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Difluoromethylbenzoxazole Pyrimidine Thioether Derivatives: A Novel Class of Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors
Ist Teil von
Journal of medicinal chemistry, 2011-12, Vol.54 (23), p.7974-7985
Ort / Verlag
United States: American Chemical Society
Erscheinungsjahr
2011
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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, SRN1) 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 μM against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC50 > 100 μM).