tetano
Editor, Senior Moderator
Angew Chem Int Ed Engl. 2013 Dec 11. doi: 10.1002/anie.201308142. [Epub ahead of print]
Serendipitous Discovery of a Potent Influenza Virus A Neuraminidase Inhibitor.
Mohan S, Kerry PS, Bance N, Niikura M, Pinto BM.
Author information
Abstract
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 (Ki =0.46 nM; Ki (zanamivir) =0.16 nM) 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.
Copyright ? 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
KEYWORDS:
antiviral agents, drug discovery, influenza A, neuraminidase inhibitors, spiro compounds
PMID:
24339250
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24339250
Serendipitous Discovery of a Potent Influenza Virus A Neuraminidase Inhibitor.
Mohan S, Kerry PS, Bance N, Niikura M, Pinto BM.
Author information
Abstract
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 (Ki =0.46 nM; Ki (zanamivir) =0.16 nM) 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.
Copyright ? 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
KEYWORDS:
antiviral agents, drug discovery, influenza A, neuraminidase inhibitors, spiro compounds
PMID:
24339250
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24339250