SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME UNSATURATED SIALIC ACID ANALOGUES AS POTENTIAL SIALIDASE INHIBITORS

This work represents a part of a larger research project directed to study the correlation between the different structures of unsaturated Neu5Ac derivatives and their inhibitory activity against viral, bacterial and mammalian sialidases. So, interested in finding the general features to define a potent and selective inhibitor of a particular kind of sialidase, we have set up many rapid, simple and efficient protocols to introduce new substituents into the DANA structure. In this thesis we accomplish: - the synthesis of new C-4α aminated DANA derivatives; - the first synthesis of N-perfluorinated C-4 epimers of DANA, clarifying also their mechanism formation and the key role of the oxazoline derivative; - the first Ritter-like reaction performed on Neu5Ac derivatives, to obtain new 4β-N-acetylated Neu5Ac2en derivatives; - The extension of the Ritter reaction leading to formulate a general nucleophilic substitution at C-4 position of e Neu5Ac glycals, synthesizing a great number of compounds by the rapid introduction of alcohols, thiols, sulfonamides and alogens; -The set up of a general method to introduce nucleophiles at C-2 position of Neu5Ac analogues to obtain new 3,4 unsaturated alkylglycosides, to be biologically tested, or to be used as synthetic intermediate to functionalize C-3 and C-4 positions of neuraminic acid derivatives; - The preliminary fluorimetric sialidase inhibition assays of part of the obtained compounds, against Vibrio cholerae, Newcastle disease virus, Clostridium perfringens and mammalian Neu3 sialidases. We obtain interesting results especially regarding the NDV neuraminidase inhibition data, suggesting the possibility to design a selective NDV NA inhibitor by tuning the substituent at C-5 position.