Among them, 22c with the quinoline core showed strong PI3Kα kinase inhibitory activity (IC 50 = 0.22 nM) and mTOR kinase inhibitory activity (IC 50 = 23 nM). Finally, molecular docking was used to confirm the binding mode with PI3Kα and mTOR.

Furthermore, the phosphorylation level of AKT, an important downstream effector of PI3K, was evaluated by Western blot assay. Then, the effects of the most potent inhibitor on cell cycle and apoptosis were performed.

Enzyme inhibition assay and cell anti-proliferation assay were employed to assess all derivatives. Herein, a series of 36 sulfonamide methoxypyridine derivatives with three different aromatic skeletons were synthesized as novel potent PI3K/mTOR dual inhibitors based on a scaffold hopping strategy. Meanwhile, inhibiting both PI3K and mammalian rapamycin receptor (mTOR) can simultaneously improve the efficiency of anti-tumor therapy. Phosphatidylinositol 3-kinase (PI3K) plays an important role in cell proliferation, survival, migration, and metabolism, and has become an effective target for cancer treatment.

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