Discovery of 1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamide derivatives as potent anticancer agents:...

The present investigation describes the design and synthesis of twenty-eight novel 1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamide derivatives based on Tasquinimod as the lead scaffold. The compounds were evaluated for cytotoxicity against A549 (lung), HCT116 (colon), and MCF7 (breast) cancer cell lines, as well as the noncancerous MRC-5 lung fibroblast cell line, and compared with Tasquinimod. Except for compounds 8e (HCT116), 6b (A549), and 5c (MCF7), all derivatives showed greater potency than Tasquinimod. Compounds 6g, 7f, and 7g exhibited broad-spectrum activity with low toxicity toward MRC-5 cells (IC₅₀ ≥ 100 μM) and were selected as lead candidates for mechanistic studies. Cell cycle analysis and mitochondrial membrane potential assays demonstrated that the potent compounds 6g, 7f, and 7g induce cell cycle arrest and disrupt mitochondrial function. In silico studies demonstrated that these compounds exhibit strong drug-likeness. Moreover, molecular docking analysis of the hub targets revealed favourable binding interactions with key cancer-related proteins, suggesting their potential inhibitory activity and supporting their predicted anticancer role. Collectively, these findings suggest that the compounds represent promising lead candidates for subsequent in vivo evaluation and potential development as novel anticancer agents.