Benjamin Alexander Mayes

Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.

4-Chloro-3-fluoro-2-methyl-aniline-pyrrolidine-2,5-dione (1/1).

Chlorination of 3-fluoro-2-methylaniline with N-chlorosuccinimide gave one major regioisomer whose structure was determined by X-ray crystallography. The product was found to have cocrystallized with succinimide, giving the title compound, C7H7ClFN·C4H5NO2. The crystal structure is stabilized by N—H⋯O hydrogen-bonding and π–π stacking interactions with a centroid–centroid distance of 3.4501 (8) Å.

2-De­oxy-2-fluoro-2-C-methyl-d-ribono-1,4-lactone (fluoro­methyl­rib)

The relative stereochemistry of the fluoro substituent (as ribo) and the ring size of the lactone (as five) in the title compound, C6H9FO4, have been established by X-ray crystallographic analysis.