Influenza A viruses (IAVs) belong to the Orthomixoviridae, a family of enveloped viruses with a single-stranded negative-sense and eight-segmented RNA genome. They are the most prevalent pathogens for both humans and animals, causing the so-called seasonal flu and widespread pandemics. A part from the use of vaccines, viral infections can be inhibited at several crucial steps by the use of antiviral agents. It is possible to have an antiviral effect both targeting important proteins for the virus life cycle and targeting host proteins that play crucial roles during influenza virus infection. RNA-dependent RNA polymerase is a heterotrimeric complex of about 250 kDa, essential for the life cycle of the virus. It is composed of three different subunits: PA (polymerase acidic protein), PB1 and PB2 (polymerase basic proteins 1 and 2). Each of them is essential for the activity of the enzyme. Playing a critical role during the life cycle of the virus, RNA-dependent RNA polymerase has become a promising target for the development of anti-influenza drugs in recent years. Based on the mechanism of the interactions between inhibitor and polymerase, compounds targeting RNA-dependent RNA polymerase can be subdivided into four subtypes: PA endonuclease inhibitors, PB1 inhibitors, PB2 cap-binding inhibitors and RdRp disrupting compounds. The PA-PB1 interaction, probably the most interesting one for the development of new inhibitors, is well characterized as is known to occur between the C-terminal region of PA (PA-C) and the N-terminal region of PB1 (PB1-N). The research doctorate activity was focused on the synthesis and biological evaluation of novel anti-influenza agents acting as PPI inhibitors, in particular, disrupting the PA-PB1 interaction. A library of molecules characterized by a hybrid structure constituted by the 3-cyano-4,6-diphenylpyridinic core, previously identified with an high-throughput screening, together with an aminoacidic side chain in C2 was synthesized. Then, since SAR and molecular dynamic simulation studies seem to show that the cyano group is not essential for the antiviral activity, and considering that it is often related to potential cytotoxicity, it was decided to remove the CN group in C3 position, synthesizing a series of pyrimidine and pyridine derivatives having the 2-mercapto-N-(m-tolyl)acetamide chain in C2 position and different aromatic substituents in C4 and C6 positions of the pyrimidine or pyridine ring. Another part of the PhD work was devoted to the synthesis of two series of substituted pyrazolo[3,4-b]pyridines active as A1 adenosine antagonists and to enantioselective Pd(0)-catalyzed C-H activation reactions and related topics, such as the development of new chiral bifunctional phosphine/carboxylate ligands to employ in these reactions.
|Titolo della tesi:||Synthesis of properly substituted pyridine and pyrimidine derivatives and their biological evaluation as potential antiviral agents|
|Data di discussione:||11-mar-2019|
|Appare nelle tipologie:||Tesi di dottorato|