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

Arun K Ghosh; Jacqueline N Williams; Satish Kovela; Jun Takayama; Hannah M Simpson; D Eric Walters; Shin-Ichiro Hattori; Manabu Aoki; Hiroaki Mitsuya

doi:10.1016/j.bmcl.2019.08.006

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

Bioorg Med Chem Lett. 2019 Sep 15;29(18):2565-2570. doi: 10.1016/j.bmcl.2019.08.006. Epub 2019 Aug 5.

Authors

Arun K Ghosh¹, Jacqueline N Williams², Satish Kovela², Jun Takayama², Hannah M Simpson², D Eric Walters³, Shin-Ichiro Hattori⁴, Manabu Aoki⁵, Hiroaki Mitsuya⁶

Affiliations

¹ Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. Electronic address: akghosh@purdue.edu.
² Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
³ Department of Pharmaceutical Sciences, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
⁴ Department of Refractory Viral Infections, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan.
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.
⁶ 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.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Ethers, Cyclic / chemical synthesis
Ethers, Cyclic / chemistry
Ethers, Cyclic / pharmacology*
HIV Protease / metabolism*
HIV Protease Inhibitors / chemical synthesis
HIV Protease Inhibitors / chemistry
HIV Protease Inhibitors / pharmacology*
Humans
Ligands
Molecular Structure
Quinine / analogs & derivatives*
Quinine / chemical synthesis
Quinine / chemistry
Quinine / pharmacology
Structure-Activity Relationship

Substances

Ethers, Cyclic
HIV Protease Inhibitors
Ligands
squaramide
Quinine
HIV Protease
p16 protease, Human immunodeficiency virus 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding