Structure-based design, synthesis, and biological evaluation of navel pyrrolyl aryl sulfones: HIV-1 non-nucleoside reverse transcriptase inhibitors active at nanomolar concentrations

Pyrrolyl aryl sulfones (PASs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inh ibitors acting at the non-nucleosicie binding site of this enzyme (Artico, M.; et al. J. Med. Chem. 1996, 39, 522-530). Compound 3, the most patent in hibitor within the series (EC50 = 0.14 mu M, IC50 = 0.4 mu M, and SI > 1429 ), was then selected as a lead compound for a synthetic project based on mo lecular modeling studies. Using the three-dimensional structure of RT cocry stallized with the alpha-APA derivative R95845, we derived a model of the R T/3 complex by taking into account previously developed structure-activity relationships. Inspection of this model and docking calculations on virtual compounds prompted the design of novel PAS derivatives and related analogu es. Our computational approach proved to be effective in making qualitative predictions, that is in discriminating active versus inactive compounds. A mong the compounds synthesized and tested, 20 was the most active one, with EC50 = 0.045 mu M, IC50 = 0.05 mu M, and SI = 5333. Compared with the lead 3, these values represent a 3- and 8-fold improvement in the cell-based an d enzyme assays, respectively, together with the highest selectivity achiev ed so far in the PAS series.