Design, Synthesis and Biological Evaluation of 4-Aryl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one Derivatives as a PI3K alpha Inhibitor

摘要

A novel series of 4-aryl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives were designed as a phosphoinositide 3-kinase alpha (PI3K alpha) inhibitor by scaffold hopping. The target compounds, characterized by H-1-NMR C-13-NMR and high resolution (HR)-MS, were synthesized from diethyl malonate and ethyl chloroacetate by nucleophilic substitution, ring-closure, chlorination and Suzuki reaction, etc. The biological activities were evaluated with cytotoxic activity in vitro on Uppsala 87 Malignant Glioma (U87MG) and prostate cancer-3 (PC-3) by Cell Counting Kit-8 (CCK-8). The results showed that compound 9c displayed the higher inhibition than the positive control PI-103, and high PI3K alpha inhibitory activity with IC50 of 113 +/- 9 nM in the same order of magnitude as BEZ235. In addition, the LogK(ow) values and molecular docking studies were performed to further investigate the drug-like properties of target compounds and interactions between 9c and PI3K alpha.