DIARYLSULFONES, A NOVEL CLASS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INTEGRASE INHIBITORS

A majority of reported human immunodeficiency virus type 1 integrase ( HIV-1 IN) inhibitors are polyhydroxylated aromatic compounds containin g two phenyl rings separated by aliphatic or aromatic linkers. Most in hibitors possessing a catechol moiety exhibit considerable toxicity in cellular assays. In an effort to identify nonhydroxylated analogs, a series of aromatic sulfones were tested for their ability to inhibit t he 3' processing and strand transfer steps that are necessary for HIV replication. Several aromatic sulfones have preciously been shown to h ave moderate activity against HIV-1 reverse transcriptase in cellular assays; however, their inhibitory potencies against IN have not been e xplored. In the present study, the inhibitory effect of a series of su lfones and sulfonamides against IN was determined. Among 52 diaryl sul fones tested, 4 were determined to be highly potent (50% inhibitory co ncentration [IC50], 0.8 to 10 mu g/ml), 5 had good potencies (IC50, 11 to 50 mu g/ml), 10 showed moderate potencies (IC50, 51 to 100 mu g/ml ), and 33 were inactive (IC50, > 100 mu g/ml) against IN. All of the a ctive compounds exhibited similar potencies against HIV-2 IN. Sulfa dr ugs, used extensively in treating Pneumocystis carinii pneumonia, a le ading cause of morbidity and mortality in AIDS patients, were also exa mined. Among 19 sulfonamides tested, sulfasalazine (IC50, 50 mu g/ml) was the most potent. We conclude that potent inhibitors of IN can be d esigned based on the results presented in this study.