title: Highly favorable antiviral activity and resistance profile of the novel thiocarboxanilide pentenyloxy ether derivatives UC-781 and UC-82 as inhibitors of human immunodeficiency virus type 1 replication.
abstract: The novel human immunodeficiency virus type 1-specific thiocarboxanilide derivatives that contain either a substituted furanyl (UC-781) or thienyl (UC-82) ring linked to the thiocarboxy group and a pentenyloxyether chain linked to the 4-chlorophenyl ring in meta position show highly favorable antiviral properties. Compounds UC-781 and UC-82 discovered by scientists at Uniroyal Chemical Ltd. proved to be > or = 5-10-fold more inhibitory to wild-type human immunodeficiency virus type 1 strains (EC50 approximately 0.002 microgram/ml) than the thiocarboxanilide oxime ether UC-10 and other non-nucleoside reverse transcriptase inhibitors such as nevirapine, bis(heteroaryl)piperazine, and tetrahydroimidazo[4,5,l-jk][1,4]-benzodiazepin-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 (EC50 < or = 0.02 microgram/ml) in suppressing the replication of mutant virus strains that contained mutations in their reverse transcriptase that conferred resistance to other non-nucleoside reverse transcriptase 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). The antiviral activity of the compounds was only slightly affected by the presence of high concentrations of human serum, and the compounds were shown to be highly stable in the presence of human serum for at least 24 hr at room temperature.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: H
authors.initials: H
authors.lastname: Pelemans
authors.forename: S
authors.initials: S
authors.lastname: Aquaro
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: A
authors.initials: A
authors.lastname: Karlsson
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001798:Blood Proteins / Q000378:metabolism; D002478:Cells, Cultured; D020008:Delavirdine; D004351:Drug Resistance; D005663:Furans / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008969:Molecular Sequence Data; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects; D013854:Thioamides; D013876:Thiophenes / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D001798:Blood Proteins; D005663:Furans; D007211:Indoles; D010879:Piperazines; D013854:Thioamides; D013876:Thiophenes; C100669:UC 82; D020008:Delavirdine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; C100668:UC-781