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

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• 作者：Jarinrat Kongkamnerd^a ; ^d ; Luca Cappelletti^b ; Adolfo Prandi^b ; Pierfausto Seneci^b ; ^c ; ^{pierfausto.seneci@unimi.it} ; Thanyada Rungrotmongkol^d ; Nutthapon Jongaroonngamsang^d ; Pornchai Rojsitthisak^d ; Vladimir Frecer^e ; ^f ; ^g ; ^{frecer@fpharm.uniba.sk} ; Adelaide Milani^h ; Giovanni Cattoli^h ; Calogero Terregino^h ; Ilaria Capua^h ; Luca Beneduceⁱ ; Andrea Gallottaⁱ ; Paolo Pengoⁱ ; ^{pengo@xeptagen.com} ; Giorgio Fassinaⁱ ; Stanislav Miertus^e ; Wanchai De-Eknamkul^a ; ^{dwanchai@chula.ac.th}
• 关键词：Neuraminidase inhibitors ; Avian influenza ; Screening assay
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 March, 2012
• 年：2012
• 卷：20
• 期：6
• 页码：2152-2157
• 全文大小：461 K

文摘

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 ¡À 3.0 nM (oseltamivir 25 ¡À 4 nM), while PMC-35 showed a significant inhibitory effect on N3 with an IC₅₀ of 0.1 ¡À 0.03 nM (oseltamivir 0.2 ¡À 0.02 nM). 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.