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

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.