Potent HIV-1 protease inhibitors incorporating squaramide-derived P2 ligands: Design, synthesis, and biological evaluation.

Authors:
Dr Kovela Satish, PhD
Dr Kovela Satish, PhD
Indian Institute of Chemical Technology, Hyderabad
Synthetic and medicinal chemistry
Hyderabad, Telangana | India

Bioorg Med Chem Lett 2019 Sep 5;29(18):2565-2570. Epub 2019 Aug 5.

Department of Refractory Viral Infections, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD 20892, USA; Division of Clinical Sciences, Kumamoto University Hospital, Kumamoto 860-8556, Japan.

We describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing a squaramide-derived scaffold as the P2 ligand in combination with a (R)-hydroxyethylamine sulfonamide isostere. Inhibitor 3h with an N-methyl-3-(R)-aminotetrahydrofuranyl squaramide P2-ligand displayed an HIV-1 protease inhibitory K value of 0.51 nM. An energy minimized model of 3h revealed the major molecular interactions between HIV-1 protease active site and the tetrahydrofuranyl squaramide scaffold that may be responsible for its potent activity.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2019.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711809PMC
September 2019
2.420 Impact Factor

Publication Analysis

Top Keywords

hiv-1 protease
16
synthesis biological
8
biological evaluation
8
protease inhibitors
8
design synthesis
8
protease inhibitory
4
displayed hiv-1
4
inhibitory 051 nm
4
051 nm energy
4
energy minimized
4
p2-ligand displayed
4
squaramide p2-ligand
4
r-hydroxyethylamine sulfonamide
4
combination r-hydroxyethylamine
4
sulfonamide isostere
4
inhibitor n-methyl-3-r-aminotetrahydrofuranyl
4
n-methyl-3-r-aminotetrahydrofuranyl squaramide
4
potent activity
4
minimized model
4
active site
4

Similar Publications