铈替尼
抗细菌
嘧啶
化学
生物信息学
结核分枝杆菌
体内
二氢叶酸还原酶
体外
立体化学
药理学
生物化学
肺结核
克里唑蒂尼
生物
酶
医学
生物技术
病理
外科
恶性胸腔积液
基因
胸腔积液
作者
Pingxian Liu,Yang Yang,Yunxiang Tang,Tao Yang,Zitai Sang,Xiaogang Li,Tianyu Zhang,Youfu Luo
标识
DOI:10.1016/j.ejmech.2018.11.054
摘要
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.
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