Design, synthesis, and biological evaluation of new 3-hydroxy-2-oxo-3-trifluoromethylindole as potential HIV-1 reverse transcriptase inhibitors
Design, synthesis, and biological evaluation of new 3-hydroxy-2-oxo-3-trifluoromethylindole as potential HIV-1 reverse transcriptase inhibitors
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DOI：
10.1007/s00044-007-9004-0
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发表时间：
2007-01-01
影响因子：
2.6
通讯作者：
de Frugulhetti, Izabel Christina P. P.
中科院分区：
文献类型：
--
作者：
Boechat, Nubia;Kover, Warner B.;de Frugulhetti, Izabel Christina P. P.
三氟甲基（CF 3）存在于各种治疗类别的市售药物中，因为它能够改变并经常改善其生物活性。依法韦仑是一种三氟甲基化的人类免疫缺陷病毒I型（HIV-1）逆转录酶（RT）抑制剂，在抗HIV化疗中显示出良好的效果。本论文以开发高效的非核苷类化合物为目标，设计并合成了几种新型的3-羟基-2-氧代-3-三氟甲基吲哚类逆转录酶抑制剂。我们使用不同的取代靛红作为起始原料。最终产物含有依法韦仑中存在的基团CF 3和药效基团氧代吲哚。我们已经使用分子对接HIV-1 RT作为一种工具，设计推定的非核苷类逆转录酶抑制剂（NNRTI）。在此基础上，合成了一系列新的3-羟基-2-氧代-3-三氟甲基吲哚类化合物。结果表明，这些化合物能够与NNRT结合位点发生重要的相互作用，这鼓励我们将它们提交用于生物测定。研究的所有化合物在RNA依赖性DNA聚合酶（RDDP）测定中均具有显著活性，并且对Vero细胞系无毒性。因此，所设计的分子代表了良好的起始结构，为进一步的修饰和构效关系（SAR）的研究。
The trifluoromethyl group (CF3) is present in commercially available drugs of various therapeutic classes owing to its ability to modify and frequently improve their biological activities. Efavirenz is a trifluoromethylated inhibitor of human immunodeficiency virus type I (HIV-1) reverse transcriptase (RT) that shows good results in anti-HIV chemotherapy. With the objective of developing efficient non-nucleoside compounds, we have designed and synthesized some new 3-hydroxy-2-oxo-3-trifluoromethylindole as potential RT inhibitors. We used different substituted isatins as starting, materials. The final products contain the group CF3, present in Efavirenz, and a pharmacophoric group, oxoindole. We have used molecular docking with HIV-1 RT as a tool to design putative non-nucleoside reverse transcriptase inhibitors (NNRTIs). Based on the calculation results obtained, a series of new 3-hydroxy-2-oxo-3-trifluoromethylindoles were synthesized as a novel class of potential RT inhibitors. The results showed that these compounds are capable of important interactions with the NNRT binding site, which encouraged us to submit them for biological assay. All compounds studied are significantly active in the RNA-dependent DNA-polymerase (RDDP) assay, and were not toxic toward the Vero cell line. Hence, the designed molecules represent good starting structures for further modification and structure-activity relationship (SAR) studies.