Li Chungen, Tian Xirong, Huang Zongkai, Gou Xupeng, Yusuf Buhari, Li Cong, Gao Yamin, Liu Song, Wang Yanmei, Yang Tao, Liu Zhiyong, Sun Qingxiang, Zhang Tianyu, Luo Youfu
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.
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
J Med Chem. 2023 Feb 23;66(4):2699-2716. doi: 10.1021/acs.jmedchem.2c01647. Epub 2023 Feb 3.
Discovery of novel antitubercular drugs is an effective strategy against drug-resistant tuberculosis (TB). Our previous study has identified as a novel antitubercular compound. Herein, we perform a comprehensive structure-activity relationship (SAR) based on , 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 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, showed an acceptable safety 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 . Overall, this study identified as a novel promising lead compound with the potential to develop candidates for the treatment of drug-resistant TB.
发现新型抗结核药物是对抗耐药结核病（TB）的有效策略。我们之前的研究已将[具体化合物名称未给出]鉴定为一种新型抗结核化合物。在此，我们基于[具体化合物名称未给出]进行了全面的构效关系（SAR）研究，表明中心嘧啶环部分对其衍生物的抗结核活性至关重要，并且用疏水性取代基取代萘基具有良好的耐受性。代表性衍生物[具体化合物名称未给出]对H37Ra、H37Rv和临床耐药结核杆菌表现出强效活性，最低抑菌浓度（MIC）值为0.5 - 1.0μg/mL。同时，[具体化合物名称未给出]显示出可接受的安全性，口服生物利用度良好，值为40.7%。差示扫描荧光法、等温滴定量热法和分子对接分析表明PknB可能是化合物[具体化合物名称未给出]的靶点之一。总体而言，本研究确定[具体化合物名称未给出]为一种新型有前景的先导化合物，具有开发耐药结核病治疗候选药物的潜力。
