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.