Novel compounds with promising HuH-7 inhibitory activity as new cancer drug candidates: derivatives of N,N′-diphenylurea linked with 1,2,3-triazole

Targeted cancer drug therapy has emerged as a critical treatment modality for advanced hepatocellular carcinoma (HCC). The discovery and development of novel anti-HCC drug therapeutics with improved pharmacological properties remains an urgent priority in oncology drug discovery. In this study, we designed and synthesised a new series of 1,2,3-triazole-cored structures incorporating aryl urea. Fifteen analogs were prepared <i>via</i> nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. These synthesised compounds were evaluated for their potential antitumor activities. Notably, compounds <b>3c</b> and <b>3g</b> exhibited the lowest IC₅₀ values (10.80 ± 0.14 and 11.62 ± 3.72 μM) against HuH-7 cells. Further investigations suggested compound <b>3c</b> and <b>3g</b> induced cell apoptosis, stimulated DNA damage, and autophagy against HuH-7 cells. Acute toxicity measurement also demonstrated the safety of the compounds. These findings suggested the triazole-cored analogs <b>3c</b> and <b>3g</b> are suggested to be promising candidates for the treatment of HCC and their potential for further pharmaceutical development.