Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase

PloS One
Cinzia ColomboAnna Bernardi

Abstract

The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; sialidase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme in...Continue Reading

References

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Citations

Dec 13, 2018·Future Medicinal Chemistry·Paola ChiodelliMarco Rusnati
Jul 31, 2019·Medicinal Research Reviews·Alice TamburriniAnna Bernardi
Oct 7, 2020·Natural Product Reports·Roberto G S BerlinckIgor D Jurberg

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Methods Mentioned

BETA
glycosylation
acetylation
NMR
X-ray
column chromatography

Software Mentioned

OpenEye
PPW
complex2img
SHELXL
Epik
SADABS
GraphPad Prizm
XPREP
SAINT +
OEChem Toolkit

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