Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.

J Med Chem 2018 05 15;61(10):4561-4577. Epub 2018 May 15.

Departments of Infectious Diseases and Hematology , Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556 , Japan.

The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2' ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2' ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. 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.

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b00298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044451PMC
May 2018
18 Reads
6.253 Impact Factor

Publication Analysis

Top Keywords

hiv-1 protease
16
protease inhibitors
8
design synthesis
8
inhibitors
5
protease
5
hiv-1
5
maintained excellent
4
antiviral activity
4
excellent antiviral
4
potency maintained
4
exceptional enzyme
4
enzyme inhibitory
4
inhibitory potency
4
activity panel
4
multidrug-resistant hiv-1
4
variants umbrella-like
4
umbrella-like ligand
4
ligand inhibitors
4
hiv-1 variants
4
exhibited exceptional
4

Similar Publications