Cesarini Sara, Spallarossa Andrea, Ranise Angelo, Fossa Paola, La Colla Paolo, Sanna Giuseppina, 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):4160-72. doi: 10.1016/j.bmc.2007.12.050. Epub 2007 Dec 25.
In order to expand the structure-activity relationship (SAR) studies on Thiocarbamates (TCs), a recently discovered class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 38 analogues of the lead O-[2-(2-pyridyl)ethyl]-N-phenylthiocarbamate 1 were prepared by parallel solution-phase synthesis. The SAR strategy was focused on the variation (mono- and disubstitution) of the N-phenyl ring and the replacement of the 2-pyridyl with 4-pyridyl, 2-thienyl and phenyl rings. The majority of the new TCs proved to prevent the wild-type HIV-1 multiplication in MT-4 cell culture and the most potent congeners displayed an EC(50) value of 100 nM. Two TCs were active also at micromolar concentrations against the Y181C- and/or K103N/Y181C-resistant mutants. Docking simulations helped to rationalize the SARs.
为了扩展对硫代氨基甲酸盐（TCs）的构效关系（SAR）研究，硫代氨基甲酸盐是最近发现的一类强效非核苷HIV-1逆转录酶抑制剂，通过平行溶液相合成制备了先导化合物O-[2-(吡啶-2-基)乙基]-N-苯基硫代氨基甲酸盐1的38种类似物。SAR策略集中在N-苯环的变化（单取代和双取代）以及用吡啶-4-基、噻吩-2-基和苯环取代吡啶-2-基。大多数新的TCs被证明能阻止MT-4细胞培养中野生型HIV-1的增殖，最有效的同系物显示出100 nM的EC(50)值。两种TCs在微摩尔浓度下对Y181C和/或K103N/Y181C耐药突变体也有活性。对接模拟有助于合理化构效关系。
