Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and remains one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, has been widely used in the systemic treatment of advanced HCC, but its clinical efficacy is limited due to acquired resistance, poor selectivity, and adverse effects. To address these limitations, a series of novel sorafenib derivatives incorporating a 1,2,3-triazole moiety were rationally designed and synthesized via a molecular hybridization strategy. The N,N-diphenylurea fragment of sorafenib was retained, while the C-ring pyridine was replaced by various substituted 1,2,3-triazoles to improve antitumor potency and induce DNA damage. Biological evaluation revealed that compounds 12e, 12 g and 12j exhibited potent anti-proliferative activity against HepG2 cells, with IC₅₀ values of 6.49 ± 0.17 μM, 6.53 ± 1.27 μM, and 7.21 ± 0.30 μM, respectively. These compounds significantly inhibited colony formation and cell migration, elevated intracellular ROS levels, and induced mitochondrial-mediated apoptosis and DNA damage, as evidenced by DAPI staining, Annexin V/PI flow cytometry, TUNEL assays, and upregulation of pro-apoptotic proteins (Bax, cleaved-caspase-3/9, cleaved-PARP) along with downregulation of Bcl-2. Moreover, western blot analysis showed marked activation of DNA damage markers (p-H2AX) and suppression of the PI3K/AKT signaling pathway. In vivo, compounds 12e and 12 g effectively inhibited tumor growth in a HepG2 xenograft mouse model without significant systemic toxicity, as confirmed by tumor volume/weight analysis, organ index, serum transaminase levels, and histological evaluation. These findings demonstrate that 1,2,3-triazole-modified sorafenib derivatives possess promising antitumor activity and favorable safety profiles. Compounds 12e, 12 g and 12j represent promising lead candidates for further development of targeted therapeutics against liver cancer.
