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Issue 48, 2015
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Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands

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Abstract

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.

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

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Article information


Submitted
16 Sep 2015
Accepted
06 Oct 2015
First published
14 Oct 2015

Org. Biomol. Chem., 2015,13, 11607-11621
Article type
Paper
Author version available

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

A. K. Ghosh, C. D. Martyr, L. A. Kassekert, P. R. Nyalapatla, M. Steffey, J. Agniswamy, Y. Wang, I. T. Weber, M. Amano and H. Mitsuya, Org. Biomol. Chem., 2015, 13, 11607
DOI: 10.1039/C5OB01930C

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