Design, Synthesis and Antiproliferative Activity Studies of Novel 1,2,3-Triazole-Urea Hybrids

The development of novel targeted therapies for hepatocellular carcinoma remains a critical need in oncology. This study aimed to design and evaluate a new series of triazole-urea hybrid compounds for their anti-cancer potential.

A series of urea compounds bearing terminal alkynyl groups were synthesized via an assembly and post-modification strategy. Subsequent Click chemistry yielded the novel triazole-urea hybrids (3a-3e, 5a-5e, 7a-7e). Their anti-proliferative effects were assessed against multiple human cancer cell lines (lung: H460, H1299, A549, PC-9; liver: Huh-7; breast: MCF-7) and normal liver cells (L02) using the CCK-8 assay. Mechanisms were investigated through apoptosis, autophagy, and DNA damage assays. An acute oral toxicity study was conducted in female KM mice at a dose of 500 mg/kg, with thorough monitoring of body weight, organ coefficients, and histopathology of major organs.

Most compounds exhibited potent, concentration- and time-dependent anti-proliferative activity against Huh-7 liver cancer cells, with only marginal effects on other tested cancer lines. Crucially, no cytotoxicity was observed in normal L02 cells. Mechanistic studies revealed that the lead compound induced apoptosis, autophagy, and DNA damage in Huh-7 cells. The in vivo assay demonstrated no drug-related mortality or significant adverse effects on body weight, organ coefficients, or histology at 500 mg/kg over 14 days, indicating a high maximum tolerated dose and an excellent preliminary safety profile.

These findings demonstrate the selective anti-liver cancer efficacy and favorable in vivo safety of these triazole-urea hybrids, particularly compound 3c, underscoring their strong potential as promising therapeutic candidates for hepatocellular carcinoma.