PYRROLOBENZOTHIAZEPINONES AND PYRROLOBENZOXAZEPINONES - NOVEL AND SPECIFIC NONNUCLEOSIDE HIV-1 REVERSE-TRANSCRIPTASE INHIBITORS WITH ANTIVIRAL ACTIVITY

Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepin ones were investigated as potential anti-AIDS drugs. These compounds w ere found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appr eciable activity on HIV-2 cytopathic effects, and against HBV as well as calf-thymus DNA alpha-polymerase. Their potency is influenced by su bstituents at position 6 and on the fused aromatic ring. Specifically, small lipophilic substituents at C-6 were preferred, whereas substitu tions on the benzo-fused ring were found to be detrimental to activity , with respect to the unsubstituted compounds. Modification of the pi- system at C-6 is well tolerated, although the replacement of the benzo -fused with a [2,3]naphtho-fused ring leads to a less active compound. Maximum potency and specificity is achieved with a phenyl and an ethy l group at position 6 of the pyrrolobenzoxazepinone system. In the enz ymatic assay the oxazepinone derivative (+/-)-6-ethyl-6-phenylpyrrolo[ 2,1-d][1,5] 16e (IC50 = 0.25 mu M) was found to be more potent than ne virapine (IC50 = 0.5 mu M), tested in the same experimental conditions using rC . dG as a template-primer. In cell culture assay benzoxazepi ne 16e was active against HIV-1, both wild type and AZT-sensitive, and HIV-1 (IIIB) strains, but not against HIV-2. In enzyme assay although 16e inhibited HIV-1 RT, it was inactive against the nevirapine-resist ant recombinant RT Y181C at 50 mu M. Molecular modeling studies sugges t that these derivatives present a 3D pharmacophoric arrangement simil ar to that of other nonnucleoside inhibitors such as nevirapine.