Efficient Synthesis and Anti-Tubercular Activity of a Series of Spirocycles: An Exercise in Open Science.
Efficient Synthesis and Anti-Tubercular Activity of a Series of Spirocycles: An Exercise in Open Science.
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DOI：
10.1371/journal.pone.0111782
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Todd MH
中科院分区：
文献类型：
--
作者：
Badiola KA;Quan DH;Triccas JA;Todd MH
全球估计有 20 亿人受结核病困扰，每年导致 130 万人死亡。化疗解决方案依赖于多年前开发的药物，过去 40 年来仅批准了一种新疗法。鉴于耐药菌株的增加，迫切需要开发更强大的药物开发管道。葛兰素史克 (GlaxoSmithKline) 最近将 177 种新型抗结核先导化合物的结构和活性以及其中一些系列的持续优化结果公开。由于许多化合物来自筛选活动，其来源尚不清楚，并且在许多情况下合成路线并未报告。在这里，我们展示了使用 oxa-Pictet-Spengler 反应有效合成 GSK 化合物一族（称为“Spiros”）的几种新型类似物。从药物化学的角度来看，这些新化合物很有吸引力，其中一些对强毒菌株具有有效作用，表明此类化合物值得进一步研究。该研究是使用开源方法进行的，为社区提供了对所有原始实验数据的实时完全访问。
Tuberculosis afflicts an estimated 2 billion people worldwide and causes 1.3 million deaths annually. Chemotherapeutic solutions rely on drugs developed many years ago, with only one new therapeutic having been approved in the last 40 years. Given the rise of drug-resistant strains, there is an urgent need for the development of a more robust drug development pipeline. GlaxoSmithKline recently placed the structures and activities of 177 novel anti-tubercular leads in the public domain, as well as the results of ongoing optimisation of some of the series. Since many of the compounds arose from screening campaigns, their provenance was unclear and synthetic routes were in many cases not reported. Here we present the efficient synthesis of several novel analogues of one family of the GSK compounds—termed “Spiros”—using an oxa-Pictet–Spengler reaction. The new compounds are attractive from a medicinal chemistry standpoint and some were potent against the virulent strain, suggesting this class is worthy of further study. The research was carried out using open source methodology, providing the community with full access to all raw experimental data in real time.
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影响因子：
6.6
作者：
MCCALLUM, C;PETHYBRIDGE, AD
通讯作者：
PETHYBRIDGE, AD
影响因子：
3.6
作者：
AbdelMagid, AF;Carson, KG;Shah, RD
通讯作者：
Shah, RD
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Grzegorzewicz, Anna E.;Ha Pham;Gundi, Vijay A. K. B.;Scherman, Michael S.;North, Elton J.;Hess, Tamara;Jones, Victoria;Gruppo, Veronica;Born, Sarah E. M.;Kordulakova, Jana;Chavadi, Sivagami Sundaram;Morisseau, Christophe;Lenaerts, Anne J.;Lee, Richard E.;McNeil, Michael R.;Jackson, Mary
通讯作者：
Jackson, Mary
影响因子：
4
作者：
Stanley, Sarah A.;Grant, Sarah Schmidt;Kawate, Tomohiko;Iwase, Noriaki;Shimizu, Motohisa;Wivagg, Carl;Silvis, Melanie;Kazyanskaya, Edward;Aquadro, John;Golas, Aaron;Fitzgerald, Michael;Dai, Huanqin;Zhang, Lixin;Hung, Deborah T.
通讯作者：
Hung, Deborah T.
影响因子：
4.9
作者：
Tahlan, Kapil;Wilson, Regina;Boshoff, Helena I.
通讯作者：
Boshoff, Helena I.