Exploring the anticancer potential of nitrated N-substituted-4-hydroxy-2-quinolone-3-carboxamides: synthesis, biological assessment, and computational analysis

Cancer remains the second leading cause of mortality globally, necessitating the development of novel therapeutic agents. In this work, we synthesized 34 derivatives of nitrated N-substituted-4-hydroxy-2-quinolone-3-carboxamides, which were spectroscopically analyzed using FT-IR, NMR (¹H and ¹³C), and elemental analysis. Derivatives tailored with m-CF₃ (10), m-OCH₃ (13), m-Cl (16), and m-F (20) benzyl moiety exhibited distinctive cytotoxicity against human colon cancer (HCT-116) cells with IC_50s of 23.41, 27.14, 28.43, and 22.95 µM. Analogue 11 showed 100% inhibitory activity against ovarian cancer (NCI/ADR-RES), colon cancer (COLO 205), CNS cancer (SF-295), and melanoma (SK-MEL-2) cells. Cheminformatics analysis further revealed insights into the physicochemical and drug-like properties of these analogues, highlighting their potential to bind PI3Kα through alignment with key pharmacophoric features required for effective enzyme interaction. Molecular docking studies against both wild-type and mutant PI3Kα elucidated binding interactions, suggesting that specific substituents enhance selectivity and potency. This study highlights the therapeutic potential of quinolone derivatives in targeting cancer-related pathways and contributes valuable data to the ongoing search for more effective anticancer therapies.