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

Abstract

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 IC50s 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.