Discovery of 7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives as the potential epidermal growth factor receptors for tyrosine kinase inhibitors

  • Qian Xie
  • Jingjing Wang
  • Miao Liu
  • Xin Wang
  • Di Jiao
  • Qingqing Ma
  • Zhe Jin
  • Qingguo Meng
  • Chun HuEmail author
Original Research


Small molecule tyrosine kinase inhibitors (TKIs) targeting at epidermal growth factor receptor (EGFR) in recent years have made great progress in the treatment of advanced non-small cell cancer (NSCLC). Although as the first-line treatment for sensitizing EGFR mutation-positive metastatic NSCLC, gefitinib has also behaved quite a lot of side effect and EGFR tolerance. Herein, a novel series of 7-bromo-1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives were designed and synthesized, and screened for their inhibitory activity on the EGFR high-expressing human lung adenocarcinoma cell line A549 and human large cell lung cancer cell line NCI-H460 by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The calculated IC50 values were reported. Compound 8h demonstrated the most potent inhibitory activity (IC50 = 9.57 ± 2.20 μmol L–1 for A549 and IC50 = 13.04 ± 1.21 μmol L–1 for NCI-H460), comparable to the positive-control gefitinib (IC50 = 8.58 ± 1.65 μmol L–1 for A549 and IC50 = 18.66 ± 5.01 μmol L–1 for NCI-H460). Conclusively, 7-bromo- 1,4-dihydrothieno[3’,2’:5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives as the EGFR–TKIs were discovered, and could be used as potential leading compounds for further research.


EGFR Inhibitors Heterocycle Synthesis Anticancer activities 



This work was supported by the National Science Foundation of China (NSFC) for the grant No. 21342006 and the Program for Innovative Research Team of the Ministry of Education of China for the grant No. IRT_14R36. We thank Molegro ApS for kindly providing a free evaluation copy of their software package and Schrödinger, LLC for allowing the use of PyMOL Molecular Graphics System.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with animals, performed by any of the authors. Informed consent was obtained from all individual participants included in the study.

Supplementary material

44_2019_2354_MOESM1_ESM.doc (5.5 mb)
Supplementary Information


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Key Laboratory of Structure-based Drug Design & Discovery, Ministry of EducationShenyang Pharmaceutical UniversityShenyangChina
  2. 2.Department of PharmacyYantai UniveristyYantaiChina

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