Premium
Serendipitous Discovery of a Potent Influenza Virus A Neuraminidase Inhibitor
Author(s) -
Mohan Sankar,
Kerry Philip S.,
Bance Nicole,
Niikura Masahiro,
Pinto B. Mario
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201308142
Subject(s) - zanamivir , neuraminidase , oseltamivir , neuraminidase inhibitor , chemistry , lead compound , virology , virus , cell culture , stereochemistry , in vitro , biochemistry , biology , enzyme , covid-19 , medicine , genetics , disease , pathology , infectious disease (medical specialty)
We have previously reported a potent neuraminidase inhibitor that comprises a carbocyclic analogue of zanamivir in which the hydrophilic glycerol side chain is replaced by the hydrophobic 3‐pentyloxy group of oseltamivir. This hybrid inhibitor showed excellent inhibitory properties in the neuraminidase inhibition assay ( K i =0.46 n M ; K i (zanamivir) =0.16 n M ) and in the viral replication inhibition assay in cell culture at 10 −8 M . As part of this lead optimization, we now report a novel spirolactam that shows comparable inhibitory activity in the cell culture assay to that of our lead compound at 10 −7 M . The compound was discovered serendipitously during the attempted synthesis of the isothiourea derivative of the original candidate. The X‐ray crystal structure of the spirolactam in complex with the N8 subtype neuraminidase offers insight into the mode of inhibition.