Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety as c-Met kinase inhibitors

Qidong Tang; Linxiao Wang; Yayi Tu; Wufu Zhu; Rong Luo; Qidong Tu; Ping Wang; Chunjiang Wu; Ping Gong; Pengwu Zheng

doi:10.1016/j.bmcl.2016.02.059

Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety as c-Met kinase inhibitors

Bioorg Med Chem Lett. 2016 Apr 1;26(7):1680-4. doi: 10.1016/j.bmcl.2016.02.059. Epub 2016 Feb 21.

Authors

Qidong Tang¹, Linxiao Wang², Yayi Tu², Wufu Zhu², Rong Luo³, Qidong Tu², Ping Wang², Chunjiang Wu², Ping Gong⁴, Pengwu Zheng⁵

Affiliations

¹ School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: tangqidongcn@126.com.
² School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China.
³ Jiangxi Province Institute of Materia Medica, Nanchang 330000, PR China.
⁴ Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
⁵ School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, PR China. Electronic address: zhengpw@126.com.

PMID: 26923692
DOI: 10.1016/j.bmcl.2016.02.059

Abstract

A series of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 4 cancer cell lines (HT-29, A549, MCF-7, and PC-3) in vitro. Most compounds showed moderate to excellent potency, with the most promising analog 34 showing a c-Met IC50 value of 1.68nM. Structure-activity relationship studies indicated that electron-withdrawing groups (X=CF3, R(1)=F, R(2)=4-F) were required to decrease the higher electron density on the 5-atom linker to a proper degree to improve the inhibitory activity.

Keywords: 1,2,3-Triazole; Antiproliferative activity; Pyrrolo[2,3-b]pyridine derivatives; Synthesis; c-Met.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Drug Design
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / metabolism
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyridines / chemistry*
Pyridines / pharmacology*
Pyrroles / chemistry*
Pyrroles / pharmacology*
Structure-Activity Relationship
Triazoles / chemistry*
Triazoles / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridines
Pyrroles
Triazoles
Proto-Oncogene Proteins c-met
pyrrolo(2, 3-b)pyridine