful cytotoxic effect against A549 cells, with cell viability remaining approximately 95-100% at 100 µM. In contrast, a more pronounced response was observed in breast cancer cells. At 100 µM, compounds 1-4 reduced cell viability to 44.25%, 57.25%, 37.75%, and 61.25%, in MCF-7 cells and to 46.25%, 61.00%, 39.00%, and 45.00% in MDA-MB-468 cells, respectively. Among the tested derivatives, compound 3, bearing a para-methoxy substituent, showed the most favorable activity profile in both breast cancer cell lines. In the DPPH assay, the compounds did not exhibit notable radical scavenging activity, suggesting that their antiproliferative effects are unlikely to be directly related to classical antioxidant behavior. Overall, these findings indicate that the benzimidazole-1,3,4-oxadiazole hybrid scaffold may provide a useful starting point for the development of breast cancer-oriented antiproliferative candidates.