Amide substituted (Z)-β-enaminones were synthesized by green chemistry and stereospecific synthetic pathway as novel phosphoinositide 3-kinase (PI3K) inhibitors and breast cancer drugs. PI3K inhibition was measured by competitive ELISA. A panel of cancer cell lines including MCF-7 (breast cancer), G-361 (skin cancer), and HCT 116 (colon cancer) were used to assess the anticancer potentials. In the PI3K assay, 2c and 2f were indolent for the proposed inhibitory action, which was recognized from the obtained IC 50 (>1.0 μM). Excellent activity potential of 2a, 2b, and 2d was recognized from the IC 50 range (<0.05 μM) whereas an intermediate action potential was observed for compounds 2e and 2i (IC 50 0.1 and 0.25, respectively). The docking results exclusively proposed that the hydrophobic interactions in the PI3K binding pocket were overwhelmed by the binding affinity of the most potent ligands (2a, 2b, and 2d: inhibitory constant K i = 18.16, 84.87, and 56.14 nM). MTT assay results revealed the antiproliferative activity domination of selected compounds (2a, 2b, and 2d) toward MCF-7. The relative activities of 2a, 2b, and 2d of 84.56, 80.87, and 90.12%, respectively, were comparable to that of the standard, doxorubicin (82.16%). SAR studies demonstrated amide substituted (Z)-β-enaminones as precise PI3K inhibitors to treat breast cancer. K E Y W O R D S amide substituted (Z)-β-enaminones, anticancer, breast cancer, molecular docking, phosphoinositide 3-kinase, SAR
