Specific Targeting Highly Conserved Residues in the HIV-1 Reverse Transcriptase Primer Grip Region. Design, Synthesis, and Biological Evaluation of Novel, Potent, and Broad Spectrum NNRTIs with Antiviral Activity

Pyrrolobenzoxazepinones (PBOs) represent a new class of human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is I (R = H).  Mol. modeling studies based on the x-ray structures of HIV-1 RT prompted the synthesis of novel analogs which were tested as anti-HIV agents.  The PBO derivs. specifically designed to target the highly conserved amino acid residues within the β12-β13 hairpin, namely primer grip, proved to be very potent against the most common mutant enzymes, including the highly resistant K103N mutant strain.  Structure-activity relationships (SARs) are discussed in terms of a possible interaction with the RT binding site, depending on the nature of the substituents at C-6.  Among the pyrrolobenzoxazepines investigated, I (R = 4-CH2OC6H5) appeared to be the most promising NNRTI of the series characterized by potent antiviral activity, broad spectrum, and low cytotoxicity.  I (R = 4-CH2OC6H5) showed synergistic antiviral activity with AZT.