Activity of various thiocarboxanilide derivatives against wild-type and several mutant human immunodeficiency virus...

A large variety of carboxanilide derivates in which the original oxathiin moiety present in the prototype compound UC84 was replaced by a non-cyclic lipophilic entity has been evaluated for their inhibitory effect against wild-type human immunodeficiency virus type 1 (HIV-1/IIIB) and several mutant viruses derived thereof (i.e. HIV-1/138-Lys, HIV-1/181-Cys, HIV-1/106-Ala and HIV-1/100-IIe). Isopropoxy was the most favorable substituent resulting in molecules that were markedly inhibitory to the wild-type (EC50 0.004-0.04 microgram/ml) as well as the mutant HIV-1 strains (EC50 0.06-0.75 microgram/ml). In this respect, they proved superior to several other HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are currently the subject of clinical trials. One of the most potent HIV-1 inhibitors among the thiocarboxanilide derivatives, namely UC38, selected for a mutant virus strain in which Lys at position 101 and Gly at position 190 of the reverse transcriptase was replaced by Glu.