2. Academic Validation
  3. Structure-Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis

Structure-Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis

  • J Med Chem. 2023 Feb 23;66(4):2699-2716. doi: 10.1021/acs.jmedchem.2c01647.
Chungen Li 1,  Xirong Tian 2 3 4 5,  Zongkai Huang 1,  Xupeng Gou 1,  Buhari Yusuf 2 3 4 5,  Cong Li 1,  Yamin Gao 2 3 4 5,  Song Liu 1,  Yanmei Wang 6,  Tao Yang 1,  Zhiyong Liu 2 3 4 5,  Qingxiang Sun 1,  Tianyu Zhang 2 3 4 5,  Youfu Luo 1
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 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 3 Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 6 Institute of Traditional Chinese Medicine, Sichuan College of Traditional Chinese Medicine (Sichuan Second Hospital of TCM), Chengdu 610041, China.
PMID: 36735271 DOI: 10.1021/acs.jmedchem.2c01647
Abstract

Discovery of novel antitubercular drugs is an effective strategy against drug-resistant tuberculosis (TB). Our previous study has identified LPX-16j as a novel antitubercular compound. Herein, we perform a comprehensive structure-activity relationship (SAR) based on LPX-16j, indicating that the central pyrimidine ring moiety was crucial for the antitubercular activities of its derivatives, and replacing the naphthyl group with hydrophobic substitutes was well tolerated. The representative derivative 5a exhibited potent activity against H37Ra, H37Rv, and clinical drug-resistant TB with minimum inhibitory concentration (MIC) values of 0.5-1.0 μg/mL. Meanwhile, 5a showed an acceptable safety in vivo and displayed a favorable oral bioavailability with a value of 40.7%. The differential scanning fluorescence, isothermal titration calorimetry, and molecular docking assays indicated that PknB could be one of the targets of compound 5a. Overall, this study identified 5a as a novel promising lead compound with the potential to develop candidates for the treatment of drug-resistant TB.

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