University of Kansas Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
J Med Chem. 2012 Apr 12;55(7):3319-30. doi: 10.1021/jm300021v. Epub 2012 Mar 22.
A screen for hepatitis C virus (HCV) NS3 helicase inhibitors revealed that the commercial dye thioflavine S was the most potent inhibitor of NS3-catalyzed DNA and RNA unwinding in the 827-compound National Cancer Institute Mechanistic Set. Thioflavine S and the related dye primuline were separated here into their pure components, all of which were oligomers of substituted benzothiazoles. The most potent compound (P4), a benzothiazole tetramer, inhibited unwinding >50% at 2 ± 1 μM, inhibited the subgenomic HCV replicon at 10 μM, and was not toxic at 100 μM. Because P4 also interacted with DNA, more specific analogues were synthesized from the abundant dimeric component of primuline. Some of the 32 analogues prepared retained ability to inhibit HCV helicase but did not appear to interact with DNA. The most potent of these specific helicase inhibitors (compound 17) was active against the replicon and inhibited the helicase more than 50% at 2.6 ± 1 μM.
一种丙型肝炎病毒 (HCV) NS3 解旋酶抑制剂的筛选发现,商用染料硫黄素 S 是国家癌症研究所 827 种化合物机械组中最有效的 NS3 催化 DNA 和 RNA 解链抑制剂。硫黄素 S 和相关染料普魯啉在这里被分离成它们的纯成分,都是取代苯并噻唑的寡聚物。最有效的化合物 (P4) 是一个苯并噻唑四聚体,在 2 ± 1 μM 时抑制解链超过 50%,在 10 μM 时抑制亚基因组 HCV 复制子,在 100 μM 时没有毒性。因为 P4 也与 DNA 相互作用,所以从普魯啉丰富的二聚体成分中合成了更具特异性的类似物。所制备的 32 个类似物中的一些保留了抑制 HCV 解旋酶的能力,但似乎不与 DNA 相互作用。这些特异性解旋酶抑制剂中最有效的一种(化合物 17)对复制子有效,在 2.6 ± 1 μM 时抑制解旋酶超过 50%。