Specific Targeting Highly Conserved Residues in the HIV-1 ReverseudTranscriptase Primer Grip Region. Design, Synthesis, and BiologicaludEvaluation of Novel, Potent, and Broad Spectrum NNRTIs with AntiviraludActivity

摘要

Pyrrolobenzoxazepinones (PBOs) represent a new class of human immunodeficiency virus typeud1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 5.udMolecular modeling studies based on the X-ray structures of HIV-1 RT prompted the synthesisudof novel analogues which were tested as anti-HIV agents. The PBO derivatives specificallyuddesigned to target the highly conserved amino acid residues within the â12-â13 hairpin, namelyudprimer grip, proved to be very potent against the most common mutant enzymes, includingudthe highly resistant K103N mutant strain. Structure-activity relationships (SARs) areuddiscussed in terms of a possible interaction with the RT binding site, depending on the natureudof the substituents at C-6. Among the pyrrolobenzoxazepines investigated, 15c appeared to beudthe most promising NNRTI of the series characterized by potent antiviral activity, broadudspectrum, and low cytotoxicity. 15c showed synergistic antiviral activity with AZT.