4,6-Diphenyl-pyridines/pyrimidines and pyrazolo[3,4-d]pyrimidines: promising scaffolds as antiviral, anticancer and theranostic agents.

Nitrogen-based heterocyclic molecules received increasing attention in biological and chemical sciences, becoming a significant moiety in drug design. In this thesis, the research work has been focused on the design and the synthesis of novel derivatives based on the 4,6-diphenyl-pyridine/pyrimidine and pyrazolo[3,4-d]pyrimidine scaffolds as key pharmacophores for their antiviral and anticancer activities, respectively. The first part deals with the design and synthesis of a set of small molecules able to interfere with the Influenza (flu) RNA-dependent RNA Polymerase (RdRp) functions, exploiting the protein-protein interactions (PPIs) approach. An introduction of influenza disease and its pathogens is provided, focusing on the replicative mechanism of the influenza viruses and on the structural and functional information of the flu RdRp. The PPIs of the three polymerase subunits PA, PB1 and PB2, are reported and the inhibitors targeting the heterodimer PA-PB1 are introduced. Finally, the rational design and synthesis of new hybrid compounds bearing the 4,6-diphenyl-pyridine/pyrimidine cores are described togheter with the biological evaluation and molecular modeling studies. The second part of the dissertation focuses on the pyrazolo[3,4-d]pyrimidine compounds, on which both a lead optimization study and a theranostic design have been performed. The pyrazolo[3,4-d]pyrimidines have shown a promising activity both in in vitro and in in vivo as protein kinase inhibitors. The lead optimization study has been performed with the aim of obtaining a new class of derivatives as potent Src kinase inhibitors. The rational design, synthesis and biological analysis of the novel compounds are discussed. A further part of the project is dedicated to the design and development of potential theranostic prodrugs of two promising in-house pyrazolo[3,4-d]pyrimidines, SI306 and SI113. These prodrugs have been synthesized as potential agents for the diagnosis and the treatment of glioblastoma multiforme (GBM). The state of the art on theranostic applications of drugs, whose use is continually increasing, is also described.