Abstract

The aim of this thesis is to better understand the complex relationships that occur between metalloenzymes and their ligands, especially inhibitors. Two targets, such as HIV-1 Integrase (IN) and Carbonic Anidrase (CA), were selected and explored. IN is an Mg(II)/Mn(II) -containing enzyme, whereas CA is a Zn(II)-enzyme. The work is structured and detailed into three main chapters. Chapter one discusses about a molecular and functional study of a series of clinically developed IN inhibitors, strictly related to the b-diketo acid (DKAs) class of compounds, that belong to the family of IN strand transfer inhibitors (INSTIs). Starting from the hypothesis to identify a common pharmacophore amongst them, the chapter attempts to elucidate how the metal-chelating properties can influence the activity of these compounds. Moreover, an extensive investigation of metal complexation as a suitable strategy in the IN drug design was performed. In chapter two, which deals with CA, two different projects are presented. The first one describes how new inhibitors of CA (isozyme II) have been discovered by using a complete Virtual Screening (VS) approach. The second part reports on the design and the preparation, as well as modelling studies and enzymatic inhibitory activity, of a series of original photoprobes, as useful tools to be used in the Photoaffinity Labelling (PAL) procedure, to elucidate enzyme interactions of the sulfonamide class of CAII inhibitors. In the third chapter, a retrospective structural analysis on a series of 4-benzylidene-2-(2- hydroxybenzoyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one, previously reported as IN inhibitors, as well as an alternative versatile synthetic approach for their preparation are presented and discussed.

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