HIGHLY FAVORABLE ANTIVIRAL ACTIVITY AND RESISTANCE PROFILE OF THE NOVEL THIOCARBOXANILIDE PENTENYLOXY ETHER DERIVATIVES UC-781 AND UC-82 ASINHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION

The novel human immunodeficiency virus type 1-specific thiocarboxanili de derivatives that contain either a substituted furanyl (UC-781) or t hienyl (UC-82) ring linked to the thiocarboxy group and a pentenyloxye ther chain linked to the 4-chlorophenyl ring in meta position show hig hly favorable antiviral properties. Compounds UC-781 and UC-82 discove red by scientists at Uniroyal Chemical Ltd. proved to be greater than or equal to 5-10-fold more inhibitory to wild-type human immunodeficie ncy virus type 1 strains (EC(50) similar to 0.002 mu g/ml) than the th iocarboxanilide oxime ether UC-10 and other non-nucleoside reverse tra nscriptase inhibitors such as nevirapine, bis(heteroaryl)piperazine, a nd droimidazo[4,5,l-jk][1,4]-benzodiatepin-2(1H)-one. In addition, the compounds were able to knock out virus replication in cell culture at concentrations that were 20-50-fold lower than those of nevirapine or bis(heteroaryl)piperazine. They were also highly efficient (EC(50) le ss than or equal to 0.02 mu g/ml) in suppressing the replication of mu tant virus strains that contained mutations in their reverse transcrip tase that conferred resistance to other non-nucleoside reverse transcr iptase inhibitors (i.e., Tyr181 to Cys, Lys103 to Asn, Val106 to Ala, and Leu100 to Ile). The compounds selected for virus mutants that were only marginally resistant to the thiocarboxanilides (<10-20-fold). Th e antiviral activity of the compounds was only slightly affected by th e presence of high concentrations of human serum, and the compounds we re shown to be highly stable in the presence of human serum for at lea st 24 hr at room temperature.