OXATHIIN CARBOXANILIDE DERIVATIVES - A CLASS OF NONNUCLEOSIDE HIV-1-SPECIFIC REVERSE-TRANSCRIPTASE INHIBITORS (NNRTIS) THAT ARE ACTIVE AGAINST MUTANT HIV-1 STRAINS RESISTANT TO OTHER NNRTIS

The HIV-1-specific oxathlin carboxanilide derivative 1-methylethyl 2-m ethyl-1,4-oxathiin-3-yl)carbonyl]amino]benzoate (NSC 615985) (designat ed UC84) has potent activity against HIV-1(IIIB) (50% effective concen tration: 0.015 mu g ml(-1)). UC84 was found to select for a 138-Lys mu tant virus strain in HIV-1-infected CEM cell cultures, When the 138-Ly s mutation was introduced solely in the p51 subunit of the p51/p66 rev erse transcriptase (RT) heterodimer by site-directed mutagenesis, the enzyme proved 10-fold more resistant to UC84 than when the amino acid mutation was introduced solely in the p66 subunit of the p51/p66 RT he terodimer. These data provided clear evidence for a structural and fun ctional role of the p51 subunit in the sensitivity/resistance of the e nzyme to UC84. UC84 also proved to be virtually inactive against mutan t HIV-1 strains containing the 100-Ile, 106-Ala, 138-Lys or 181-Cys mu tation in their RT, However, minor structural changes in the molecule, such as replacement of the oxygen of the amide moiety by sulfur, or t he isopropyl ester moiety by cyclopentyl or a secondary butyl, or the methyl group of the oxathiin part by ethyl, made the compound markedly more inhibitory to one or several HIV-1 mutant strains, For example, compound 131 (1-methylethyl thyl-1,4-oxathiin-3-yl)thioxomethyl]amino] benzoate was only 2-fold more active than the parent compound UC84 aga inst wild-type HIV-1, but 30- to 100-fold more inhibitory to HIV-1 mut ant strains that contained the