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| Author(s): |
Filipe Gomes Pernichelle
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2023-11-14 |
| Examining board members: |
Elizabeth Igne Ferreira;
Celso de Oliveira Rezende Júnior;
Alcindo Aparecido Benito dos Santos;
Cauê Benito Scarim
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| Advisor: | Elizabeth Igne Ferreira |
| Abstract | |
Chagas disease is a common anthropozoonosis in Latin America and its transmission occurs through the parasite called Trypanosoma cruzi. This neglected disease presents serious public health problems in the American continent, however, due to globalization and legal and illegal immigration of people from endemic countries, several cases have been reported in other countries, such as the United States, Canada, Japan and Australia, as well as in many European countries. Currently, in the 21 countries considered endemic, approximately 75 million people are exposed to the infection, six to seven million are infected and more than 30,000 new cases arise per year. In addition, about eight thousand newborns are infected during pregnancy and around 14 thousand people die annually from Chagas, thus being the disease considered the tropical disease that kills the most in the world. Discovered more than a hundred years ago, , its chemotherapy still remains precarious, with only nifurtimox and benznidazole available on the market, and only the latter available in Brazil. Both have a low rate of effectiveness in the chronic phase of the disease and more than 80% of patients do not obtain a parasitological cure in this stage. These alarming data show the importance of searching for compounds that are more effective against T. cruzi. In view of the need to search for molecules with anti-T. cruzi and considering therapies based on nitric oxide (NO) releasers, enzymatic inhibitions of CYP51 and Fe-SOD, and protein kinases inhibition present themselves as interesting approaches for the design of new antiparasitic agents, the objective of this work was the synthesis of two new series, one of hybrid compounds, containing piperazine group as linker and with interaction in Fe-SOD, furoxane group as NO releasers and substituted aromatic group with possible interaction with CYP51 enzyme, and other with potent azaindole-derived kinase inhibitors. Most of the compounds were obtained in good yields. Submitted to antiparasitic tests against T. cruzi and to cytotoxic tests in mammal cells, the compounds did not show neither activity nor cytotoxicity, with the exception of FGP-30B and FGP-46A (50% of antiparasitic activity), that show modest activity, and FGP-33B, which was moderately cytotoxic (50% of anticellular activity). In addition, 5 azaindoles derivatives were synthesized in several synthetic steps, in good yelds in general. They are potential quinase inhibitors and will be further submitted to biological assays in T. cruzi. (AU) | |
| FAPESP's process: | 20/13347-2 - Potentially active anti-chagas disease: design and synthesis of molecular hybrids of enzymes as fe-superoxide dismutase and CYP51 with nitric oxide releasing groups |
| Grantee: | Filipe Gomes Pernichelle |
| Support Opportunities: | Scholarships in Brazil - Master |