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Design and synthesis of novel pyrimidine derivatives as potent antitubercular agents.

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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 [2]Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, 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

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关键词： Antimycobacterial Ceritinib Pyrimidine derivatives Dihydrofolate reductase inhibitors

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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. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

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出版当年[2019]版：

大类 | 1 区

医学

小类 | 1 区药物化学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

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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

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