Novel Pyrimidines as Antitubercular Agents
Novel Pyrimidines as Antitubercular Agents
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DOI：
10.1128/aac.02063-17
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发表时间：
2018-03-01
影响因子：
4.9
通讯作者：
Freundlich, Joel S.
中科院分区：
文献类型：
--
作者：
Inoyama, Daigo;Paget, Steven D.;Freundlich, Joel S.
结核分枝杆菌感染是导致全球大流行的原因。需要与现有一线治疗药物不显示交叉耐药性的新药。一个三嗪类抗结核药物的成功导致了一个相关嘧啶家族的设计。这些类似物的集中系列的合成促进了它们的体外活性、体外细胞毒性以及理化和吸收-分布-代谢-排泄特性的探索。然后评价所选嘧啶在小鼠中的药代动力学特征。这些发现为进一步发展这一系列有前途的抗结核小分子提供了理论基础，这些小分子似乎与临床化合物PA-824在活化方面有一些相似之处，同时突出了优化小分子抗结核药物的更一般性指南。
Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of smallmolecule antitubercular agents.