Synthesis and biological evaluation of novel therapeutic candidates for the treatment of infectious and rare diseases

In the current PhD thesis novel synthetic routes were developed for the synthesis of new compounds with the aim to identify therapeutic candidates for the treatment of rare and infectious diseases. Stereoselective synthetic methodologies were herein exploited to obtain compounds with selected features that would improve pharmacological activity and biological selectivity for the target pathogen or host enzymes. Based on the targeted disease for which the compounds have been conceived, this thesis consists of three main sections. The first section has been focused on Cystic Fibrosis (CF), a rare genetic disorder characterized by chronic infection and inflammation of the airways. Herein, the stereoselective synthesis of the unnatural N-Alkyl L-deoxyiminosugars was considered for their application as anti-inflammatory agents in CF. An efficient procedure was developed, involving the use of polymer-supported triphenylphosphine/iodine system (PS-TPP/I2) to prepare the alkyl chains to be assembled on the iminosugar core. Biological assays revealed a very interesting anti-inflammatory properties of these molecules also confirmed in murine models of lung infection. In the second section, the synthesis of novel candidates for the treatment of bacterial infections was reported with the aim to identify alternative therapeutics to face with the serious and global threat of antibacterial resistance. On one hand, N-alkyl D- and L-deoxyiminosugars and their cholesteryl-bearing derivatives were considered in order to evaluate the role of both the chirality and of the lipophilicity on the eventual anti-bacterial activity of these molecules. In this case, a synthetic procedure was finely tuned and the established PS-TPP/I2 activating system was exploited for the conjugation of the iminosugars with the cholesteryl moiety enabling to obtain the target compounds in a solid phase system and in one-pot procedure. On the other hand, a novel synthetic route, as alternative to the existing methods, aimed to the preparation of the corticosteroid anti-inflammatory drug Deflazacort was explored for it repurposing as antibacterial agent. For both classes of compounds, in vitro biological assays revealed a "lead" compound endowed with interesting antibacterial and antibiofilm activity. In the last section the attention has been focused on synthesis of nucleoside analogues for their use in viral diseases. Particularly, two class of sugar modified nucleosides was synthesized, cyclohexenyl nucleosides and piperidinyl nucleosides conceived as selective inhibitors of viral DNA and RNA polymerases. Eventually, propargylated purine nucleosides was prepared with the aim to exploit the potential of NAs for in vivo visualization of viral life cycle