☆ 4.7 Article

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

JOURNAL OF MEDICINAL CHEMISTRY (2011)

期刊

JOURNAL OF MEDICINAL CHEMISTRY

卷 54, 期 23, 页码 7974-7985

出版社

AMER CHEMICAL SOC

DOI: 10.1021/jm200766b

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Chemistry, Medicinal

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Tibotec Pharmaceuticals
Centre National de la Recherche Scientifique (CNRS)
Universite Claude Bernard Lyon

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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, Si) 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 2,4 showed a significant EC50 value close to 6.4 nM against HIV-1 IIIB, a moderate EC50 value close to 54 mu M against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC50 > 100 mu M).

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