Molecular Modeling, Synthesis and Biological Evaluation of <i>N</i>-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents

• Main Authors: Dima A. Sabbah, Shaima’ E. Hasan, Reema Abu Khalaf, Sanaa K. Bardaweel, Rima Hajjo, Khalid M. Alqaisi, Kamal A. Sweidan, Aya M. Al-Zuheiri
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Molecules
• Subjects: anticancer; colon cancer; PI3Kα; AKT; docking; quinolone-3-carboxamide
• Online Access: https://www.mdpi.com/1420-3049/25/22/5348
• ISSN: 1420-3049

The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of <i>N</i>-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (¹H and ¹³C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds <b>8</b> (IC₅₀ Caco-2 = 98 µM, IC₅₀ HCT-116 = 337 µM) and <b>16</b> (IC₅₀ Caco-2 = 13 µM, IC₅₀ HCT-116 = 240.2 µM). Results showed that compound <b>16 </b>significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues.