Publicação
Synthesis and evaluation of chemical probes to study the biology of liver stage malaria parasites
| Resumo: | Malaria remains one of the most prevalent and life-threatening diseases. It is caused by infection with parasites of the genus Plasmodium and transmitted to humans through female Anopheles mosquitoes. Several species of Plasmodium cause malaria in humans but P. falciparum is the most lethal specie. Malaria parasites have a complex life cycle and in order to eradicate the disease, every stages should be considered for treatment. Due to the appearance and spread of resistant parasites to current therapies, it is urgent to discover novel antimalarial drugs that are effective against both blood and liver stages of infection by malaria parasites and endowed with the ability to block the transmission of the disease to mosquito vectors. Currently, artemisinin-based combination therapies are used for uncomplicated malaria. The endoperoxide bond of artemisinin plays a key role in the fight against disease. As it only activated by a high concentration of iron (II) that is present in the digestive vacuole of the parasites infecting erythrocytes, where they degrade host hemoglobin. In contrast, basal Fe (II) concentration in mammalian cells is very low. This particularity ensures the high selectivity of endoperoxide drugs. The goal of this work was to prepare an activity-based probe (ABP) designed to identify potential molecular targets of 1,2,4,5-tetraoxane-cyanopyrimidine hybrid antimalarials. Several of these hybrids have shown to be active against the blood and liver stages of malaria parasites, and thus identification of the molecular targets associated to this dual-activity profile may become relevant in the discovery of new antimalarial drugs to be used in eradication campaigns. A hybrid ABP combining the 1,2,4,5-tetraoxane core and a cyanopyrimidine containing an alkyne handle for click chemistry was designed and synthesized. The tetraoxane contained an adamantyl moiety to confer stability to the endoperoxide motif. The synthesis of a negative ABP tetraoxane-pyrimidine nitrile probe was performed. Finally, in order to monitor the distribution and accumulation of this compound, we coupled the ABP with a fluorescent NBD-based azide reagent via click (CuAAC) chemistry to give the corresponding hybrid fluorescent probe in moderate yields. |
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| Autores principais: | Ribeiro, Joana Rita Leite |
| Assunto: | Malária Tetraoxanos Cianopirimidina Sonda baseada na atividade Teses de mestrado - 2017 |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Malaria remains one of the most prevalent and life-threatening diseases. It is caused by infection with parasites of the genus Plasmodium and transmitted to humans through female Anopheles mosquitoes. Several species of Plasmodium cause malaria in humans but P. falciparum is the most lethal specie. Malaria parasites have a complex life cycle and in order to eradicate the disease, every stages should be considered for treatment. Due to the appearance and spread of resistant parasites to current therapies, it is urgent to discover novel antimalarial drugs that are effective against both blood and liver stages of infection by malaria parasites and endowed with the ability to block the transmission of the disease to mosquito vectors. Currently, artemisinin-based combination therapies are used for uncomplicated malaria. The endoperoxide bond of artemisinin plays a key role in the fight against disease. As it only activated by a high concentration of iron (II) that is present in the digestive vacuole of the parasites infecting erythrocytes, where they degrade host hemoglobin. In contrast, basal Fe (II) concentration in mammalian cells is very low. This particularity ensures the high selectivity of endoperoxide drugs. The goal of this work was to prepare an activity-based probe (ABP) designed to identify potential molecular targets of 1,2,4,5-tetraoxane-cyanopyrimidine hybrid antimalarials. Several of these hybrids have shown to be active against the blood and liver stages of malaria parasites, and thus identification of the molecular targets associated to this dual-activity profile may become relevant in the discovery of new antimalarial drugs to be used in eradication campaigns. A hybrid ABP combining the 1,2,4,5-tetraoxane core and a cyanopyrimidine containing an alkyne handle for click chemistry was designed and synthesized. The tetraoxane contained an adamantyl moiety to confer stability to the endoperoxide motif. The synthesis of a negative ABP tetraoxane-pyrimidine nitrile probe was performed. Finally, in order to monitor the distribution and accumulation of this compound, we coupled the ABP with a fluorescent NBD-based azide reagent via click (CuAAC) chemistry to give the corresponding hybrid fluorescent probe in moderate yields. |
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