Design, synthesis, and cytotoxic activity evaluation of 1,2,4-Triazole-based Ethanone and Ferrocenylchalcone...

This study aimed to synthesize novel 3,5-disubstituted-1,2,4-triazolyl ethanone (TA) and ferrocenylchalcone derivatives (TAFe) and to evaluate their cytotoxic activities. In this context, 1,2,4-triazole ethanone derivatives (TA) were obtained from the reaction of 3,5-disubstituted-1,2,4-triazole derivatives with phenacyl bromides. These compounds were then converted into 1,2,4-triazole-based ferrocenylchalcone derivatives (TAFe) via Claisen-Schmidt condensation with ferrocenecarboxaldehyde. The cytotoxic potential of the resulting compounds was subsequently evaluated using various biological assays. The biological activities of TA and TAFe compounds were comprehensively evaluated using MTT, LDH, wound-healing, and DNA degradation assays across lung and breast cell lines. In MTT assays, both TA and TAFe series exhibited potent antiproliferative activity in the low-micromolar range (GI₅₀ ≈ 2.2-26.3 μM in lung cancer cells and ≈1.9-12.7 μM in breast cancer cells). Breast cancer cell lines, particularly MDA-MB-231, were generally more sensitive than lung cancer models. Tumor selectivity analysis based on GI₅₀ values revealed distinct biological profiles. Several compounds exhibited pronounced GI₅₀-based selectivity, indicating preferential inhibition of cancer cell proliferation relative to the corresponding normal cells. TA8 displayed a favorable profile, combining low-micromolar antiproliferative activity with GI₅₀-based selectivity, particularly against MDA-MB-231 cells. LDH assays demonstrated low membrane toxicity for both compound series (≈3-7% in lung and up to ≈19% in breast cell models). In the wound-healing assay, both TA and TAFe derivatives exhibited pronounced, cell line-dependent reductions in wound-closure. Selected compounds from both series effectively reduced wound-closure under the experimental conditions, although the magnitude of inhibition varied among cell lines. DNA fragmentation analysis further supported these findings, revealing more pronounced apoptosis-associated DNA fragmentation following TA treatment than with the corresponding TAFe derivatives. Overall, the TA derivatives demonstrated a more favorable balance between antiproliferative potency, tumor selectivity, and effects on wound-closure than the corresponding TAFe complexes, although selected TAFe derivatives exhibited cell line-dependent selectivity. These findings support TA8 as a candidate for further investigation and highlight the 1,2,4-triazole scaffold as a valuable platform for the development of novel anticancer agents.