A new strategy for the preparation of 8-quinolyl ethers 3(a-g), 5(a-g), and 7(a-d) was studied by copper (II)-catalyzed methodology in the presence of Cs 2 CO 3 and acetone-water mixture (1:1). Screening of quinolinyl-8-ethers was investigated against anticancer expressive studies to validate new chemical entity in medicinal chemistry. Approaches were evaluated against breast cancer (MCF-7), skin cancer (G-361), and colon cancer (HCT 116) cell lines. Inhibitory potentials against phosphoinositide-3-kinase (PI3K) enzyme responsible for cancer development have been evaluated by competitive ELISA studies. In PI3K assay, 3a-c were inactive (IC 50 > 5 μM), while 3e-g, 5a, 5c-e, 5g, 7a, and 7d showed a moderate activity (IC 50 ≥ 0.05 μM). Compounds (5b, 5f, 7b, and 7c) showed significant activity (IC 50 < 1.0 μM); thus, their anticancer activities were carried out. Anticancer activity was found to be selective towards breast cancer (MCF-7); 5b, 5f, 7b, and 7c showed predominant relative percentage activities of 74.12%, 79.04%, 72.56%, and 78.47%, with IC 50 values of 5b (2.27 ± 0.88 μM), 5f (1.38 ± 0.60 μM), 7b (2.64 ± 0.86 μM), and 7c (1.87 ± 0.68 μM) compared with the standard doxorubicin 73.14% inhibition (IC 50 = 1.98 ± 0.75 μM). Docking study also conducted to find out the binding interactions with p110α (PDB ID: 3T8M) enzyme. Compounds 5b, 5f, 7b, and 7c showed best docking score into the active site of PI3K 12.59, 10.51, 56.52, and 8.61 nM. Structure-activity relationship studies demonstrated that the synthesized compounds are the potential PI3K inhibitors to treat various cancer-related diseases.
