IDENTIFICATION OF NOVEL THIOCARBOXANILIDE DERIVATIVES THAT SUPPRESS AVARIETY OF DRUG-RESISTANT MUTANT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 STRAINS AT A POTENCY SIMILAR TO THAT FOR WILD-TYPE VIRUS
J. Balzarini et al., IDENTIFICATION OF NOVEL THIOCARBOXANILIDE DERIVATIVES THAT SUPPRESS AVARIETY OF DRUG-RESISTANT MUTANT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 STRAINS AT A POTENCY SIMILAR TO THAT FOR WILD-TYPE VIRUS, Antimicrobial agents and chemotherapy, 40(6), 1996, pp. 1454-1466
A large variety of carboxanilide and thiocarboxanilide derivatives in
which the original oxathiin or aliphatic moieties present in the proto
type compounds UC84 and UC38 were replaced by an (un)substituted furan
yl, thienyl, phenyl, or pyrrole entity have been evaluated for activit
y against wild-type human immunodeficiency virus type 1 strain IIIB [H
IV-1(IIIB)] and a series of mutant virus strains derived thereof. The
mutant viruses contained either the Leu-100-->Ile, Lys-103-->Asn, Val-
106-->Ala, Glu-138-->Lys, Tyr-181-->Cys, or Tyr-188-->, Leu mutation i
n their reverse transcriptase. Several 3-(2-methylfuranyl)- and 3-(2-m
ethylthienyl)-thiocarboxanilide ester, (thio)ether, and oxime ether de
rivatives showed exquisitely potent antiviral activity against wild-ty
pe HIV-1 (50% effective concentration, 0.009 to 0.021 mu M). The pente
nylethers of the 2-methylfuranyl and 2-methylthienyl derivatives (i.e.
, 313, -butenyloxy)phenyl]-2-methyl-3-furancarbothioamide or UC-781, a
nd 313, enyloxy)phenyl]-2-methyl-3-thiophenecarbothioamide or UC-82) p
roved virtually equally inhibitory for wild-type and the Ile-100, Ala-
106, and Lys-138 mutant virus strains (50% effective concentration, 0.
015 to 0.021 mu M), Their inhibitory effect against the Asn-103 and Cy
s-181 reverse transcriptase mutant virus strains,vas decreased only fo
ur- to sevenfold compared with wildtype virus, UC-781 and UC-82 should
be considered potential candidate drugs for the treatment of HIV-1-in
fected individuals.