SYNTHESIS AND ANTI-HIV ACTIVITY OF 2-SUBSTITUTED, 3-SUBSTITUTED, AND 4-SUBSTITUTED ANALOGS OF 1-[(2-HYDROXYETHOXY)METHYL]-6-(PHENYLTHIO)THYMINE (HEPT)

Several analogues of a new lead for anti-HIV-1 agents, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), in which the C-2, N-3, or C-4 position was modified were synthesized. These involve 2-thiothymine (11), 2-thiouracil (12), 4-thiothymine (17), 4-thiouracil (18), 5-methylcytosine (27), and cytosine (28) derivatives. Preparation of N-3-substituted derivatives (29 and 30) of HEPT was also carried out. Among these analogues, compound 11 exhibited excellent activity against HIV-1 HTLV-III(B) strain with an EC50 value of 0.98-mu-M, which is 7-fold more potent than that of HEPT. Removal of the 5-methyl group in compound 11 results in total loss of activity. Other compounds did not show any anti-HIV-1 activity. The 4-thio derivatives 17 and 18 were found to be rather cytotoxic. When compound 11 was evaluated for its inhibitory effects on another HIV-1 strain, HTLV-III(RE), and two HIV-2 strains, LAV-2ROD and LAV-2EHO, it proved equally inhibitory to HTLV-III(RF), whereas both HIV-2 strains were insensitive to the compound.