Avaliação do perfil de degradação e da farmacocinética de um novo derivado tiazolil-hidrazona candidato a fármaco antifúngico

Abstract

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.