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Fármacos híbridos para o tratamento da malária baseados em complexos de iões metálicos
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Advisor(s)
Abstract(s)
A malária é uma das doenças mais antigas e prevalentes do mundo. A transmissão para os humanos ocorre através da picada de um mosquito fêmea Anopheles infetado por parasitas do género Plasmodium. As espécies infetantes P. falciparum e P. vivax são as que constituem maior ameaça, originando as maiores taxas de morbilidade e mortalidade. Os casos de malária são de maior prevalência nas zonas tropicais e subtropicais de países em desenvolvimento, constituindo a doença um entrave ao desenvolvimento desses países.
O tratamento atual para a malária passa pelo uso de cloroquina (CQ) ou terapia combinada à base de Artemisinina (ACT), sendo que para casos de malária não complicada provocada por P. falciparum, o tratamento recomendado para as crianças e adultos, excetuando grávidas no primeiro trimestre de gestação, envolve o uso de uma das várias terapêuticas ACT, como por exemplo a associação Arteméter + Lumefantrina (LF). A seleção para resistências à CQ e à artemisinina e seus derivados semissintéticos, decorrente de mutações induzidas pelo parasita, têm conduzido a perda de eficácia destes compostos no tratamento da malária. Desta forma, é primordial compreender os diferentes mecanismos de ação dos antimaláricos e as suas limitações, com vista a melhorar as propriedades farmacodinâmicas e farmacocinéticas dos compostos em uso, através da inserção de novas entidades farmacológicas que possam por sinergismo melhorar a resposta final da terapêutica, ou através do desenvolvimento de novos fármacos, preferencialmente moléculas capazes de atuar em alvos terapêuticos do parasita menos explorados.
A presente dissertação resume as terapêuticas atuais para o tratamento da malária e as novas moléculas híbridas que têm sido propostas, com especial foco nos complexos híbridos contendo entidades metálicas na sua estrutura, discutindo a sua atividade antiplasmodial e potencial terapêutico, face à atividade dos antimaláricos já existentes, como a CQ
Malaria is one of the oldest and most prevalent diseases in the world . It is transmitted to humans through the bite of female Anopheles mosquito es infected with parasites of the genus Plasmodium spp T he species P. falciparum and P. v ivax are the ones that constitute the greatest threat , leading to the highest rates of morbidity and mortality. Cases of m alaria are more prevalent in tropical and subtropical areas of developing countries , representing a burden to the welfare of the populations and the development of countries affected Current treatment for malaria involves the use of chloroquine (CQ) or Artemisinin based Combination Therapy ( A CT F or uncomplicated malaria due to infection by P falciparum the recommended treatment for children and adults, except ing for women in the first trimester of pregnancy , involves the use of an A CT, for instance the association of Artem e ter + L umefantrine . Development of r esistance to CQ and artemisinin by the parasite has rendered these compounds less effective against malaria. As such , it is essential to understand the different mechanisms of action of current antimalarials, as well as their limitations, with a view to improving the pharmacodynamic and pharmacokinetic properties of the antimalarial chemotypes in use , promote their association with new entities that can synergistically improve the therapeutic response or develop novel compounds , preferably acting on different therapeutic targets of the parasite. The present dissertation summarizes the chemotherapeutic solutions in use for treatment of malaria as well as the novel compounds under development for malaria chemotherapy , with special focus on the design of hybrid molecules incorporating metallic entities in their structure discussing their respective antiplasmodial activity and properties, vis a vis the activity of the already existing antimalarials, like CQ.
Malaria is one of the oldest and most prevalent diseases in the world . It is transmitted to humans through the bite of female Anopheles mosquito es infected with parasites of the genus Plasmodium spp T he species P. falciparum and P. v ivax are the ones that constitute the greatest threat , leading to the highest rates of morbidity and mortality. Cases of m alaria are more prevalent in tropical and subtropical areas of developing countries , representing a burden to the welfare of the populations and the development of countries affected Current treatment for malaria involves the use of chloroquine (CQ) or Artemisinin based Combination Therapy ( A CT F or uncomplicated malaria due to infection by P falciparum the recommended treatment for children and adults, except ing for women in the first trimester of pregnancy , involves the use of an A CT, for instance the association of Artem e ter + L umefantrine . Development of r esistance to CQ and artemisinin by the parasite has rendered these compounds less effective against malaria. As such , it is essential to understand the different mechanisms of action of current antimalarials, as well as their limitations, with a view to improving the pharmacodynamic and pharmacokinetic properties of the antimalarial chemotypes in use , promote their association with new entities that can synergistically improve the therapeutic response or develop novel compounds , preferably acting on different therapeutic targets of the parasite. The present dissertation summarizes the chemotherapeutic solutions in use for treatment of malaria as well as the novel compounds under development for malaria chemotherapy , with special focus on the design of hybrid molecules incorporating metallic entities in their structure discussing their respective antiplasmodial activity and properties, vis a vis the activity of the already existing antimalarials, like CQ.
Description
Keywords
Malária Plasmodium spp Resistências a antimaláricos Cloroquina Terapias atc Complexos metálicos