The online version of this article (doi:10.1186/s12936-017-1755-6) contains supplementary material, which is available to authorized users.
Primaquine is an anti-malarial used to prevent Plasmodium vivax relapses and malaria transmission. However, PQ metabolites cause haemolysis in patients deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD). Fifteen PQ-thiazolidinone derivatives, synthesized through one-post reactions from primaquine, arenealdehydes and mercaptoacetic acid, were evaluated in parallel in several biological assays, including ability to block malaria transmission to mosquitoes.
All primaquine derivatives (PQ-TZs) exhibited lower cell toxicity than primaquine; none caused haemolysis to normal or G6PD-deficient human erythrocytes in vitro. Sera from mice pretreated with the test compounds thus assumed to have drug metabolites, caused no in vitro haemolysis of human erythrocytes, whereas sera from mice pretreated with primaquine did cause haemolysis. The ability of the PQ-TZs to block malaria transmission was evaluated based on the oocyst production and percentage of mosquitoes infected after a blood meal in drug pre-treated animals with experimental malaria caused by either Plasmodium gallinaceum or Plasmodium berghei; four and five PQ-TZs significantly inhibited sporogony in avian and in rodent malaria, respectively. Selected PQ-TZs were tested for their inhibitory activity on P. berghei liver stage development, in mice and in vitro, one compound (4m) caused a 3-day delay in the malaria pre-patent period.
The compound 4m was the most promising, blocking malaria transmissions and reducing the number of exoerythrocytic forms of P. berghei (EEFs) in hepatoma cells in vitro and in mice in vivo. The same compound also caused a 3-day delay in the malaria pre-patent period.
Additional file 1: Table S1. Inhibition of Plasmodium gallinaceum sporogony by PQ-TZ derivatives in Aedes mosquitoes blood fed 6 h after oral treatment (6 h) with one compound dose in relation to control mosquitoes fed in the same chicken before treatment (0 h). Table S2. Inhibition of Plasmodium berghei sporogony by PQ-TZ derivatives in Anopheles mosquitoes blood fed 2 h after oral treatment (2 h) with one dose of each compound in relation to mosquitoes blood fed in the mouse before drug treatment (0 h). Figure S1. Plasmodium berghei liver parasite burden 42 h after intravenous inoculation with sporozoites, measured by quantitative PCR in mice treated with PQ-TZ.
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- Primaquine-thiazolidinones block malaria transmission and development of the liver exoerythrocytic forms
Anna Caroline C. Aguiar
Flávio Jr. B. Figueiredo
Patrícia D. Neuenfeldt
Tony H. Katsuragawa
Bruna B. Drawanz
Antoniana U. Krettli
- BioMed Central
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