机构：[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.四川大学华西医院[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.
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.
基金：
This study was supported by the National Natural Science
Foundation of China (Nos. Do you 82173861, 81973368 and
81970738), the Project of Science and Technology Departmentof Sichuan Province (2021YJ0157 and 20−4−557), the
National Key R&D Program of China (2021YFA1300904),
and the Chinese Academy of Sciences Grants
(154144KYSB20190005, YJKYYQ20210026).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类|1 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[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.
共同第一作者：
通讯作者：
通讯机构：[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.
推荐引用方式(GB/T 7714)：
Li Chungen,Tian Xirong,Huang Zongkai,et al.Structure-Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis[J].Journal of medicinal chemistry.2023,66(4):2699-2716.doi:10.1021/acs.jmedchem.2c01647.
APA：
Li Chungen,Tian Xirong,Huang Zongkai,Gou Xupeng,Yusuf Buhari...&Luo Youfu.(2023).Structure-Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis.Journal of medicinal chemistry,66,(4)
MLA：
Li Chungen,et al."Structure-Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis".Journal of medicinal chemistry 66..4(2023):2699-2716
医学