Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis
Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis
复制标题
DOI：
10.1021/acs.jmedchem.8b01533
复制
发表时间：
2018-12-27
影响因子：
7.3
通讯作者：
Alemparte, Carlos
中科院分区：
文献类型：
--
作者：
Guardia, Ana;Baiget, Jessica;Alemparte, Carlos
社会迫切需要新的、有效的结核病治疗药物。为了启动所需的点击率领先运动，制药公司的图书馆最近被评估为起点。葛兰素史克（GSK）图书馆产生了许多高质量的点击，相关数据被置于公共领域，以刺激更广泛的社区参与。其中一个系列，螺环化合物，在这里描述。这些化合物是通过传统的内部研究和开源方法相结合来探索的。该系列得益于特别简单的结构和短的相关合成化学路线。该系列的许多成员显示出惊人的效力和低毒性，并且用其中一种类似物在小鼠模型中证实了非常有希望的体内活性。最终，由于对安全的担忧，该系列被中断，但相关数据仍然是公共领域，如果可以克服所感知的缺陷，则授权其他人恢复该系列。
Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the Spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.