Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands

作者：Ghosh Arun K^*; Martyr Cuthbert D; Kassekert Luke A; Nyalapatla Prasanth R; Steffey Melinda; Agniswamy Johnson; Wang Yuan Fang; Weber Irene T; Amano Masayuki; Mitsuya Hiroaki

来源：Organic and Biomolecular Chemistry, 2015, 13(48): 11607-11621.

DOI：10.1039/c5ob01930c

Design, synthesis, biological and X-ray crystallographic studies of a series of potent HIV-1 protease inhibitors are described. Various polar functionalities have been incorporated on the tetrahydropyranyl-tetrahydrofuran-derived P2 ligand to interact with the backbone atoms in the S2-subsite. The majority of the inhibitors showed very potent enzyme inhibitory and antiviral activity. Two high-resolution X-ray structures of 30b- and 30j-bound HIV-1 protease provide insight into ligand-binding site interactions. In particular, the polar functionalities on the P2-ligand appear to form unique hydrogen bonds with Gly48 amide NH and amide carbonyl groups in the flap region.

• 出版日期2015