Efficient Synthesis of Amine-Linked 2,4,6-Trisubstituted Pyrimidines as a New Class of Bacterial FtsZ Inhibitors.
Efficient Synthesis of Amine-Linked 2,4,6-Trisubstituted Pyrimidines as a New Class of Bacterial FtsZ Inhibitors.
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DOI：
10.1021/acsomega.7b00701
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发表时间：
2017-10-31
期刊：
影响因子：
4.1
通讯作者：
Wong KY
中科院分区：
文献类型：
--
作者：
Chan KF;Sun N;Yan SC;Wong ILK;Lui HK;Cheung KC;Yuan J;Chan FY;Zheng Z;Chan EWC;Chen S;Leung YC;Chan TH;Wong KY
我们最近发现了一类新的丝状温度敏感突变体 Z (FtsZ) 相互作用化合物，其具有 2,4,6-三取代嘧啶-奎宁环支架，具有中等抗菌活性。利用该支架作为分子模板，通过采用高效的收敛合成方法，成功建立了包含 99 个候选化合物的胺连接 2,4,6-三取代嘧啶化合物库，旨在探索其构效关系。针对金黄色葡萄球菌菌株的最低抑菌浓度 (MIC) 测定和针对小鼠 L929 细胞系的细胞毒性测定的结果确定了这些化合物具有有效的抗葡萄球菌特性（MIC 范围为 3 至 8 μg/mL），并且对正常细胞具有一定程度的细胞毒性（IC50 范围为 6 至 27 μM）。重要的是，三种化合物还对九种临床分离的耐甲氧西林金黄色葡萄球菌（MRSA）菌株表现出有效的抗菌活性。其中一种化合物14av_amine16表现出低自发耐药率、对大蜡螟幼虫的低毒性，并且能够拯救被致死剂量的MRSA ATCC 43300菌株感染的大蜡螟幼虫（100 mg/kg剂量下存活率为20%）。使用纯化的金黄色葡萄球菌 FtsZ 蛋白，通过饱和转移差 NMR、光散射测定和鸟苷三磷酸酶水解测定对化合物 14av_amine16 进行生物学表征，证实它与 FtsZ 蛋白相互作用。通过观察枯草芽孢杆菌的标志性丝状细胞表型和 Z 环形成的错误定位，进一步证实了 FtsZ 抑制剂的这种特性。总而言之，这些 2,4,6-三取代的嘧啶衍生物代表了金黄色葡萄球菌 FtsZ 抑制剂的新型支架。
We have recently identified a new class of filamenting temperature-sensitive mutant Z (FtsZ)-interacting compounds that possess a 2,4,6-trisubstituted pyrimidine–quinuclidine scaffold with moderate antibacterial activity. Employing this scaffold as a molecular template, a compound library of amine-linked 2,4,6-trisubstituted pyrimidines with 99 candidates was successfully established by employing an efficient convergent synthesis designed to explore their structure–activity relationship. The results of minimum inhibitory concentration (MIC) assay against Staphylococcus aureus strains and cytotoxicity assay against the mouse L929 cell line identified those compounds with potent antistaphylococcal properties (MIC ranges from 3 to 8 μg/mL) and some extent of cytotoxicity against normal cells (IC50 ranges from 6 to 27 μM). Importantly, three compounds also exhibited potent antibacterial activities against nine clinically isolated methicillin-resistant S. aureus (MRSA) strains. One of the compounds, 14av_amine16, exhibited low spontaneous frequency of resistance, low toxicity against Galleria mellonella larvae, and the ability to rescue G. mellonella larvae (20% survival rate at a dosage of 100 mg/kg) infected with a lethal dose of MRSA ATCC 43300 strain. Biological characterization of compound 14av_amine16 by saturation transfer difference NMR, light scattering assay, and guanosine triphosphatase hydrolysis assay with purified S. aureus FtsZ protein verified that it interacted with the FtsZ protein. Such a property of FtsZ inhibitors was further confirmed by observing iconic filamentous cell phenotype and mislocalization of the Z-ring formation of Bacillus subtilis. Taken together, these 2,4,6-trisubstituted pyrimidine derivatives represent a novel scaffold of S. aureus FtsZ inhibitors.
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