Synthesis of polycyclic compounds with antiviral activity

• Main Author: Torres Costa, Eva
• Other Authors: Vázquez Cruz, Santiago, Universitat de Barcelona. Departament de Farmacologia i Química Terapèutica
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: Universitat de Barcelona 2013
• Subjects: Influenzavirus; Vacunes antivíriques; Influenza viruses; Viral vaccines; Avian flu
• Online Access: http://hdl.handle.net/2445/47145; http://hdl.handle.net/10803/124040

[eng] Research for new antivirals to treat Influenza A virus infections has gained importance during this last decade due to the imminent danger of an Influenza pandemic. For some years, several new strains of this virus have appeared worldwide causing small outbreaks with a notable relevance, for example the ‘avian flu’ (H5N1 in 2007; H7N9 in 2012) and ‘swine flu’ (H1N1 in 2009), that have triggered the assumption that a new pandemic is coming. There are several strategies to treat an Influenza A virus infection targeting some of its surface proteins. In this Thesis, several compounds inhibiting the M2 channel of the virus are designed, synthesized and evaluated. Our approach is based on the synthesis of amantadine’s analogues by ring expansion, contraction and rearrangement. Amantadine is a drug already approved by the FDA for the treatment of Influenza A virus and it is known to target the M2 channel. Although it is no longer in use, because the FDA has recommended against its use, due to the appearance of resistance, it possessed good activity and an acceptable pharmacological behaviour. Our main goal was to synthesize an analogue of amantadine that was able to overcome the resistant virus and provide a new therapeutic alternative to the already marketed neuraminidase inhibitors such as Oseltamivir and Zanamivir. Importantly, we took advantage of the wide expertise of our research group in synthesizing polycyclic compounds to start a new research field that was based on the application of these optimized synthetic routes to the Medicinal chemistry. We established some external collaboration in order to set up the milestones and to build the rationale of the current project. These new collaborations are the following: - Prof. Lieve Naesens research group in the Rega Institute for Medical Research in Leuven, Belgium. This group of virologist made the plaque reduction assays and the study of the mutants to establish the mechanism of action of the tested compounds. - Lawrence H. Pinto research group of the ...