Planejamento racional e síntese de híbridos de hidrazonas na busca de compostos ativos contra helmintíases e viroses
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Arquivos
Data
2023-12-01
Autores
Pavani, Thaís Fernanda Amorim [UNIFESP]
Orientadores
Rando, Daniela Gonçales Galasse [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Neste projeto, foram exploradas duas abordagens para encontrar novos compostos no combate
a verminoses e viroses. No caso das verminoses, o foco é a esquistossomose, uma doença que
afeta milhões de pessoas globalmente, a pesquisa buscou alternativas ao praziquantel, o único
medicamento disponível, a fim de evitar resistência. Para as viroses, com destaque para o
SARS-CoV-2, causador da COVID-19, o objetivo foi encontrar compostos eficazes no
tratamento da doença, uma vez que ainda não existe um fármaco específico para este fim.
Frente ao exposto, este trabalho tem por finalidade explorar uma série de N-acilidrazonas
derivadas de tiossemicarbazidas e vinilsulfonas previamente reportadas na literatura como
potenciais agentes esquistossomicidas, e uma série de hidrazonas e hidrazidas derivadas de
quinolinas, para serem testadas contra vermes adultos de S. mansoni in vitro e in vivo e para
triagem experimental por High Content Screening (HCS) contra SARS-CoV-2. Foram
sintetizados 50 compostos sendo 16 derivados N-acilidrazônicos, 27 hidrazonas derivadas da
7-cloroquinolina e sete hidrazidas também derivadas da 7-cloroquinolina. Nove das Nacilidrazonas foram testadas contra S. mansoni in vitro, destas, apenas o GPQF-817 apresentou
atividade e, a partir desse resultado, novas alterações estruturais foram realizadas visando a
melhoria da atividade esquistossomicida. 26 quinolinas também foram testadas contra S.
mansoni in vitro, cinco apresentaram atividade, sendo o composto GPQF-8Q10 o mais ativo,
levando a morte de 100 % dos vermes em 24h a 25 μM. O GPQF-8Q8 se mostrou o composto
mais promissor nos ensaios in vivo, levando a redução dos ovos encontrados nas fezes em
52,8% e nos ovos encontrados no intestino em 45,8%. Os derivados quinolínicos exibiram
baixa citotoxicidade em células Vero e no ensaio in vivo empregando modelo animal C. elegans,
indicando um índice de seletividade favorável. Os compostos foram ainda submetidos a ensaios
contra SARS-CoV-2 e o vírus da Chikungunya, todavia, tanto os derivados N-acilidrazônicos
quanto os derivados quinolínicos não apresentaram atividade significativa. Os resultados
sugerem, ao menos para os compostos híbridos de quinolinas e hidrazonas, um potencial para
o desenvolvimento de novos candidatos para o tratamento da esquistossomose. Outros estudos
ainda são necessários para elucidar o alvo específico de atuação desses compostos, no entanto,
os achados neste trabalho oferecem um ponto de partida.
In this project, two approaches were explored to discover new compounds for combating helminth infections, with a focus on schistosomiasis, a disease that affects millions of people globally. The research aimed to find alternatives to praziquantel, the only available medication, in order to prevent the development of resistance. Regarding viral infections, with a particular emphasis on SARS-CoV-2, the causative agent of COVID-19, the objective was to identify effective compounds for disease treatment, as there is currently no specific pharmaceutical for this purpose. In light of the above, the purpose of this work was to investigate a series of N-acylhydrazones derived from thiosemicarbazones and vinyl sulfones, previously reported in the literature as potential schistosomicidal agents, along with a series of hydrazones and hydrazides derived from quinolines. These compounds were to be tested against adult S. mansoni worms in both in vitro and in vivo assays, with screening conducted through High Content Screening (HCS) against SARS-CoV-2. A total of 50 compounds were synthesized, including 16 N-acylhydrazone derivatives, 27 hydrazones derived from 7-chloroquinoline, and seven hydrazides, also derived from 7-chloroquinoline. Nine of the N-acylhydrazones were tested in vitro against S. mansoni, with only GPQF-817 demonstrating activity. As a result, structural modifications were made to enhance schistosomicidal activity. Additionally, 26 quinolines were tested in vitro against S. mansoni, with five showing activity. Notably, GPQF-8Q10 proved to be the most active compound, causing the death of 100% of the worms within 24 hours at a concentration of 25 μM. GPQF-8Q8 emerged as the most promising compound in in vivo assays, reducing the number of eggs found in feces by 52.8% and the number of eggs found in the intestines by 45.8%. The quinoline derivatives exhibited low cytotoxicity in Vero cells and showed a favorable selectivity index in in vivo tests using the C. elegans animal model. Nevertheless, when subjected to assays against SARS-CoV-2 and the Chikungunya virus, none of the five of the N-acylhydrazones and 22 of the quinoline derivatives demonstrated significant activity. These studies suggest that, at least for the quinoline and hydrazone hybrid compounds, there is potential for the development of new candidates for schistosomiasis treatment. Further investigations are required to elucidate the specific mechanisms of action of these compounds. However, the findings in this work provide a promising starting point.
In this project, two approaches were explored to discover new compounds for combating helminth infections, with a focus on schistosomiasis, a disease that affects millions of people globally. The research aimed to find alternatives to praziquantel, the only available medication, in order to prevent the development of resistance. Regarding viral infections, with a particular emphasis on SARS-CoV-2, the causative agent of COVID-19, the objective was to identify effective compounds for disease treatment, as there is currently no specific pharmaceutical for this purpose. In light of the above, the purpose of this work was to investigate a series of N-acylhydrazones derived from thiosemicarbazones and vinyl sulfones, previously reported in the literature as potential schistosomicidal agents, along with a series of hydrazones and hydrazides derived from quinolines. These compounds were to be tested against adult S. mansoni worms in both in vitro and in vivo assays, with screening conducted through High Content Screening (HCS) against SARS-CoV-2. A total of 50 compounds were synthesized, including 16 N-acylhydrazone derivatives, 27 hydrazones derived from 7-chloroquinoline, and seven hydrazides, also derived from 7-chloroquinoline. Nine of the N-acylhydrazones were tested in vitro against S. mansoni, with only GPQF-817 demonstrating activity. As a result, structural modifications were made to enhance schistosomicidal activity. Additionally, 26 quinolines were tested in vitro against S. mansoni, with five showing activity. Notably, GPQF-8Q10 proved to be the most active compound, causing the death of 100% of the worms within 24 hours at a concentration of 25 μM. GPQF-8Q8 emerged as the most promising compound in in vivo assays, reducing the number of eggs found in feces by 52.8% and the number of eggs found in the intestines by 45.8%. The quinoline derivatives exhibited low cytotoxicity in Vero cells and showed a favorable selectivity index in in vivo tests using the C. elegans animal model. Nevertheless, when subjected to assays against SARS-CoV-2 and the Chikungunya virus, none of the five of the N-acylhydrazones and 22 of the quinoline derivatives demonstrated significant activity. These studies suggest that, at least for the quinoline and hydrazone hybrid compounds, there is potential for the development of new candidates for schistosomiasis treatment. Further investigations are required to elucidate the specific mechanisms of action of these compounds. However, the findings in this work provide a promising starting point.