473739-21-8Relevant articles and documents
Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants
Ghosh, Arun K.,Rao, Kalapala Venkateswara,Nyalapatla, Prasanth R.,Osswald, Heather L.,Martyr, Cuthbert D.,Aoki, Manabu,Hayashi, Hironori,Agniswamy, Johnson,Wang, Yuan-Fang,Bulut, Haydar,Das, Debananda,Weber, Irene T.,Mitsuya, Hiroaki
, p. 4267 - 4278 (2017/06/05)
Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2′ ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.
