Structure-Activity Analysis of Vinylogous Urea Inhibitors of Human Immunodeficiency Virus-Encoded Ribonuclease H
Structure-Activity Analysis of Vinylogous Urea Inhibitors of Human Immunodeficiency Virus-Encoded Ribonuclease H
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DOI：
10.1128/aac.00434-10
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发表时间：
2010-09-01
影响因子：
4.9
通讯作者：
Le Grice, Stuart F. J.
中科院分区：
文献类型：
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作者：
Chung, Suhman;Wendeler, Michaela;Le Grice, Stuart F. J.
最近发现，Vinylogous脲类化合物2-氨基-5,6,7,8-四氢- 4h -环庚[b]噻吩-3-carboxamide和N-[3-（氨基羰基）- 4,5-二甲基-2-噻吩基]-2-呋喃羧酰胺（分别为化合物1和2）是HIV-1和HIV-2逆转录酶（RT） RNase H活性的中效抑制剂。这两种化合物共享一个3-CONH(2)-取代的噻吩环，但在其他结构上不相关，这阻碍了药效团的精确定义。因此，我们研究了一系列携带化合物1的噻吩环的酰胺、胺和环烷烃修饰的葡萄状脲。而环庚烷和环己烷取代衍生物保留效力，环戊烷和环辛烷取代消除活性。在环庚烷环存在下，修饰2- nh(2)或3-CONH(2)官能团降低了效价。对于化合物2，研究了二甲基噻吩环含有2- nh(2)和3-CONH(2)功能修饰的葡萄状脲。2- nh(2)修饰的类似物显示出与化合物2相当或更强的效力，其中最活跃的化合物16反映了2- nh(2)和3-CONH(2)基团的分子内环化。利用分子模型确定了p51拇指子结构域的抑制剂结合位点，表明与p66 RNase H结构域催化保守的His539相互作用可能是抑制RNase H活性的基础。总的来说，我们的数据表明，葡萄状脲的多个功能基团有助于它们作为RNase H抑制剂的效力。最后，单分子光谱分析表明，葡萄质脲具有改变逆转录酶取向的特性，可以模拟起始+链DNA合成的模式RNA-DNA杂交。
Vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b] thiophene-3-carboxamide and N-[3-(aminocarbonyl)- 4,5-dimethyl-2-thienyl]-2-furancarboxamide (compounds 1 and 2, respectively) were recently identified to be modestly potent inhibitors of the RNase H activity of HIV-1 and HIV-2 reverse transcriptase (RT). Both compounds shared a 3-CONH(2)-substituted thiophene ring but were otherwise structurally unrelated, which prevented a precise definition of the pharmacophore. We have therefore examined a larger series of vinylogous ureas carrying amide, amine, and cycloalkane modifications of the thiophene ring of compound 1. While cycloheptane-and cyclohexane-substituted derivatives retained potency, cyclopentane and cyclooctane substitutions eliminated activity. In the presence of a cycloheptane ring, modifying the 2-NH(2) or 3-CONH(2) functions decreased the potency. With respect to compound 2, vinylogous ureas whose dimethylthiophene ring contained modifications of the 2-NH(2) and 3-CONH(2) functions were investigated. 2-NH(2)-modified analogs displayed potency equivalent to or enhanced over that of compound 2, the most active of which, compound 16, reflected intramolecular cyclization of the 2-NH(2) and 3-CONH(2) groups. Molecular modeling was used to define an inhibitor binding site in the p51 thumb subdomain, suggesting that an interaction with the catalytically conserved His539 of the p66 RNase H domain could underlie inhibition of RNase H activity. Collectively, our data indicate that multiple functional groups of vinylogous ureas contribute to their potencies as RNase H inhibitors. Finally, single-molecule spectroscopy indicates that vinylogous ureas have the property of altering the reverse transcriptase orientation on a model RNA-DNA hybrid mimicking initiation plus-strand DNA synthesis.