Discovery of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives as novel, potent and selective c-Met kinase inhibitors: Synthesis, SAR study, and biological activity

Li Zhang; Jingyun Zhao; Beichen Zhang; Tao Lu; Yadong Chen

doi:10.1016/j.ejmech.2018.03.049

Discovery of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives as novel, potent and selective c-Met kinase inhibitors: Synthesis, SAR study, and biological activity

Eur J Med Chem. 2018 Apr 25:150:809-816. doi: 10.1016/j.ejmech.2018.03.049. Epub 2018 Mar 21.

Authors

Li Zhang¹, Jingyun Zhao¹, Beichen Zhang¹, Tao Lu², Yadong Chen³

Affiliations

¹ Department of Organic Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
² Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China. Electronic address: lut163@163.com.
³ Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China. Electronic address: ydchen@cpu.edu.cn.

PMID: 29602036
DOI: 10.1016/j.ejmech.2018.03.049

Abstract

A series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives were designed, synthesized and evaluated for their biological activity. Most of these compounds showed potent activities against c-Met kinase and cell growth inhibition. The most promising compound, 7d, has the IC₅₀ values of 2.02 and 88 nM to inhibit c-Met kinase activity and cell growth in the MKN45 cell line, respectively. In addition, 7d is highly selective to c-Met and exhibits over 2500-fold selective inhibition to 16 tyrosine kinases evaluated.

Keywords: Inhibitors; SAR; Synthesis; [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole; c-Met.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Structure-Activity Relationship
Thiadiazoles / chemical synthesis
Thiadiazoles / chemistry
Thiadiazoles / pharmacology*
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*

Substances

1,2,4-triazolo-(3,4-b)-1,3,4-thiadiazoles
Antineoplastic Agents
Protein Kinase Inhibitors
Thiadiazoles
Triazoles
Proto-Oncogene Proteins c-met