Difluoromethylbenzoxazole Pyrimidine Thioether Derivatives: A Novel Class of Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

详细信息    查看全文

• 作者：J茅r茅mie Boyer ; Eric Arnoult ; Maurice M茅debielle ; J茅r么me Guillemont ; Johan Unge ; Dirk Jochmans
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 8, 2011
• 年：2011
• 卷：54
• 期：23
• 页码：7974-7985
• 全文大小：523K
• 年卷期：v.54,no.23(December 8, 2011)
• ISSN：1520-4804

文摘

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_RN1) 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 EC₅₀ value close to 6.4 nM against HIV-1 IIIB, a moderate EC₅₀ value close to 54 渭M against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC₅₀ > 100 渭M).