Discovery of Chromeno[4,3-c]pyrazol-4(2H)-one Containing Carbonyl or Oxime Derivatives as Potential, Selective Inhibitors PI3Kα

Abstract

A series of novel chromeno[4,3-c]pyrazol-4(2H)-one containing carbonyl or oxime derivatives (4a–n, 5a–n) have been synthesized and evaluated their biological activities as phosphatidyl inositol 3-kinase (PI3K) inhibitors. Out of them, compound 5l showed the most potent antiproliferative activities against HCT-116 with IC₅₀ of 0.10 µM in vitro, and exhibited the most potent activity for PI3Kα with the value of 0.012 µM. Docking simulation of 5l into PI3Kα active site were performed to determine the probable binding model, and it indicated that compound 5l could be optimized as a potential inhibitor of PI3Kα in the further study.

Graphical Abstract