Abstract
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).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology
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Benzoxazoles / chemical synthesis*
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Benzoxazoles / chemistry
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Benzoxazoles / pharmacology
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Cell Line, Tumor
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HIV Reverse Transcriptase / genetics
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HIV Reverse Transcriptase / metabolism*
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HIV-1 / drug effects
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HIV-1 / genetics
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Humans
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Mutation
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology
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Structure-Activity Relationship
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Sulfides / chemical synthesis*
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Sulfides / chemistry
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Sulfides / pharmacology
Substances
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2-(difluoro-((4-ethylpyrimidinyl)thio)methyl)benzoxazole
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Anti-HIV Agents
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Benzoxazoles
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Pyrimidines
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Reverse Transcriptase Inhibitors
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Sulfides
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase
Associated data
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PDB/2YKM
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PDB/2YKN
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PDB/3MEE