Synthesis and in vitro study of novel neuraminidase inhibitors against avian influenza virus

Evidences of oseltamivir resistant influenza patients raised the need of novel neuraminidase inhibitors. In this study, five oseltamivir analogs PMC-31–PMC-36, synthesised according to the outcomes of a rational design analysis aimed to investigate the effects of substitution at the 5-amino and 4-am...

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Published in:Bioorganic & medicinal chemistry 2012-03, Vol.20 (6), p.2152-2157
Main Authors: Kongkamnerd, Jarinrat, Cappelletti, Luca, Prandi, Adolfo, Seneci, Pierfausto, Rungrotmongkol, Thanyada, Jongaroonngamsang, Nutthapon, Rojsitthisak, Pornchai, Frecer, Vladimir, Milani, Adelaide, Cattoli, Giovanni, Terregino, Calogero, Capua, Ilaria, Beneduce, Luca, Gallotta, Andrea, Pengo, Paolo, Fassina, Giorgio, Miertus, Stanislav, De-Eknamkul, Wanchai
Format: Article
Language:English
Subjects:
Alkylation
Animals
Antiviral activity
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
antiviral properties
Avian influenza
Avian influenza virus
Baculovirus
Binding Sites
Birds - virology
Enzymes
Exo- alpha -sialidase
Fowl plague
in vitro studies
Influenza A virus
Influenza A virus - chemistry
Influenza A virus - drug effects
Influenza A virus - enzymology
Influenza A Virus, H7N1 Subtype - chemistry
Influenza A Virus, H7N1 Subtype - drug effects
Influenza A Virus, H7N1 Subtype - enzymology
Influenza A Virus, H7N3 Subtype - chemistry
Influenza A Virus, H7N3 Subtype - drug effects
Influenza A Virus, H7N3 Subtype - enzymology
Influenza in Birds - drug therapy
Influenza in Birds - enzymology
inhibitory concentration 50
Models, Molecular
Neuraminidase - antagonists & inhibitors
Neuraminidase - chemistry
Neuraminidase - metabolism
Neuraminidase inhibitors
Oseltamivir
Oseltamivir - analogs & derivatives
Oseltamivir - chemical synthesis
Oseltamivir - pharmacology
patients
Screening assay
sialidase
Structure-activity relationships
viruses
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Summary:Evidences of oseltamivir resistant influenza patients raised the need of novel neuraminidase inhibitors. In this study, five oseltamivir analogs PMC-31–PMC-36, synthesised according to the outcomes of a rational design analysis aimed to investigate the effects of substitution at the 5-amino and 4-amido groups of oseltamivir on its antiviral activity, were screened for their inhibition against neuraminidase N1 and N3. The enzymes used as models were from the avian influenza A H7N1 and H7N3 viruses. The neuraminidase inhibition assay was carried out by using recombinant species obtained from a baculovirus expression system and the fluorogenic substrate MUNANA. The assay was validated by using oseltamivir carboxylate as a reference inhibitor. Among the tested compounds, PMC-36 showed the highest inhibition on N1 with an IC50 of 14.6±3.0nM (oseltamivir 25±4nM), while PMC-35 showed a significant inhibitory effect on N3 with an IC50 of 0.1±0.03nM (oseltamivir 0.2±0.02nM). The analysis of the inhibitory properties of this panel of compounds allowed a preliminary assessment of a structure–activity relationship for the modification of the 4-amido and 5-amino groups of oseltamivir carboxylate. The substitution of the acetamido group in the oseltamivir structure with a 2-butenylamido moiety reduced the observed activity, while the introduction of a propenylamido group was well tolerated. Substitution of the free 5-amino group of oseltamivir carboxylate with an azide, decreased the activity against both N1 and N3. When these structural changes were both introduced, a dramatic reduction of activity was observed for both N1 and N3. The alkylation of the free 5-amino group in oseltamivir carboxylate introducing an isopropyl group seemed to increase the inhibitory effect for both N1 and N3 neuraminidases, displaying a more pronounced effect against N1.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.01.026