A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis
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DOI：
10.1038/35016103
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发表时间：
2000-06-22
期刊：
影响因子：
64.8
通讯作者：
Baker, WR
中科院分区：
文献类型：
--
作者：
Stover, CK;Warrener, P;Baker, WR
导致结核病的结核分枝杆菌是全世界最大的单一传染性死亡原因，每年造成约200万人死亡（1）。据估计，世界上有三分之一的人口感染了潜伏的M。肺结核2例。结核病和艾滋病流行之间的协同作用（3-5），以及多重耐药临床分离的M。结核病再次确认结核病是主要的公共卫生威胁。然而，具有新作用机制的新抗结核药物在三十多年来一直没有开发出来。本文报道了一系列具有抗结核活性的含硝基咪唑并吡喃核的化合物。在通过依赖于M的机制激活后。结核杆菌F420辅因子、硝基咪唑并吡喃抑制蛋白质和细胞壁脂质的合成。与目前的抗结核药物相比，硝基咪唑并吡喃对复制型和静止型结核分枝杆菌都表现出杀菌活性。结核先导化合物PA-824对多重耐药M.结核病和有前途的口服活性的动物感染模型。我们的结论是，硝基咪唑并吡喃类化合物提供了一种具有治疗结核病潜力的小分子的实用品质。
Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually(1). Estimates indicate that one-third of the world population is infected with latent M. tuberculosis(2). The synergy between tuberculosis and the AIDS epidemic(3-5), and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrug-resistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis.