Ultrasound-Assisted Synthesis and Biological Profiling of 1,3,5-Triazine Derivatives with Antiproliferative Activity in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains one of the most aggressive breast cancer subtypes and is associated with limited therapeutic options, underscoring the urgent need for novel treatment strategies. In this study, a library of seventeen 1,3,5-triazine derivatives potentially targeting TNBC was developed using an activity-based approach. Compounds were synthesized via an ultrasound-assisted protocol, providing an efficient and environmentally friendly methodology. The synthesized library was evaluated in vitro against the human TNBC cell lines MDA-MB-468, MDA-MB-231, and Hs578T, as well as the non-tumorigenic epithelial cell line MCF10A. Compounds <b>9</b> and <b>17</b> exhibited the most promising antiproliferative activity against TNBC cell lines (MDA-MB-468: IC₅₀ = 36.62 µM for <b>9</b> and 38.29 µM for <b>17</b>; MDA-MB-231: IC₅₀ = 37.32 µM for <b>9</b> and 32.86 µM for <b>17</b>; Hs578T: IC₅₀ = 57.26 µM for <b>9</b> and 34.87 µM for <b>17</b>), while maintaining acceptable selectivity toward non-cancerous cells. The lead compounds were further assessed in vivo using a <i>Danio rerio</i> model to evaluate general toxicity and cardiotoxicity. In addition, ADME parameters were predicted for all compounds using biomimetic chromatography. Overall, compounds <b>9</b> and <b>17</b> emerged as promising small-molecule candidates for TNBC treatment, requiring further toxicological evaluation in more human-relevant in vivo models.