Abstract
A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived HIV-1MF delavirdine-resistant variant.
MeSH terms
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Amino Acid Substitution
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Animals
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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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Cell Line
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Delavirdine / pharmacology*
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Drug Resistance, Microbial
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / genetics
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HIV-1 / drug effects
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HIV-1 / enzymology
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Leucine / genetics
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Mice
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Proline / genetics
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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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Anti-HIV Agents
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Pyrimidines
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Reverse Transcriptase Inhibitors
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Sulfides
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Proline
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Delavirdine
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HIV Reverse Transcriptase
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Leucine