Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo,Journal of Medicinal Chemistry

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Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-21 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00949
Shuaishuai Ni ₁ , Hanwen Wei ₁ , Baoli Li ₁ , Feifei Chen ₂ , Yifu Liu ₁ , Wenhua Chen ₁ , Yixiang Xu ₁ , Xiaoxia Qiu ₁ , Xiaokang Li ₁ , Yanli Lu ₁ , Wenwen Liu ₁ , Linhao Hu ₁ , Dazheng Lin ₁ , Manjiong Wang ₁ , Xinyu Zheng ₁ , Fei Mao ₁ , Jin Zhu ₁ , Lefu Lan ₂ , Jian Li ₁

Affiliation

Our previous work (Wang et al. J. Med. Chem. 2016, 59, 4831−4848) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.

中文翻译：

与利奈唑胺和万古霉素与耐甲氧西林，利奈唑胺和中古霉素的金黄色葡萄球菌感染相比，金黄色葡萄球菌毒素致病因子的新型抑制剂

我们以前的工作（Wang等。 J. Med。化学 2016年， 59， 4831−4848）揭示了有效的苯并环烷烃衍生的金黄色素抑制剂可抵抗耐甲氧西林的金黄色葡萄球菌（S. aureus）感染，并伴有不良的水溶性和高的hERG抑制作用和剂量（预先给药）。在这项研究中，已经克服了上述缺陷，提出了92种苯并二氢吡喃和香豆兰衍生物作为新型抑制剂。衍生物69和105表现出出色的色素抑制活性和低hERG抑制作用，并通过盐类型选择提高了溶解度。69和105的广泛且有效的抗菌谱与利奈唑胺和万古霉素相比，首先在小鼠的肝脏和心脏中正常给药以对抗有色的金黄色葡萄球菌纽曼，Mu50（万古霉素中间性金黄色葡萄球菌）和NRS271（耐利奈唑胺的金黄色葡萄球菌）。总而言之，69和105都有潜力被开发为针对毒力因子的良好抗菌候选药物。

更新日期：2017-09-21

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