Structure-activity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide.

摘要: A series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide (UC84) were evaluated for activity against human immunodeficiency virus (HIV) determine structural requirements anti-HIV activity. Twenty-seven representative more than 400 Uniroyal Chemical Company (UC) structure-activity relationships. Several highly active, with 50% effective concentrations in nanomolar range and therapeutic indices > 1,000. Highly synergistic was observed each compound when used combination 3'-azido-3'-deoxythymidine; additive slightly interactions dideoxycytidine. In NNRTI costatolide, only UC38 synergistically inhibited HIV type 1. Residues RT which, mutated, impart resistance isolates selected cell culture, variants site-directed mutations, RTs containing defined single amino acid changes. The mutations included changes acids 100, 101, 103, 106, 108, 181. results culture indicate that interact at two vulnerable sites, selecting UC-resistant Y-to-C mutation position 181 (Y181C) or L100I substitution. resistant isolate both Y181C calanolide A, an which retains mutation, UC10 rapidly a K103N mutation. merits potential candidate agents be rational drugs design as part armamentarium active are discussed.