Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents.
Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents.
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DOI：
10.1021/ja311058q
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发表时间：
2013-03-06
影响因子：
15
通讯作者：
Miller, Marvin J.
中科院分区：
文献类型：
--
作者：
Tiwari, Rohit;Moraski, Garrett C.;Krchnak, Viktor;Miller, Patricia A.;Colon-Martinez, Mariangelli;Herrero, Eliza;Oliver, Allen G.;Miller, Marvin J.
多药耐药（MDR）和广泛耐药（XDR）形式的结核病（TB）的发展刺激了全球范围内的研究工作，以扩大新的药物管道。硝基芳香族化合物，包括1，3-苯并噻嗪-4-酮（BTZ）及其相关药物，是一类有前途的新型结核病治疗药物。研究表明，体内产生的BTZ亚硝基中间体会导致十戊烯基磷酰基-β-D-核糖2 '氧化酶（DprE 1）的自杀抑制，该氧化酶负责细胞壁阿拉伯半乳聚糖的生物合成。我们设计并合成了新型抗结核药物，灵感来自BTZ和其他硝基芳香族化合物。计算结果表明，BTZ 043及相关硝基芳香族化合物中未取代的芳香碳是最缺电子的，可能更容易受到亲核攻击。我们对BTZ 043和我们和其他人合成的其他硝基芳香族化合物的化学研究证实了假设的反应性。结果表明，亲核试剂，如硫醇盐，氰化物和氢化物诱导非酶还原的硝基在这些化合物中存在的相应的亚硝基中间体通过在这些化合物中存在的未取代的缺电子的芳香族碳加成。此外，我们在这里证明，这些化合物是很好的候选人的经典冯里希特反应。这些化学研究为硝基芳族抗TB剂的作用机制提供了替代假设，其中DprE 1活性位点处的半胱氨酸硫醇（酯）或氢化物源可以以类似于von Richter反应的方式引发硝基还原为亚硝基中间体，从而引发DprE 1的抑制。
The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitro aromatic compounds, including 1, 3-Benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-β-D-ribose 2′ oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitro aromatic compounds synthesized by us and the others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide and hydride induce non-enzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron deficient aromatic carbon present in these compounds. Furthermore we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypotheses for the mechanism of action of nitro aromatic anti-TB agents in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1.
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影响因子：
3.6
作者：
Adam, W;Krebs, O;Vougioukalakis, GC
通讯作者：
Vougioukalakis, GC
DOI：
10.1039/ct9211900768
发表时间：
1921-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY
影响因子：
--
作者：
Haworth, RD;Lapworth, A
通讯作者：
Lapworth, A
影响因子：
3.6
作者：
AbdelMagid, AF;Carson, KG;Shah, RD
通讯作者：
Shah, RD
影响因子：
1.8
作者：
Fukuyama, T;Cheung, M;Kan, T
通讯作者：
Kan, T
影响因子：
5.1
作者：
EYER, P
通讯作者：
EYER, P