Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Bioorg Med Chem Lett. 2011 Feb 1;21(3):899-903. doi: 10.1016/j.bmcl.2010.12.084. Epub 2010 Dec 22.
The present study was undertaken to optimize the anti-tubercular activity of 2-acetamido-2-deoxy-β-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 μg/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 anti-tubercular 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.
本研究旨在优化我们之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盐（OCT313，Glc-NAc-DMDC）的抗结核活性。OCT313 的结构修饰包括用吡咯烷二硫代氨基甲酸盐（PDTC）取代 C-1 上的 DMDC 基团，用丙基、丁基、苄基或油酸基团取代 C-2 上的乙酰基。这些衍生物的抗分枝杆菌活性针对结核分枝杆菌（MTB）进行了评估。Glc-NAc-吡咯烷二硫代氨基甲酸盐（OCT313HK，Glc-NAc-PDTC）表现出最强的抗结核活性，最小抑菌浓度（MIC）为 6.25-12.5μg/ml。OCT313HK 的抗菌活性高度特异于 MTB 和牛分枝杆菌 BCG，但对鸟分枝杆菌、耻垢分枝杆菌、金黄色葡萄球菌和大肠杆菌没有活性。重要的是，OCT313HK 对 MTB 临床分离株也有效，包括耐多药（MDR）和广泛耐药（XDR）菌株。有趣的是，OCT313HK 主要发挥杀菌活性，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 是否也能激活 OCT313HK，EthA 是一种常见的含硫代酰胺类抗结核药物的激活剂。与我们的预期相反，二硫代氨基甲酸盐糖衍生物和二硫代氨基甲酸盐的抗结核活性不依赖于 ethA 表达，而与含硫代酰胺类药物相反。总的来说，这项研究提出了 OCT313HK 作为一种针对 MTB 的新型有效化合物，特别是有希望克服耐药性。
