The thiocarboxanilides UC-10 and UC-781 have an additive inhibitory effect against human immunodeficiency virus type 1 reverse transcriptase and replication in cell culture when combined with Other antiretroviral drugs

The thiocarboxanilides represent a structural class of potent and selective human immunodeficiency virus type (HIV-1)-specific reverse transcriptase (RT) inhibitors. Combinations of the clinical candidate thiocarboxanilides UC-10 (oxime ether derivative) and UC-781 (pentenyloxy ether derivative) with a variety of nucleoside RT inhibitors (NRTls) and non-nucleoside RT inhibitors (NNRTls), two HIV protease inhibitors and one fusion/uncoating inhibitor were evaluated for their inhibitory effects on HIV-1 RT activity and HIV-1 replication in CEM cell cultures. The inhibitory activity of the NNRTls including UC-10, UC-781, nevirapine, BHAP, alpha-APA, 8-chloro-TIBO, MKC-442 and the quinoxaline HEY 097 against HIV-1 RT was highly dependent on the nature of the template/primer used in the HIV-1 RT reaction. However, fractionary inhibitory concentration (FIC) indexes for all drug concentrations evaluated in the combination experiments of UC-781 and the other NNRTls fell within the range 0.5-1.5. This points to a predominantly additive effect of the thiocarboxanilides and other NNRTls in the inhibition of HIV-1 RT Similar FIC indexes were observed for the combination of UC-781 with the NRTI triphosphates AZT-TP, d4T-TP, ddCTP, ddATP and 3TC-TP and the NRTI diphosphate PMEApp against HIV-1 RT. All these drug combinations showed similar additive inhibitory effects on HIV-1 replication in cell culture. Also, the combinations of UC-10 or UC-781 with the protease inhibitors Ro31-8959/008 and ABT 84538.0 and the fusion/uncoating inhibitor bicyclam JM 3100 showed an additive effect (FIC within the 0.5-1.5 range). Thus, irrespective of the nature of the drugs, their combination with the thiocarboxanilides proved merely additive. In no case were antagonistic anti-HIV activity or increased cytotoxicity observed. In conclusion, thiocarboxanilides combined with a variety of clinically used anti-HIV agents result in additive anti-HIV activity.