Evidences of oseltamivir resistant influenza patients raised the need of novel neuraminidase inhibitors. In this study, five oseltamivir analogs PMC-31-PMC-36, synthesized according to the outcomes of a rational design anal. 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 ref. inhibitor. Among the tested compds., PMC-36 (I) showed the highest inhibition on N1 with an IC50 of 14.6 ± 3.0 nM (oseltamivir 25 ± 4 nM), while PMC-35 showed a significant inhibitory effect on N3 with an IC50 of 0.1 ± 0.03 nM (oseltamivir 0.2 ± 0.02 nM). The anal. of the inhibitory properties of this panel of compds. 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 obsd. 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 redn. of activity was obsd. for both N1 and N3. The alkylation of the free 5-amino group in oseltamivir carboxylate introducing an iso-Pr group seemed to increase the inhibitory effect for both N1 and N3 neuraminidases, displaying a more pronounced effect against N1.

Synthesis and in vitro study of novel neuraminidase inhibitors against avian influenza virus / J. Kongkamnerd, L. Cappelletti, A. Prandi, P. Seneci, T. Rungrotmongkol, N. Jongaroonngamsang, P. Rojsitthisak, V. Frecer, A. Milani, G. Cattoli, C. Terregino, I. Capua, L. Beneduce, A. Gallotta, P. Pengo, G. Fassina, S. Miertus, W. De-Eknamkul. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 20:6(2012), pp. 2152-2157.

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

P. Seneci;
2012

Abstract

Evidences of oseltamivir resistant influenza patients raised the need of novel neuraminidase inhibitors. In this study, five oseltamivir analogs PMC-31-PMC-36, synthesized according to the outcomes of a rational design anal. 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 ref. inhibitor. Among the tested compds., PMC-36 (I) showed the highest inhibition on N1 with an IC50 of 14.6 ± 3.0 nM (oseltamivir 25 ± 4 nM), while PMC-35 showed a significant inhibitory effect on N3 with an IC50 of 0.1 ± 0.03 nM (oseltamivir 0.2 ± 0.02 nM). The anal. of the inhibitory properties of this panel of compds. 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 obsd. 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 redn. of activity was obsd. for both N1 and N3. The alkylation of the free 5-amino group in oseltamivir carboxylate introducing an iso-Pr group seemed to increase the inhibitory effect for both N1 and N3 neuraminidases, displaying a more pronounced effect against N1.
avian influenza; neuraminidase inhibitors; screening assay
Settore CHIM/06 - Chimica Organica
Settore BIO/13 - Biologia Applicata
Settore CHIM/08 - Chimica Farmaceutica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/190946
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