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

Org Biomol Chem 2015 Dec 14;13(48):11607-21. Epub 2015 Oct 14.

Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.

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.

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http://dx.doi.org/10.1039/c5ob01930cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666783PMC
December 2015
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