Structure-Activity Relationships of 1--6-(phenylthio)thymine Analogues: Effect of Substitutions at the C-6 Phenyl Ring and at the C-5 Position on Anti-HIV-1 Activity

Article abstract of DOI:10.1021/jm00080a020

The effect of substitution on the pyrimidine moiety of 1-<(2-hydroxyethoxy)methyl>-6-(phenylthio)thymine (HEPT) and 1-<(2-hydroxyethoxy)methyl>-6-(phenylthio)-2-thiothymine (HEPT-S) on anti-HIV-1 activity was investigated by synthesizing a series of 5-methyl-6-(arylthio) and 5-substituted-6-(phenylthio) derivatives.Preparation of the 5-methyl-6-(arylthio) derivatives was carried out based on either LDA lithiation of 1-<<2-(tert-butyldimethylsiloxy)ethoxy>methyl>thymine (3) and 1-<<2-(tert-butyldimethylsiloxy)ethoxy>methyl>-2-thiothymine (4) followed by reaction with diaryl disulfides or an addition-elimination reaction of 1-<<2-(tert-butyldimethylsiloxy)ethoxy>methyl>-6-(phenylsulfinyl)thymine (31) with aromatic thiols.Preparation of the 5-substituted-6-(phenylthio) derivatives was carried out based on either C-5 lithiation of the 1-<<2-(tert-butyldimethylsiloxy)ethoxy>methyl>-6-(phenylthio)uracil (41) with LTMP or the LDA lithiation of 5-alkyl-1-<<2-(tert-butyldimethylsiloxy)ethoxy>methyl>-2-thiouracil derivatives 45-47.Substitution at the meta position of the C-6-(phenylthio) ring by the methyl group improved the original anti-HIV-1 activity of HEPT, and introduction of two m-methyl groups to the phenylthio ring further potentiated the activity -1-<(hydroxyethoxy)methyl>thymine (28), 0.26 μM; 6-<(3,5-dimethylphenyl)thio>-1-<(2-hydroxyethoxy)methyl>-2-thiothymine (30), 0.22 μM>.When the 5-methyl group was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity of HEPT was also improved remarkably -6-(phenylthio)-2-thiouracil (48), 0.11 μM; 5-isopropyl-1-<(2-hydroxyethoxy)methyl>-6-(phenylthio)-2-thiouracil (50), 0.059 μM; 5-ethyl-1-<(2-hydroxyethoxy)methyl>-6-(phenylthio)-2-thiouracil (54), 0.12 μM; 5-isopropyl-1-<(2-hydroxyethoxy)methyl>-6-(phenylthio)-2-thiouracil (56), 0.063 μM>. 6-<(3,5-Dimethylphenyl)thio>-5-ethyl-1-<(2-hydroxyethoxy)methyl>thymine derivatives 51 and 57 and 6-<(3,5-dimethylphenyl)thio>-5-isopropyl-1-<(2-hydroxyethoxy)methyl>thymine derivatives 52 and 58 inhibited the replication of HIV-1 in the nanomolar concentration range.