Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3Kα: 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives.

A series of novel 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives were synthesized and evaluated for their biological activities as PI3K inhibitors. In vitro biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 4l exhibited the most potent and selective activity for PI3Kα, with the value of 0.014 μM, an approximately 30-fold increase in comparison with LY294002. Docking simulation was performed to position compound 4l into the PI3Kα active site and the result showed that compound 4l could bind well at the PI3Kα active site and it indicated that compound 4l could be a potential inhibitor of PI3Kα.