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 deriv atives with both arylthio and alkoxy moieties were prepared. These novel py rimidines share chemical similarities with DABOs and HEPTs, two classes of nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcrip tase inhibitors (NNRTIs), which have been widely studied of late. All new d erivatives were tested in MT-4 cells to explore their potential in vivo ant i-HIV activity. Like other NNRTIs, they selectively inhibit HIV-1 but not H IV-2. The majority of test derivatives were found to have low potency and w ere sometimes more cytotoxic than zidovudine and emivirine (formerly MKC-44 2), 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 proven that these derivatives target RT. Struct ure-activity relationship studies established a correlation between the ant i-HIV-l activity and the meta substitution on the phenyl ring; furthermore, oxidation of sulphide to sulphone significantly increased the potency of c ertain derivatives.