Structure-Activity Relationship Studies on Potential Non-Nucleoside DABO-Like Inhibitors of HIV-1 Reverse Transcriptase

Using 2,6-dichloro-4-aminopyrimidine, a number of uracil and cytosine derivatives with both arylthio and alkoxy moieties were prepared. These novel pyrimidines share chemical similarities with DABOs and HEPTs, two classes of nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors (NNRTIs), which have been widely studied of late. All new derivatives were tested in MT-4 cells to explore their potential in vivo anti-HIV activity. Like other NNRTIs, they selectively inhibit HIV-1 but not HIV- 2. The majority of test derivatives were found to have low potency and were sometimes more cytotoxic than zidovudine and emivirine (formerly MKC-442), used here as reference drugs. Uracil and cytosine derivatives bearing a sec-butoxy chain and a methyl-substituted benzenesulphonyl moiety were the most potent. Enzyme assays proved that these derivatives target RT. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the meta substitution on the phenyl ring; furthermore, oxidation of sulphide to sulphone significantly increased the potency of certain derivatives.