A DIARYLSULPHONE NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR WITH AUNIQUE SENSITIVITY PROFILE TO DRUG-RESISTANT VIRUS ISOLATES

Structure-activity relationship evaluations with a series of diarylsul phone non-nucleoside reverse transcriptase (RT) inhibitors indicated t hat the steric properties of the molecule and compound lipophilicity p rimarily contributed to the overall level of activity of the compounds against human immunodeficiency virus type 1 (HIV-1). The most active compounds in the diarylsulphone series had an orthonitro group and yie lded anti-HIV activity at sub-micromolar concentrations, Compounds of the diarylsulphone class exhibited antiviral properties similar to oth er members of the pharmacologic class of HIV-1 specific nonnucleoside reverse transcriptase inhibitors, including activity in a wide variety of established and primary human cells, activity against a wide varie ty of laboratory and clinical virus isolates, and activity when challe nged at high multiplicity of infection. Synergistic inhibition of HIV- 1 was observed when the diarylsulphone NSC 667952 was used with the nu cleoside analogues AZT, ddl, 3TC and d4T, the protease inhibitor KNI 2 72 and the sulphonated dye resobene; additive effects were observed wh en NSC 667952 was used with the nucleoside analogue ddC and other non- nucleoside RT inhibitors. The diarylsulphones exhibited a unique sensi tivity profile when evaluated against both virus isolates and purified reverse transcriptase containing non-nucleoside reverse transcriptase inhibitor resistance-engendering mutations. Unlike other members of t he class of nonnucleoside compounds, NSC 667952 remained active agains t virus isolates with the L100I amino acid change in the RT, The compo und was, however, highly sensitive to Y181C, K103N and K101E amino aci d changes in the RT. The diarylsulphone selected for resistant virus p opulations which possessed the Y181C amino acid change in the reverse transcriptase and which exhibited enhanced sensitivity to the non-nucl eoside inhibitors calanolide A and costatolide.