Cesarini Sara, Spallarossa Andrea, Ranise Angelo, Bruno Olga, La Colla Paolo, Secci Barbara, Collu Gabriella, Loddo Roberta
Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy.
Bioorg Med Chem. 2008 Apr 1;16(7):4173-85. doi: 10.1016/j.bmc.2007.12.046. Epub 2007 Dec 25.
To acquire further insight into the structure-activity relationship (SAR) of the thiocarbamates (TCs) described in the preceding work, 57 analogues of the lead compound O-(2-phenylethyl)-N-phenylthiocarbamate I were prepared by parallel solution-phase synthesis. We varied the 2-phenylethyl moiety (mono-substitution on the phenyl ring and modification of the ethyl linker), keeping constant the N-phenyl ring substitutions which have given the best results in the previous series. Most of the new TCs inhibited wild-type HIV-1 at micro- and nanomolar concentrations in MT-4 cell-based assays. Some TCs were also active at micromolar concentrations against the Y181C and/or K103N/Y181C resistant mutants. The SARs were rationalized by docking simulations.
为了进一步深入了解前作中描述的硫代氨基甲酸盐（TCs）的构效关系（SAR），通过平行溶液相合成制备了先导化合物O-(2-苯乙基)-N-苯基硫代氨基甲酸盐I的57种类似物。我们改变了2-苯乙基部分（苯环上的单取代和乙基连接基的修饰），同时保持N-苯环取代不变，在前一系列中这些取代取得了最佳结果。在基于MT-4细胞的试验中，大多数新的TCs在微摩尔和纳摩尔浓度下抑制野生型HIV-1。一些TCs在微摩尔浓度下对Y181C和/或K103N/Y181C耐药突变体也有活性。通过对接模拟对构效关系进行了合理化分析。
