N-Benzyl-6-Chloro-4-Hydroxy-2-Quinolone-3-Carboxamides: Synthesis, Computational Studies, and Biological Investigation as Anticancer Agents

Cancer remains the second leading cause of death worldwide, highlighting the urgent need for novel therapeutic agents. In this work, twenty derivatives of <i>N</i>-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 <i>o</i>-CH₃ (<b>8</b>), <i>p</i>-OCH₃ (<b>10</b>), <i>m</i>-CH₃ (<b>18</b>), <i>p</i>-CH₃ (<b>19</b>), and <i>p</i>-CF₃ (<b>21</b>) 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.