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Doctoral Thesis
DOI
10.11606/T.42.2013.tde-19032014-170035
Document
Author
Full name
Desirée Cigaran Schuck
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2013
Supervisor
Committee
Garcia, Celia Regina da Silva (President)
Soares, Irene da Silva
Wrenger, Carsten
Wunderlich, Gerhard
Zalis, Mariano Gustavo
Title in Portuguese
Novos compostos sintéticos com ação no ciclo de vida de parasitas da malária humana, Plasmodium falciparum .
Keywords in Portuguese
Plasmodium
Antimaláricos
Citometria de fluxo
Malária
Melatonina
Abstract in Portuguese
Apesar dos esforços mundiais a malária ainda é uma doença com altas taxas de morbidade e mortalidade. Investigamos o efeito de moléculas sintéticas relacionadas a melatonina e a triptamina no ciclo celular de P. falciparum, bem como mostramos que essa classe de compostos apresenta ação antimalárica significativa. Avaliamos também 5 novas hidroxinaftoquinonas sintéticas em cultura in vitro de P. falciparum, todas apresentaram atividade antimalárica, tendo N3 destacado-se por apresentar um IC50 na faixa nanomolar. Mostramos que o possível mecanismo de ação de N3 é inibindo o potencial de membrana mitocondrial. Em células de mamíferos HEK293, N3 não mostrou toxicidade significativa. No modelo de infecção utilizando P. berghei (ANKA GFP) o composto N3 não foi capaz de curar os animais infectados, apesar da redução significativa da parasitemia no quarto dia após a infecção. Nessa tese mostramos o uso da citometria de fluxo como uma ferramenta prática possibilitando a avaliação do ciclo do parasita.
Title in English
New synthetic compounds with action on the life cycle of the human parasites Plasmodium falciparum.
Keywords in English
Plasmodium
Antimalarials
Flow Cytometry
Malaria
Melatonin
Abstract in English
Despite the worldwide effort the malaria is still a devastating disease. We have tested melatonin and synthetic related indoles molecules on P. falciparum cell cycle and showed the potential antimalarial activity. We have tested 5 new synthetic hydroxynaphthoquinones on in vivo culture of P. falciparum 3D7, all of them showed antimalarial activity, but only N3 showed an IC50 in the nanomolar range. We demonstrate that the probable mechanism of action of N3 is inhibiting the mitochondrial membrane potential. In mammalian cells, N3 did not show cytotoxicity. Subsequently, we tested the compound N3 in murine infection model of P. berghei. After 4 days the parasitemia was assessed and the survival monitored for 30 days. N3 was not able to cure the infected animals, despite the initial reduction of parasitemia on 4th day post-infection. In this thesis we have demonstrated the use of flow cytometry as a useful and powerful tool in malaria research.
 
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Publishing Date
2014-03-29
 
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