Publicação
Novel mitochondrial electron transport-chain inhibitors as potencial antimalarial agents
| Resumo: | The bc1 complex is an attractive a validated drug target in the fight against malaria. The mitochondrial electron transport-chain, in which this complex is involved, is fundamental in Plasmodium sp.. The parasites do not possess the requested enzymatic machinery to salvage pyrimidines from their metabolism and, therefore, have to perform de novo pyrimidine biosynthesis to enable their survival. Blockage of this pathway leads to their death. The present work focused on the development of novel inhibitors with structural similarity to known bc1 complex antagonists. Also, this work aimed at delivering novel leads for drug development. 4-Pyridonimines with extended lipophilic side chains showed potential as isosteric replacements for 4(1H)-pyridones. The structure of those compounds was derived from structure-based design and they were active in vitro against P. falciparum. The most active compound presented an IC50 of ca. 1 μM, and the mode of action was hypothesized through docking studies. A series of 4-quinolonimines was also prepared. Those presented enhanced antiplasmodial activity in comparison to the previous set of compounds, with IC50s ranging from 0.5 to 1 μM. These also showed outstanding activity against the liver stage of P. berghei. Despite the mechanism of action not being clear at the moment, the compounds demonstrated to bind to hematin. However, the docking studies in the Qo site of the bc1 complex also showed a good fit of the compounds. Flavones were also synthesized with the aim of optimizing the antiplasmodial activity of stigmatellin. All compounds showed modest activity against both blood and liver stages, with the most active compound presenting an IC50 of 6 μM against P. falciparum W2 strain. Finally, the virtual screening study that was performed allowed the discovery of novel scaffolds with antiplasmodial activity. A combination of ligand- and receptor-based approaches was successful in retrieving 7 active compounds out of the 23 that were purchased. One of them presented an IC50 of 2 μM in vitro. |
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| Autores principais: | Rodrigues, Tiago Correia de Oliveira, 1982- |
| Assunto: | Teses de doutoramento - 2010 |
| Ano: | 2010 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | The bc1 complex is an attractive a validated drug target in the fight against malaria. The mitochondrial electron transport-chain, in which this complex is involved, is fundamental in Plasmodium sp.. The parasites do not possess the requested enzymatic machinery to salvage pyrimidines from their metabolism and, therefore, have to perform de novo pyrimidine biosynthesis to enable their survival. Blockage of this pathway leads to their death. The present work focused on the development of novel inhibitors with structural similarity to known bc1 complex antagonists. Also, this work aimed at delivering novel leads for drug development. 4-Pyridonimines with extended lipophilic side chains showed potential as isosteric replacements for 4(1H)-pyridones. The structure of those compounds was derived from structure-based design and they were active in vitro against P. falciparum. The most active compound presented an IC50 of ca. 1 μM, and the mode of action was hypothesized through docking studies. A series of 4-quinolonimines was also prepared. Those presented enhanced antiplasmodial activity in comparison to the previous set of compounds, with IC50s ranging from 0.5 to 1 μM. These also showed outstanding activity against the liver stage of P. berghei. Despite the mechanism of action not being clear at the moment, the compounds demonstrated to bind to hematin. However, the docking studies in the Qo site of the bc1 complex also showed a good fit of the compounds. Flavones were also synthesized with the aim of optimizing the antiplasmodial activity of stigmatellin. All compounds showed modest activity against both blood and liver stages, with the most active compound presenting an IC50 of 6 μM against P. falciparum W2 strain. Finally, the virtual screening study that was performed allowed the discovery of novel scaffolds with antiplasmodial activity. A combination of ligand- and receptor-based approaches was successful in retrieving 7 active compounds out of the 23 that were purchased. One of them presented an IC50 of 2 μM in vitro. |
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