Oseltamivir analogues bearing N-substituted guanidines as potent neuraminidase inhibitors

Caitlin A Mooney; Stuart A Johnson; Peter 't Hart; Linda Quarles van Ufford; Cornelis A M de Haan; Ed E Moret; Nathaniel I Martin

doi:10.1021/jm401977j

Oseltamivir analogues bearing N-substituted guanidines as potent neuraminidase inhibitors

J Med Chem. 2014 Apr 10;57(7):3154-60. doi: 10.1021/jm401977j. Epub 2014 Mar 31.

Authors

Caitlin A Mooney¹, Stuart A Johnson, Peter 't Hart, Linda Quarles van Ufford, Cornelis A M de Haan, Ed E Moret, Nathaniel I Martin

Affiliation

¹ Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.

PMID: 24649802
DOI: 10.1021/jm401977j

Abstract

A series of oseltamivir analogues bearing an N-substituted guanidine unit were prepared and evaluated as inhibitors of neuraminidases from four strains of influenza. The two most potent analogues identified contain relatively small N-guanidine substituents (N-methyl and N-hydroxyl) and display enhanced inhibition with IC50 values in the low nanomolar range against neuraminidases from wild-type and oseltamivir-resistant strains. Potential advantages of including the N-hydroxyguanidine moiety in neuraminidase inhibitors are also discussed.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Drug Resistance, Viral / drug effects
Drug Resistance, Viral / genetics
Guanidines / chemistry*
Humans
Influenza A virus / drug effects*
Influenza, Human / drug therapy
Influenza, Human / virology
Models, Molecular
Molecular Structure
Mutation / genetics
Neuraminidase / antagonists & inhibitors*
Neuraminidase / genetics
Neuraminidase / metabolism
Oseltamivir / chemistry*
Oseltamivir / pharmacology*
Structure-Activity Relationship

Substances

Antiviral Agents
Guanidines
Oseltamivir
Neuraminidase