Synthesis and evaluation of anti-tubercular activity of new dithiocarbamate sugar derivatives
Synthesis and evaluation of anti-tubercular activity of new dithiocarbamate sugar derivatives
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DOI：
10.1016/j.bmcl.2010.12.084
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发表时间：
2011-02-01
影响因子：
2.7
通讯作者：
Onozaki, Kikuo
中科院分区：
文献类型：
--
作者：
Horita, Yasuhiro;Takii, Takemasa;Onozaki, Kikuo
本文对我们以前报道的先导化合物2-乙酰氨基-2-脱氧-β-D-吡喃葡萄糖基N，N-二甲基二硫代氨基甲酸酯（OCT 313，Glc-NAc-DMDC）的抗结核活性进行了优化。OCT 313的结构修饰包括用吡咯烷二硫代氨基甲酸酯（PDTC）替换C-1处的DMDC基团，以及用丙基、丁基、苄基或油酸基团替换C-2处的乙酰基。这些衍生物的抗结核分枝杆菌（MTB）的抗分枝杆菌活性进行了评价。Glc-NAc-吡咯烷二硫代氨基甲酸酯（OCT 313 HK，Glc-NAc-PDTC）具有最强的抗结核活性，其最小抑制浓度（MIC）为6.25-12.5 μ g/ml。OCT 313 HK的抗菌活性对结核分枝杆菌和牛分枝杆菌BCG具有高度特异性，但对鸟分枝杆菌、耻垢分枝杆菌、金黄色葡萄球菌或大肠杆菌没有特异性。重要的是，OCT 313 HK对MTB临床分离株也有效，包括多重耐药（MDR）和广泛耐药（XDR）菌株。有趣的是，OCT 313 HK表现出主要的杀菌活性，并且在高浓度下也表现出溶菌活性。我们接下来研究了分枝杆菌单加氧酶EthA（含硫脲类抗结核药物的常见激活剂）是否也激活了OCT 313 HK。与我们的预期相反，与含硫脲的药物相反，二硫代氨基甲酸酯糖衍生物和二硫代氨基甲酸酯的抗结核活性不依赖于ethA表达。总体而言，这项研究表明OCT 313 HK是一种新的有效的抗MTB化合物，特别有希望克服耐药性。(C)2010爱思唯尔有限公司版权所有。
The present study was undertaken to optimize the anti-tubercular activity of 2-acetamido-2-deoxy-beta-D-glucopyranosyl N,N-dimethyldithiocarbamate (OCT313, Glc-NAc-DMDC), a lead compound previously reported by us. Structural modifications of OCT313 included the replacements of the DMDC group at C-1 by pyrrolidine dithiocarbamate (PDTC) and the acetyl group at C-2 by either propyl, butyl, benzyl or oleic acid groups. The antimycobacterial activities of these derivatives were evaluated against Mycobacterium tuberculosis (MTB). Glc-NAc-pyrrolidine dithiocarbamate (OCT313HK, Glc-NAc-PDTC) exhibited the most potent anti-tubercular activity with the minimal inhibitory concentration (MIC) of 6.25-12.5 mu g/ml. The antibacterial activity of OCT313HK was highly specific to MTB and Mycobacterium bovis BCG, but not against Mycobacterium avium, Mycobacterium smegmatis, Staphylococcus aureus or Escherichia coli. Importantly, OCT313HK was also effective against MTB clinical isolates, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Interestingly, OCT313HK was exerted the primary bactericidal activity, and it was also exhibited the bacteriolytic activity at high concentrations. We next investigated whether the mycobacterial monooxygenase EthA, a common activator of thiocarbamide-containing antitubercular drugs, also activated OCT313HK. Contrary to our expectations, the anti-tubercular activity of dithiocarbamate sugar derivatives and dithiocarbamates were not dependent on ethA expression, in contrast to thiocarbamide-containing drugs. Overall, this study presents OCT313HK as a novel and potent compound against MTB, particularly promising to overcome drug resistance. (C) 2010 Elsevier Ltd. All rights reserved.