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

[Display omitted] 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 squ...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-09, Vol.29 (18), p.2565-2570
Main Authors: Ghosh, Arun K., Williams, Jacqueline N., Kovela, Satish, Takayama, Jun, Simpson, Hannah M., Walters, D. Eric, Hattori, Shin-ichiro, Aoki, Manabu, Mitsuya, Hiroaki
Format: Article
Language:English
Subjects:
Bis-tetrahydrofuran
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
HIV-1 protease
Humans
Inhibitor
Ligands
Molecular Structure
Quinine - analogs & derivatives
Quinine - chemical synthesis
Quinine - chemistry
Quinine - pharmacology
Squaramide
Structure-Activity Relationship
Synthesis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] 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 Ki 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.
ISSN:0960-894X
1464-3405
1464-3405
DOI:10.1016/j.bmcl.2019.08.006