Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses
Journal
Bioorganic and Medicinal Chemistry
Journal Volume
18
Journal Issue
11
Pages
4074-4084
Date Issued
2010
Author(s)
Abstract
Unlike the group-2 neuraminidase, the group-1 neuraminidase of influenza virus possesses a flexible loop (the 150-loop) and a cavity (the 150-cavity) adjacent to the active site, and renders a conformational change from the 'open' form to the 'closed' form on binding with substrate (sialo-glycoprotein) or inhibitor (e.g., zanamivir). Zanamivir derivative 8a having an extended (piperazinocarbonyl)propyl substituent at the internal N-position of the guanidino group is designed as a possible inhibitor on the basis of computer docking to the open form of N1 subtype neuraminidase. Indeed, compound 8a exhibits strong neuraminidase inhibition and good anti-influenza activity against H1N1 virus with IC50 = 2.15 μM and EC50 = 0.77 μM, respectively. This study may provide a clue to future design of better group-1 neuraminidase inhibitors. © 2010 Elsevier Ltd. All rights reserved.
SDGs
Type
journal article