Design, Synthesis and Biological Evaluation of Novel Quinoline-Based mTOR Inhibitors as Potential Anticancer Agents

Research Article

Abstract

A series of novel quinoline and tetrahydroquinoline derivatives were designed and synthesized as potential mTOR inhibitors for anticancer activity. Structure-based drug design methods were employed using homology modeling of the mTOR kinase domain based on PI3K gamma crystal structure. Pharmacophore modeling identified essential features for mTOR inhibition, including hydrogen bond acceptors, donors, hydrophobic regions, and aromatic rings. Five compounds were synthesized: (6-chloro-2-phenylquinolin-4-yl)(1H-imidazol-1-yl)methanone [C₁], (6-chloro-2-phenylquinolin-4-yl)(piperidin-1-yl)methanone [C₂], 6-nitro-2-phenyl-N-(pyridine-2-yl)-1,2,3,4-tetrahydroquinoline-4-carboxamide [C₃], {2-[4-(dimethylamino)phenyl]-6-nitro-1,2,3,4-tetrahydroquinolin-4-yl}(piperidin-1-yl)methanone [C₄], and {2-[4-(dimethylamino)phenyl]-6-nitro-1,2,3,4-tetrahydroquinolin-4-yl}(1H-imidazol-1-yl)methanone [C₅]. The compounds were characterized using UV, IR, NMR spectroscopy and mass spectrometry. Molecular docking studies revealed favorable interactions with key amino acid residues in the mTOR active site. In vitro cytotoxicity studies against HCT116 colorectal cancer cells showed IC₅₀ values of 97.38 and 113.2 µM/ml for compounds C₁ and C₂ respectively. Acute toxicity studies indicated an LD₅₀ value between 300-2000 mg/kg body weight. The synthesized compounds showed potential as mTOR inhibitors with anticancer activity necessitating further investigation.