Synthesis of 6-(3,5-dichlorobenzyl) derivatives as isosteric analogues of the HIV drug 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil (GCA-186).
The HIV-1 inhibitors described in this paper is closely related to 6-(3,5-dimethylbenzyl)-1-(ethoxy methyl)-5-isopropyluracil (GCA-186) an anti-HIV-1 drug that is highly active against both wild type and mutated HIV-1 strains. The two methyl groups on the 6-benzyl moiety have been shown to improve the binding stability of the drug to the NNRTI-binding site in reverse transcriptase of drug mediated mutant HIV-1 viruses. The methyl groups are replaced with isosteric chloro-atoms to avoid metabolism due to the two methyl groups. However, the isosteric chloro derivatives show tenfold less activity against HIV-1 than their corresponding methyl derivatives. The synthesis and the antiviral activities of the corresponding 1-(allyloxy- and indanyloxy)methyl-6-(3,5-dichlorobenzyl)-5-ethyluracil derivatives are also reported.
Sørensen
Esben R
ER
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Odense M, Denmark.
El-Brollosy
Nasser R
NR
Jørgensen
Per T
PT
Pedersen
Erik B
EB
Nielsen
Claus
C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007536:Isomerism; D008826:Microbial Sensitivity Tests / Q000379:methods; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
C510377:6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil; D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil