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.
Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China; 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.
Eur J Med Chem. 2019 Feb 1;163:169-182. doi: 10.1016/j.ejmech.2018.11.054. Epub 2018 Nov 26.
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-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N-(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.
各种耐药结核分枝杆菌（Mtb）菌株的出现，促使人们探索新的药物，这些药物与现有的治疗方法没有交叉耐药性。通过筛选 MedChemExpress 生物活性化合物库，发现色瑞替尼对 Mtb H37Ra 具有活性。色瑞替尼在体外的 MIC 值为 9.0 μM，在感染自发光 H37Ra 的 BALB/c 小鼠模型中表现出体内疗效。然后，合成了 32 种新型色瑞替尼衍生物，并在体外评估了它们的抗分枝杆菌活性。合成化合物的抗分枝杆菌活性受到嘧啶核 4 位取代的极大影响，嘧啶核 2 位存在 2-异丙氧基-5-甲基-4-（哌啶-4-基）苯胺时，活性增强。评估了三种最有效化合物的体内抗结核活性。5-氯-N-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N-(萘-1-基)嘧啶-2,4-二胺（16j）显著降低了小鼠体内的 Mtb 负担。这一结果表明 16j 具有作为一种具有优越抗结核活性的新型药物的潜力。磺胺甲恶唑与 16j 联合用药的实验结果和计算机模拟表明，二氢叶酸还原酶是 16j 的潜在分子靶标。
