Design, synthesis and biological evaluation of novel 3H-imidazole [4,5-b] pyridine derivatives as selective mTOR inhibitors

Lingzhi Zhang; Tantan Bu; Xiaobo Bao; Tingting Liang; Yiran Ge; Yungen Xu; Qihua Zhu

doi:10.1016/j.bmcl.2017.06.010

Design, synthesis and biological evaluation of novel 3H-imidazole [4,5-b] pyridine derivatives as selective mTOR inhibitors

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3395-3398. doi: 10.1016/j.bmcl.2017.06.010. Epub 2017 Jun 3.

Authors

Lingzhi Zhang¹, Tantan Bu¹, Xiaobo Bao², Tingting Liang², Yiran Ge³, Yungen Xu⁴, Qihua Zhu⁵

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
² Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China. Electronic address: xu_yungen@hotmail.com.
⁵ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China. Electronic address: zhuqihua@vip.126.com.

PMID: 28633896
DOI: 10.1016/j.bmcl.2017.06.010

Abstract

A series of 3H-imidazo [4,5-b] pyridines derivatives were designed and synthesized as selective mTOR inhibitors. The systematic optimization of the molecules resulted in the identification of two compounds 10d and 10n with nanomolar mTOR inhibitory activity and selectivity over PI3Kα. Besides, compounds 10d and 10n demonstrated attractive potency against human breast cancer cells (MCF-7) and human ovarian cancer cell (A2780).

Keywords: 3H-Imidazo [4,5-b] pyridine; Antitumor; Mammalian target of rapamycin; Synthesis; mTOR inhibitors.

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

Imidazoles
Protein Kinase Inhibitors
Pyridines
MTOR protein, human
TOR Serine-Threonine Kinases