Université de Lyon, Université Claude Bernard Lyon 1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR CNRS-UCBL-INSA, Equipe Synthèse de Molécules d'Intérêt Thérapeutique, Bâtiment Curien, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.
J Med Chem. 2011 Dec 8;54(23):7974-85. doi: 10.1021/jm200766b. Epub 2011 Nov 4.
This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, S(RN)1) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 24 showed a significant EC(50) value close to 6.4 nM against HIV-1 IIIB, a moderate EC(50) value close to 54 μM against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC(50) > 100 μM).
本文报道了新型二氟甲基苯并恶唑（DFMB）嘧啶硫醚衍生物的合成及其作为非核苷 HIV-1 逆转录酶抑制剂的抗病毒性质。通过结构生物学研究和传统药物化学的结合，我们使用单电子转移链过程（自由基亲核取代，S(RN)1）合成了该新型类别的几个成员，并发现它们对野生型 HIV-1 逆转录酶具有很强的抑制作用，细胞毒性低，但对耐药株的活性中等。最有前途的化合物 24 对 HIV-1 IIIB 的 EC(50)值接近 6.4 nM，对 NNRTI 耐药的双突变体（K103N + Y181C）的 EC(50)值接近 54 μM，但选择性指数 >15477（CC(50) > 100 μM）。
