Synthesis and biological evaluation of nitrogen heterocycle systems as potential antiviral agents

Viruses are obligate intracellular parasites that consist of either double- or single-stranded DNA or RNA enclosed in a protein coat called capsid. Some viruses also possess a lipid envelope that, like the capsid, may contain antigenic glycoproteins. Most of them contain or encode enzymes essential for their replicative cycle inside host cells, sometimes usurping their metabolic machinery. Traditional therapeutic approaches have mostly focused on targeting specific viral components or enzymes. This pathogen-directed strategy, while successful in numerous cases, in many others results ineffective due to the emergence of drug-resistance. A different approach, addressed to target host-factors essential for viral replication, has recently draw an increasing attention. My PhD project aimed at synthesizing new nitrogen heterocycle systems, designed especially against RNA viruses, such as those belonging to Flaviviridae, Orthomyxoviridae and Paramyxoviridae families. Among them there are, respectively, pathogens responsible for diseases with a high epidemiological impact, as BVDV in cattle and HCV in humans, influenza A and B viruses and respiratory syncytial virus (RSV). The project has been organized into the following phases: 1. Chemical synthesis of the novel compound series. During my PhD I designed and synthesized diverse chemical series of different chemotypes, in order to obtain new antiviral agents: the acridine nucleus, the dihydrotriazine scaffold, the benzimidazole ring as well as anilino and benzenesulfonamide derivatives. Previous studies performed by the research group where I develop my Ph.D. thesis identified some prototypes for the different classes endowed with intrinsic antiviral activity; thus, during my Ph.D. research work I explored various possibilities of functionalisation with the aim of increasing their potency and selectivity profiles towards the respective antiviral target. 2. Characterization of the new compounds. Each newly synthesized compound have been characterised by spectroscopic methods (such as UV, IR, 1H-NMR and 13C-NMR) and elemental analysis. 3. Evaluation of cytotoxicity, antiviral activity in vitro, enzymatic assays and computational studies have been performed in collaboration with several national and international research groups, to assess the biological activity and to identify/confirm the respective molecular targets.