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Synthesis of novel sialidase inhibitors to target influenza A virus and Chagas’ disease

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  • Medicine


Microsoft Word - Thesis corrections_24_11_10.doc Synthesis of novel sialidase inhibitors to target influenza A virus and Chagas’ disease Ricardo Resende A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Pharmacy and Pharmacology September 2010 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with its author. A copy of this thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and they must not copy it or use material from it except as permitted by law or with the consent of the author. This thesis may be available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation Signed Date Abstract This thesis is divided into two parts. Part One describes inhibitors towards influenza neuraminidase and Part Two describes inhibitors towards Trypanosoma cruzi trans-sialidase. In Part One, a description of the influenza virus is given followed by details of the current approved therapies and our approach. Influenza is a virus that has the ability to cause a pandemic with a possible high mortality rate. The life cycle of the influenza virus exhibits several key stages that, if inhibited, would hinder its replication and have potential as therapeutic targets. The two currently approved drugs on the market (zanamivir (25) and oseltamivir (6)) target influenza neuraminidase. Influenza neuraminidase has the function of cleaving terminal sialic acid groups from glycoconjugates present at the surface of cells, enabling the release of the newly formed viral particles. Our strategy towards the syntheses of novel inhibitors against influenza neuraminidase is based on 2,3-difluorosialic acid (19). Modifications were made at position C-5 of sialic acid to replace the 5-N-acetamido with a 5-N ­ trifluoroacetamido group. The formation of 5

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