Pyrrolobenzoxazepinone derivatives as non-nucleoside HIV-1 RT inhibitors: Further structure-activity relationship studies and identification of more potent broad-spectrum HIV-1 RT inhibitors with antiviral activity

Pyrrolobenzoxazepinone (PBO) derivatives represent a new class of human imm unodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT ) inhibitors (NNRTs) whose prototype is (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d ][1,5]benzoxazepin-7(6H)-one (6). Docking studies based on the three-dimens ional structure of RT prompted the synthesis and biological evaluation of n ovel derivatives and analogues of 6 featuring a meta-substituted phenyl or a 2-thienyl ring at C-6 and a pyridine system in place of the fused-benzene ring to yield pyrrolopyridoox-azepinones (PPOs). Compared with the lead 6 and nevirapine, several of the synthesized compounds (PBOs 13a-d and PPOs 1 3i-k) displayed higher inhibitory activity against wildtype RT and clinical ly relevant mutant RTs containing the single amino acid substitutions L100I , K103N, V106A, Y181I, and Y188L. The most potent inhibitors were further e valuated for in vitro antiviral activity on lymphocytes and monocyte-macrop hages, for cytotoxicity on a panel of cell lines, and for potential synergi stic antiviral activity with AZT. Pharmacokinetic studies performed on 13b, 13c, and 13i showed that these compounds achieve high concentrations in th e brain. The results of the biological and pharmacokinetic experiments sugg est a potential clinical utility of analogues such as 13b-d, 13i, and 13j, in combination with nucleoside RT inhibitors, against strains of HIV-1 bear ing those mutations that confer resistance to known NNRTI.