Planejamento racional de oxadiazóis com potencial para tratamento de infecções fúngicas invasivas
Data
2023-12-11
Autores
Melo, Vanusa Alves de 
Orientadores
Rando, Daniela Gonçales Galasse
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
As infecções fúngicas invasivas (IFIs) são relevantes no cenário mundial devido à sua alta incidência como doenças oportunistas causando infecção em humanos. Neste contexto, as infecções por Candida albicans são responsáveis por quadros de alta gravidade no que concerne às infecções sanguíneas nosocomiais e formação de biofilmes, tornando-se um grave problema de saúde pública. Dentre as limitadas alternativas de antifúngicos disponíveis no mercado, a eficácia do tratamento tem sido cada vez mais reduzida devido ao surgimento de multirresistência aos fármacos utilizados, bem como a gravidade em relação a toxicidade e efeitos colaterais adversos como por exemplo, a anfotericina B, justificando dessa forma, a urgência na pesquisa e desenvolvimento de novos fármacos antifúngicos de uso sistêmico. Estudos anteriores realizados pelo grupo colaborador MICOTEC da Universidade Estadual de Maringá, identificaram dois potenciais derivados oxadiazólicos codificados LMM6 e LMM11 que exibiram perfil fungicida e fungistático, respectivamente. Com base nessas duas moléculas foram desenvolvidos 11 compostos intermediários oxadiazólicos e avaliados in vitro contra C. albicans, P. brasiliensis, A. fumigatus e C. neoformans. Ainda, foram analisados em vermes adultos de S. mansoni, como resultado da parceria do grupo GPQFfesp e o Núcleo de Pesquisas em Doenças Negligenciadas da Universidade de Guarulhos. Foram determinadas concentrações efetivas in vitro de 50% (EC50) e 90% (EC90) contra vermes adultos de S. mansoni e o composto GPQF1331 apresentou propriedades esquistossomicida com 100% de mortalidade e redução de atividade motora dos parasitas após 48 horas na concentração de 50µM. interessantemente, este também foi um dos intermediários sintéticos que apresentou atividade contra P. brasiliensis na concentração de 4 µg/mL (20µM) em estudos de concentração inibitória mínima (CIM). Quanto a síntese de acoplamento entre o ácido 4-clorosulfonilbenzoico e N-etilcicloexilamina diversas tentativas de sínteses foram realizadas, porém sem sucesso. Isso implica na necessidade de mais estudos cinéticos e termodinâmicos visto que, o impedimento estérico imposto pelos grupos substituintes da amina secundaria e do próprio ácido 4-clorosulfonilbenzoico constituíram um desafio maior do que o esperado. De modo geral, o desenvolvimento deste trabalho abre espaço para o estudo de processos sintéticos mais eficientes, e construção de moléculas variadas a partir de núcleos oxadiazólicos, estruturas privilegiadas do ponto de vista da química medicinal, mas cuja derivação, neste caso, apresentou desafios que requerem maior tempo de estudo. Estes compostos, contudo, merecem atenção pois apresentam promissor potencial como protótipos para agentes antifúngicos e anti-helmínticos.
Invasive fungal infections (IFIs) are relevant worldwide due to their high incidence as opportunistic diseases causing infection in humans. In this context, Candida albicans infections are responsible for severe conditions, particularly concerning nosocomial blood infections and the formation of biofilms, becoming a serious public health problem. Among the limited antifungal alternatives available on the market, the effectiveness of treatment has been increasingly reduced due to the emergence of multi-resistance to the drugs used, as well as the severity of toxicity and adverse side effects, such as amphotericin B, justifying thus, the urgency in research and development of new antifungal drugs for systemic use. Previous studies carried out by the MICOTEC collaborative group at the State University of Maringá, identified two potential oxadiazole derivatives coded LMM6 and LMM11 that exhibited a fungicidal and fungistatic profile, respectively. Based on these two molecules, 11 intermediate oxadiazole compounds were developed and evaluated in vitro against C. albicans, P. brasiliensis, A. fumigatus and C. neoformans. Furthermore, they were analyzed in adult S. mansoni worms, because of the partnership between the GPQFfesp group and the Center for Research on Neglected Diseases at the University of Guarulhos. In vitro effective concentrations of 50% (CE50) and 90% (CE90) were determined against adult S. mansoni worms and the compound GPQF1331 showed schistosomicidal properties with 100% mortality and reduction in motor activity of the parasites after 48 hours at the concentration of 50μM. interestingly, this was also one of the synthetic intermediates that showed activity against P. brasiliensis at a concentration of 4 μg/mL (20μM) in minimum inhibitory concentration (MIC) studies. Regarding the coupling synthesis between 4-chlorosulfonylbenzoic acid and N-ethylcyclohexylamine, several synthetic attempts were carried out, but without success. This implies the need for more kinetic and thermodynamic studies since the steric hindrance imposed by the substituent groups of the secondary amine and 4-chlorosulfonylbenzoic acid itself constituted a greater challenge than expected. In general, the development of this work opens space for the study of more efficient synthetic processes, and the construction of varied molecules from oxadiazole nuclei, privileged structures from the point of view of medicinal chemistry, but whose derivation, in this case, presented challenges that require more study time. These compounds, however, deserve attention as they have promising potential as prototypes for antifungal and anthelmintic agents.
Invasive fungal infections (IFIs) are relevant worldwide due to their high incidence as opportunistic diseases causing infection in humans. In this context, Candida albicans infections are responsible for severe conditions, particularly concerning nosocomial blood infections and the formation of biofilms, becoming a serious public health problem. Among the limited antifungal alternatives available on the market, the effectiveness of treatment has been increasingly reduced due to the emergence of multi-resistance to the drugs used, as well as the severity of toxicity and adverse side effects, such as amphotericin B, justifying thus, the urgency in research and development of new antifungal drugs for systemic use. Previous studies carried out by the MICOTEC collaborative group at the State University of Maringá, identified two potential oxadiazole derivatives coded LMM6 and LMM11 that exhibited a fungicidal and fungistatic profile, respectively. Based on these two molecules, 11 intermediate oxadiazole compounds were developed and evaluated in vitro against C. albicans, P. brasiliensis, A. fumigatus and C. neoformans. Furthermore, they were analyzed in adult S. mansoni worms, because of the partnership between the GPQFfesp group and the Center for Research on Neglected Diseases at the University of Guarulhos. In vitro effective concentrations of 50% (CE50) and 90% (CE90) were determined against adult S. mansoni worms and the compound GPQF1331 showed schistosomicidal properties with 100% mortality and reduction in motor activity of the parasites after 48 hours at the concentration of 50μM. interestingly, this was also one of the synthetic intermediates that showed activity against P. brasiliensis at a concentration of 4 μg/mL (20μM) in minimum inhibitory concentration (MIC) studies. Regarding the coupling synthesis between 4-chlorosulfonylbenzoic acid and N-ethylcyclohexylamine, several synthetic attempts were carried out, but without success. This implies the need for more kinetic and thermodynamic studies since the steric hindrance imposed by the substituent groups of the secondary amine and 4-chlorosulfonylbenzoic acid itself constituted a greater challenge than expected. In general, the development of this work opens space for the study of more efficient synthetic processes, and the construction of varied molecules from oxadiazole nuclei, privileged structures from the point of view of medicinal chemistry, but whose derivation, in this case, presented challenges that require more study time. These compounds, however, deserve attention as they have promising potential as prototypes for antifungal and anthelmintic agents.