STRUCTURE-ACTIVITY AND CROSS-RESISTANCE EVALUATIONS OF A SERIES OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE 1-SPECIFIC COMPOUNDS RELATED TO OXATHIIN CARBOXANILIDE

A series of compounds related to the nonnucleoside reverse transcripta se (RT) inhibitor (NNRTI) oxathiin carboxanilide (UC84) were evaluated for activity against the human immunodeficiency virus (HIV) to determ ine structural requirements for anti-HN activity, Twenty-seven compoun ds representative of the more than 400 Uniroyal Chemical Company (UC) compounds were evaluated for structure-activity relationships. Several of the compounds evaluated were highly active, with 50% effective con centrations in the nanomolar range and therapeutic indices of > 1,000. Highly synergistic anti-HIV activity was observed for each compound w hen used in combination with 3'-azido-3'-deoxythymidine; additive to s lightly synergistic interactions were observed with the compounds used in combination with dideoxycytidine. In combination with the NNRTI co statolide, only UC38 synergistically inhibited HIV type 1. Residues in the RT which, when mutated, impart resistance to the carboxanilide co mpounds were defined by evaluation of the UC compounds against a panel of NNRTI-resistant virus isolates selected in cell culture, against v irus variants with site-directed mutations, and against RTs containing defined single amino acid changes. The mutations included changes in RT amino acids 100, 101, 103, 106, 108, and 181. The results with isol ates selected in cell culture indicate that the carboxanilide compound s interact with the RT at two vulnerable sites, selecting UC resistant virus isolates,vith the Y-to-C mutation at position 181 (Y181C) or th e L100I substitution. A resistant virus isolate containing both Y181C and K101E amino acid changes and another with both Y181C and V106A mut ations were isolated. In combination with calanolide A, an NNRTI which retains activity against virus isolates with the single Y181C mutatio n, UC10 rapidly selected a virus isolate,vith the K103N mutation. The merits of selecting potential candidate anti-HIV agents to be used in rational combination drug design as part of an armamentarium of highly active anti-HIV compounds are discussed.