N-Benzyl-6-Chloro-4-Hydroxy-2-Quinolone-3-Carboxamides: Synthesis, Computational Studies, and Biological...

Cancer remains the second leading cause of death worldwide, highlighting the urgent need for novel therapeutic agents. In this work, twenty derivatives of N-benzyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides were synthesized and spectroscopically analyzed using FT-IR, NMR (¹H and ¹³C), and elemental analysis. Substitution of benzyl moiety with o-CH₃ (8), p-OCH₃ (10), m-CH₃ (18), p-CH₃ (19), and p-CF₃ (21) demonstrated three-fold distinct cytotoxicity against human colon cancer (HCT-116) cells with IC_50s of 72.0, 100.0-112.0 µM. The cheminformatics calculations disclosed that the analogues possess diverse physicochemical properties and invariable predictions across six drug-likeness scoring models, supporting their potential cytotoxicity profile against colorectal cancer cell lines (Caco-2 and HCT-116). The docking studies against both wild-type and mutant PI3Kα clarified binding interactions, implying that particular functionalities improve efficacy and selectivity. This study provides further evidence for the therapeutic promise of quinolones in targeting cancer-specific pathways and expedites the process for developing potent anticancer agents.