2. Academic Validation
  3. Design and synthesis of novel pyrimidine derivatives as potent antitubercular agents

Design and synthesis of novel pyrimidine derivatives as potent antitubercular agents

  • Eur J Med Chem. 2019 Feb 1;163:169-182. doi: 10.1016/j.ejmech.2018.11.054.
Pingxian Liu 1,  Yang Yang 1,  Yunxiang Tang 2,  Tao Yang 1,  Zitai Sang 1,  Zhiyong Liu 3,  Tianyu Zhang 4,  Youfu Luo 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
  • 2 Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China; State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510530, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510530, China.
  • 4 State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510530, China. Electronic address: zhang_tianyu@gibh.ac.cn.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China. Electronic address: luo_youfu@scu.edu.cn.
PMID: 30508666 DOI: 10.1016/j.ejmech.2018.11.054
Abstract

The emergence of various drug-resistant Mycobacterium tuberculosis (Mtb) strains has necessitated the exploration of new drugs that lack cross-resistance with existing therapeutics. By screening the MedChemExpress bioactive compound library, ceritinib was identified as a compound with activity against Mtb H37Ra. Ceritinib had a MIC value of 9.0 μM in vitro and demonstrated in vivo efficacy in a BALB/c mouse model infected with autoluminescent H37Ra. Then, 32 novel ceritinib derivatives were synthesized, and their antimycobacterial activities were evaluated in vitro. The antimycobacterial activities of the synthesized compounds were drastically affected by substitutions at position 4 of the pyrimidine nucleus and were enhanced by the presence of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline at position 2 of the pyrimidine nucleus. The in vivo antitubercular activities of the three most potent compounds were evaluated. 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(naph thalen-1-yl) pyrimidine-2,4-diamine (16j) remarkably reduced the Mtb burden of mice. This result suggested the potential of 16j as a novel drug with superior antitubercular activities. The results of experiments on the combination of sulfamethoxazole with 16j and in silico modeling suggest that dihydrofolate reductase is the potential molecular target of 16j.

Keywords

Antimycobacterial; Ceritinib; Dihydrofolate reductase inhibitors; Pyrimidine derivatives.

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