Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives

Highlights•Development of acetylated hybrids with antiproliferative activity on cancer cells•Structural data indicate the binding of the hybrid compounds to cell cycle regulators•Hybrid compounds induce DNA damage and arrest cancer cells at the G2/M phase•Hybrid compounds modulate the metabolomic profile of cancer cellsSummaryThe development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies.Graphical abstract