Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies.

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

ChemMedChem 2019 Nov 4;14(21):1863-1872. Epub 2019 Oct 4.

Departments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan.

We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC value. Boronic acid derived inhibitor with bis-THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-Crn-THF ligand also showed potent enzyme K but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIV and HIV viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions.

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http://dx.doi.org/10.1002/cmdc.201900508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842059PMC
November 2019
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