Design, synthesis and evaluation of 2, 6, 8-substituted Imidazopyridine derivatives as potent PI3Kα inhibitors

Abstract

Inhibition of PI3K pathway has become a desirable strategy for cancer treatment. In this work, a series of 2, 6, 8-substituted Imidazo[1,2-a]pyridine derivatives were designed and screened for their activities against PI3Kα and a panel of PI3Kα-addicted cancer cells. Among them, compound 35 was identified as a PI3Kα inhibitor with nanomolar potency as well as acceptable antiproliferative activity. Flow cytometry analysis confirmed 35 induced cell cycle arrest and apoptosis in T47D cells. In addition, it also showed desirable in vitro ADME properties. The design, synthesis, and SAR exploration of 35 are described within.

Keywords:

• PI3Kα
• synthesis
• Imidazo[12-a]pyridine derivatives
• antitumor activity

Acknowledgements

We would also like to thank Guangzhou Yinfo Information Technology Co., Ltd. for providing a friendly and versatile web server (https://cloud.yinfotek.com) to aid the docking studies.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by National-Local Joint Engineering Research Center for Innovative and Generic Chemical Drug, Guizhou Provincial Natural Science Foundation [No.[2022]4017], National Science Foundation of Health and Family planning Commission of Guizhou Province (gzwkj2022-472), Clinical Medical Technology Innovation Guidance Project of Hunan Provincial Science and Technology Department (2020SK52003).