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

被引：9

作者：

Li, Chungen ^{[1
,2
]}

Tian, Xirong ^{[3
,4
,5
,6
]}

Huang, Zongkai ^{[1
,2
]}

Gou, Xupeng ^{[1
,2
]}

Yusuf, Buhari ^{[3
,4
,5
,6
]}

Li, Cong ^{[1
,2
]}

Gao, Yamin ^{[3
,4
,5
,6
]}

Liu, Song ^{[1
,2
]}

Wang, Yanmei

Yang, Tao ^{[1
,2
]}

Liu, Zhiyong ^{[3
,4
,5
,6
]}

Sun, Qingxiang ^{[1
,2
]}

Zhang, Tianyu ^{[3
,4
,5
,6
]}

Luo, Youfu ^{[1
,2
]}

机构：

[1] Sichuan Univ, West China Hosp, Canc Ctr, West China Med Sch,State Key Lab Biotherapy & Canc, Chengdu 610041, Peoples R China

[2] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China

[3] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, Guangzhou 510530, Peoples R China

[4] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangdong Hong Kong Macao Joint Lab Resp Infect Di, Hong Kong 510530, Guangdong, Peoples R China

[5] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, China New Zealand Joint Lab Biomed & Hlth, Guangzhou 510530, Peoples R China

[6] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 04期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

DISCOVERY; DESIGN;

D O I：

10.1021/acs.jmedchem.2c01647

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu g/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.

引用

页码：2699 / 2716

页数：18

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