Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).
A series of 33 N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (1, HEPT) were synthesized and evaluated for their anti-HIV-1 activity. In particular, the influence of substitution of the terminal hydroxy group of the acyclic structure of HEPT and the structural rigidity of this side chain were investigated. Halo (7, 8), azido (9), and amino (10-15) derivatives were synthesized from HEPT via the p-tosylate derivative 6. Acylation of the primary amine 15 afforded the amido analogs 16-20. The diaryl derivatives 26-29 were prepared by reaction of HEPT, or of the 6-(2-pyridylthio) analog 23, with diaryl disulfides in the presence of tri-n-butylphosphine. Compounds 39-41, in which the N-1 side chain is rigidified by incorporation of an E-configured double bond, were obtained by palladium(0)-catalyzed coupling of several different 6-(arylthio)uracil derivatives (37, 38) with allyl acetates 33. Compounds 13, 40a,c,d,f, and 41, incorporating an aromatic ring at the end of the acyclic side chain, were found to be more potent than the known diphenyl-substituted HEPT analog BPT (2), two of them, 40c,d, being 10-fold more active.
Pontikis
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Institut Curie, Section Recherche, UMR CNRS 176, Paris, France.
Benhida
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Aubertin
A M
AM
Grierson
D S
DS
Monneret
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C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
C106589:5-ethyl-1-(3-(2-furyl)prop-2-en-1-yl)-6-(phenylthio)uracil; C106590:5-ethyl-6-(phenylthio)-1-(3-(2-thienyl)prop-2-en-1-yl)uracil; C106591:6-((3,5-dimethylphenyl)thio)-5-ethyl-1-(3-(2-furyl)prop-2-en-1-yl)uracil; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D014498:Uracil; D054303:HIV Reverse Transcriptase