Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses

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.

Zanamivir derivative having an extended (piperazinocarbonyl)propyl substituent at the internal N-position of the guanidinium group is designed as an inhibitor specifically against the group-1 neuraminidases of influenza viruses.Figure optionsDownload as PowerPoint slide