Primaquine-thiazolidinones block malaria transmission and development of the liver exoerythrocytic forms

Anna Caroline C Aguiar,Fidel Zavala,Antoniana U Krettli,Photini Sinnis,Tony H Katsuragawa,Flávio Jr B Figueiredo,Wilson Cunico,Patrícia D Neuenfeldt,Bruna B Drawanz

doi:10.1186/s12936-017-1755-6

Abstract

BackgroundPrimaquine 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.ResultsAll 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.ConclusionsThe 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.

Highlights

Primaquine is an anti-malarial used to prevent Plasmodium vivax relapses and malaria transmission
Aiming to find candidates less toxic than PQ, a total of 15 PQ thiazolidinone derivatives (PQ-TZs) were synthesized through modification of the amino-terminal group [9] and evaluated for: (i) in vitro haemolytic activity against glucose-6-phosphate dehydrogenase (G6PD) normal or deficient erythrocytes; (ii) toxicity in vitro to hepatoma and kidney cells; (iii) blocking effect on the malaria sporogonic cycle in mosquitoes and; (iv) ability to interfere with the development of Plasmodium berghei liver stages in vivo and in vitro
Primaquine derivatives are not as toxic as primaquine To evaluate the toxicity of PQ derivatives on nucleated cells in vitro, HepG2 cells, a human hepatoma cell line, and a monkey kidney cell line (BGM), were incubated with the compounds for 24 h

Summary

Introduction

Primaquine is an anti-malarial used to prevent Plasmodium vivax relapses and malaria transmission. 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. Aiming to find candidates less toxic than PQ, a total of 15 PQ thiazolidinone derivatives (PQ-TZs) were synthesized through modification of the amino-terminal group [9] and evaluated for: (i) in vitro haemolytic activity against G6PD normal or deficient erythrocytes; (ii) toxicity in vitro to hepatoma and kidney cells; (iii) blocking effect on the malaria sporogonic cycle in mosquitoes and; (iv) ability to interfere with the development of Plasmodium berghei liver stages in vivo and in vitro.

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