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

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Abstract
The thiocarboxanilides represent a structural class of potent and selective human immunodeficiency virus type 1 (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 (NRTIs) and non-nucleoside RT inhibitors (NNRTIs), 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 NNRTIs including UC-10, UC-781, nevirapine, BHAR α-APA, 8-chloro-TIBO, MKC-442 and the quinoxaline HBY 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 NNRTIs fell within the range 0.5–1.5. This points to a predominantly additive effect of the thiocarboxanilides and other NNRTIs 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.

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