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
J. Balzarini et al., 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, Antiviral chemistry & chemotherapy, 6(3), 1995, pp. 169-178
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