Investigating the Anticancer Promise of Synthesized Methylated <i>N</i> ‐Substituted‐4‐Hydroxy‐2‐Quinolone‐3‐Carboxamides: Biological and Computational Characterization

ABSTRACT Cancer is a multifaceted disease that places a significant burden on healthcare systems and economies, driving the urgent need for novel therapeutic agents to curb its prevalence and impact. Thirty‐three analogues of N ‐substituted‐7‐and 8‐methyl‐4‐hydroxy‐2‐quinolone‐3‐carboxamides were synthesized and characterized using FT‐IR, NMR ( 1 H and 13 C), HRMS, and elemental analysis. The analogues displayed potential cytotoxicity against human colon cancer (HCT‐116) and epithelial colorectal adenocarcinoma (Caco‐2) cells. Compounds bearing a phenyl ring tailored with o ‐CF 3 ( 26 ) and a phenyl ring substituted with o ‐COOH and p ‐CH 3 ( 29 ) exert preferential inhibitory activity against HCT‐116 with IC 50s 9.4 and 7.8 μM. The bioinformatics calculations interpret the selectivity of analogues against HCT‐116. The principal component analysis (PCA) discloses that the analogues are regarded as lead‐like and nominated for hit‐to‐lead and lead optimization stages of drug discovery. Docking studies illustrate that analogues accommodate the kinase domain of PI3Kα and engage with key binding residues. The promising outcome of this work emphasizes the significance of this scaffold as anticancer agents.