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Synthesis of polycyclic compounds with antiviral activity

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Universitat de Barcelona. Departament de Farmacologia i Química Terapèutica

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[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 Northwestern University, Evanston, Illinois, USA. This group of biochemist made the patch clamp assay to check if our compounds targeted the M2 channel. - Prof. Javier Luque of Universitat de Barcelona, Barcelona, España. This group made the docking and molecular dynamics of our compounds. In the following figures, the general structures of the compounds synthesized in the current Thesis are shown. Several of them showing an outstanding activity that allowed us to publish in the most important journals of the Medicinal Chemistry field: It it worth to mention that, several compounds have shown better activity than the reference compound, Amantadine. The most distinguished compounds are the following: Compound 1, 2 and 3 showed a superior activity against H1N1 strain in the cell culture assay while being almost inactive in the patch clamp assay. Prof. Lieve Naesen’s research group tried to identify the mechanism of action of these compounds selecting the mutants of hemagglutinin under the pressure of our compounds, revealing that this protein was the target of the first cluster of molecules. Compound 4 and 5 showed an outstanding activity against the wild-type and V27A M2 channels of influenza A virus. Taken together, all of these results show that tuning the polycyclic scaffold of amantadine could be the way to overcome the already stated resistance. A second part of this current Thesis consisted in a collection of compounds that have activity against vaccinia virus. These compounds are analogues of Tecovirimat®, a compound that it is currently in phase III clinical trials. When we started this project, we wanted to explore the impact in the EC50 of changing the polycyclic scaffold of the Tecovirimat® molecule, a common tool used in Medicinal Chemistry. We synthesized nearly 40 compounds and we obtained activities similar to Tecovirimat®, although none of our molecules was better than the reference compound.

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Tesis Doctorals - Departament - Farmacologia i Química Terapèutica

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Synthesis of polycyclic compounds with antiviral activity