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

J. Balzarini, H. Pelemans, S. Aquaro, C. F. Perno, M. Witvrouw, D. Schols, E. De Clercq, A. Karlsson

Research output: Contribution to journalArticle

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 ≤5-10-fold more inhibitory to wild-type human immunodeficiency virus type 1 strains (EC50 ~0.002 μg/ml) than the thiocarboxanilide oxime ether UC-10 and other non-nucleoside reverse transcriptase inhibitors such as nevirapine, his(heteroaryl)piperazine, and tet rahydroimidazo[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 ≤ 0.02 μg/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 (

Original languageEnglish
Pages (from-to)394-401
Number of pages8
JournalMolecular Pharmacology
Volume50
Issue number2
Publication statusPublished - Aug 1996

ASJC Scopus subject areas

  • Pharmacology

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