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Isabela da Costa Césarhttp://lattes.cnpq.br/3601439104543399Renata Barbosa de OliveiraRicardo José AlvesChristian Fernandeshttp://lattes.cnpq.br/7860329445381226Pedro Henrique Cavalcanti Franco2022-03-28T18:51:22Z2022-03-28T18:51:22Z2020-02-20http://hdl.handle.net/1843/40509As infecções fúngicas têm se tornado um relevante problema em saúde pública por apresentarem uma crescente incidência, principalmente em pacientes imunodebilitados e hospitalizados. Estima-se que 1,7 bilhão de pessoas no mundo estejam infectadas com algum fungo, levando a 1,4 milhão de óbitos anuais. O arsenal terapêutico antifúngico é limitado pelo baixo investimento da indústria farmacêutica neste campo, pelas poucas opções de alvos moleculares seletivos às células fúngicas e por problemas relacionados à farmacocinética e à crescente resistência de fungos patogênicos. Neste contexto, o Laboratório de Química Farmacêutica da Universidade Federal de Minas Gerais desenvolveu moléculas com potencial a fármacos antifúngicos, dentre as quais destaca-se a RI76. O perfil de degradação desta molécula foi estudado e sua susceptibilidade a hidrólise e conversão em um produto de degradação foi descoberta por meio de um método indicativo de estabilidade, desenvolvido em sistema de cromatografia a líquido de alta eficiência acoplada a detector de arranjo de diodos (CLAE-DAD) e validado segundo a RDC 166/2017 da ANVISA e o guia ICH Q2(R1). O produto de degradação, denominado PD76, apresentou atividade antifúngica superior ao de seu precursor. Adicionalmente, um método de quantificação por ressonância magnética nuclear (RMN) foi desenvolvido e validado para a determinação absoluta da pureza de lotes sintetizados de RI76, medição não possível em CLAE-DAD devido à inexistência de padrões de referência desta substância. Por fim, um método bioanalítico por cromatografia a líquido acoplada à espectrometria de massas sequencial foi desenvolvido para a avaliação farmacocinética de RI76 e PD76 em modelo murino. Uma avaliação preliminar do comportamento farmacocinético demonstrou concentrações plasmáticas de até 250 ng/mL para PD76 e 200 ng/mL para RI76, após administração de uma dose de 100 mg/kg.Fungal infections are becoming a relevant issue in public health services for its increasing incidence, especially in immune debilitated and hospitalized patients. It is estimated that 1.7 billion people across the world are infected with some type of fungus, which leads to 1.4 million deaths annually. The therapeutic options for antifungal treatment are limited due to a low investment from pharmaceutical companies on this field, few potential targets and mechanisms of action, pharmacokinetics (PK) issues and to the increasing resistance of pathogenic fungi. In this context, the Laboratório de Química Farmacêutica from Universidade Federal de Minas Gerais has developed molecules with a potential application as antifungal agents, from which RI76 stands out. The degradation profile of this molecule was studied and its susceptibility to hydrolysis and conversion to a single degradation product was determined using a stability-indicating method developed in a high-performance liquid chromatography system coupled to diode array detector (HPLC-DAD) and validated according to ANVISA’s RDC 166/17 and ICH’s Q2(R1) guideline. This product, named PD76, has shown a more potent antifungal activity than its precursor. Additionally, a quantitative nuclear magnetic resonance (NMR) method was developed and validated to measure the absolute purity of synthesized RI76 batches, as such measurement would not be possible in HPLC-DAD due to the lack of reference standards for this substance. Finally, a bioanalytical method using HPLC coupled to tandem mass spectrometry was developed for the PK profiling of RI76 and PD76 in murine model. A preliminary assessment of its PK behaviour has shown plasmatic concentrations up to 250 ng/mL for PD76 and 200 ng/mL for RI76 after a single-dose administration of 100 mg/kg.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em Ciências FarmacêuticasUFMGBrasilFARMACIA - FACULDADE DE FARMACIAhttp://creativecommons.org/licenses/by-nd/3.0/pt/info:eu-repo/semantics/openAccesstiazolil-hidrazonacromatografia a líquido de alta eficiênciaressonância magnética nuclear quantitativaespectrometria de massasantifúngicoAvaliação do perfil de degradação e da farmacocinética de um novo derivado tiazolil-hidrazona candidato a fármaco antifúngicoEvaluation of the degradation profile and pharmacokinetics of a novel thiazolyl-hydrazone derivative as an antifungal drug candidateinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALDissertação PHC Franco_pósdefesa.pdfDissertação PHC Franco_pósdefesa.pdfapplication/pdf3455178https://repositorio.ufmg.br/bitstream/1843/40509/6/Disserta%c3%a7%c3%a3o%20PHC%20Franco_p%c3%b3sdefesa.pdf6d7dcc15eebdd065c09a9b049142307dMD56LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/40509/7/license.txtcda590c95a0b51b4d15f60c9642ca272MD57CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805https://repositorio.ufmg.br/bitstream/1843/40509/2/license_rdf00e5e6a57d5512d202d12cb48704dfd6MD521843/405092022-03-28 15:51:22.492oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2022-03-28T18:51:22Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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