优化 N-苄基-5-硝基呋喃-2-甲酰胺作为抗结核药物。
Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent.
机构信息
Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.
Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.
出版信息
Bioorg Med Chem Lett. 2019 Feb 15;29(4):601-606. doi: 10.1016/j.bmcl.2018.12.053. Epub 2018 Dec 24.
The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019-0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC = 40->120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.
优化一种具有抗结核作用的硝基呋喃先导化合物（N-苄基-5-硝基呋喃-2-甲酰胺；JSF-3449）的研究，导致了一系列类似物的设计、合成和生物学特征分析。这些化合物对结核分枝杆菌 H37Rv 株具有很强的体外抗结核活性（MIC=0.019-0.20 μM），对 Vero 细胞的体外细胞毒性（CC=40->120 μM）较低。通过引入α，α-二甲基苄基部分，显著提高了化合物在小鼠肝微粒体中的稳定性和小鼠药代动力学特征。在这些化合物中，JSF-4088 因其体外抗结核活性（MIC=0.019 μM）和 Vero 细胞毒性（CC>120 μM）而受到特别关注。这些发现为进一步开发这一系列有前途的抗结核小分子提供了合理的依据。
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