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

Arun K Ghosh¹, Jacqueline N Williams¹, Satish Kovela¹

¹Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.

Bioorganic & Medicinal Chemistry Letters

|August 17, 2019

Abstract:

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_i 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.

Keywords:

Bis-tetrahydrofuran HIV-1 protease Inhibitor Squaramide Synthesis

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