Identification of novel thiocarboxanilide derivatives that suppress a variety of drug-resistant mutant human immunodeficiency virus type 1 strains at a potency similar to that for wild-type virus

Abstract

A large variety of carboxanilide and thiocarboxanilide derivatives in which the original oxathiin or aliphatic moieties present in the prototype compounds UC84 and UC38 were replaced by an (un) substituted furanyl, thienyl, phenyl, or pyrrole entity have been evaluated for activity against wild-type human immunodeficiency virus type 1 strain IIIB [HIV-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 in their reverse transcriptase. Several 3-(2-methylfuranyl)- and 3-(2-methylthienyl)-thiocarboxanilide ester, (thio)ether, and oxime ether derivatives showed exquisitely potent antiviral activity against wild-type HIV-1 (50% effective concentration, 0.009 to 0.021 microM). The pentenylethers of the 2-methylfuranyl and 2-methylthienyl derivatives (i.e., 313, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]- 2-methyl-3-furancarbothioamide or UC-781, and 314, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl] -2-methyl-3-thiophenecarbothioamide or UC-82) proved 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 microM). Their inhibitory effect against the Asn-103 and Cys-181 reverse transcriptase mutant virus strains was decreased only four- to sevenfold compared with wildtype virus. UC-781 and UC-82 should be considered potential candidate drugs for the treatment of HIV-1-infected individuals.

Crystal Structures of HIV-1 Reverse Transcriptases Mutated at Codons 100, 106 and 108 and Mechanisms of Resistance to Non-nucleoside Inhibitors

“…For Val106Ala: nevirapine (62-fold); 26,29 UC-781 (twofold). 13,28,30 For Val108Ile: nevirapine (tenfold). 27,28,31 We are undertaking systematic studies of the structures of HIV-1 RTs containing mutations that give resistance to NNRTIs in order to allow further understanding of mechanisms of drug resistance.…”

Crystal Structures of HIV-1 Reverse Transcriptase in Complex with Carboxanilide Derivatives,

“…† Although two NNIs (nevirapine and delavirdine) are currently used in anti-HIV combination therapies (11,12), problems with the selection of drug-resistant mutant HIV RT mean that efforts continue to develop NNIs which are able to inhibit mutant forms of the enzyme. The (thio)-carboxanilide compounds (13,14), represent one series of "second generation" NNIs, while other examples are the quinoxalines (15) and the benzoxazin-2-ones (16).…”

Preclinical evaluation of UC781 microbicide vaginal drug delivery

“…As such, it is a potent inhibitor of HIV-1 replication in cell culture systems [1,2]. The compound inhibits HIV-1 strains resistant to nucleoside reverse transcriptase inhibitors with a potency similar to that used for inhibition of wild-type virus [3].…”