title: Primaquine-thiazolidinones block malaria transmission and development of the liver exoerythrocytic forms.
abstract: 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.
authors.affiliation: Centro de Pesquisas René Rachou-Fiocruz, Av. Augusto de Lima 1715, Belo Horizonte, MG, 30190-002, Brazil.|Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Alfredo Balena, 190, Belo Horizonte, MG, 30130-100, Brazil.|Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD, 21205, USA.
authors.forename: Anna Caroline C
authors.initials: AC
authors.lastname: Aguiar
authors.affiliation: Centro de Pesquisas René Rachou-Fiocruz, Av. Augusto de Lima 1715, Belo Horizonte, MG, 30190-002, Brazil.
authors.forename: Flávio Jr B
authors.initials: FJ
authors.lastname: Figueiredo
authors.affiliation: Laboratório de Química Aplicada à Bioativos, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, UFPel, Campus Universitário s/no, Pelotas, RS, 98001-970, Brazil.
authors.forename: Patrícia D
authors.initials: PD
authors.lastname: Neuenfeldt
authors.affiliation: Laboratório de Epidemiologia, Fundação Osvaldo Cruz-Fiocruz Rondônia, Bairro Lagoa, Porto Velho, RO, Brazil.
authors.forename: Tony H
authors.initials: TH
authors.lastname: Katsuragawa
authors.affiliation: Laboratório de Química Aplicada à Bioativos, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, UFPel, Campus Universitário s/no, Pelotas, RS, 98001-970, Brazil.
authors.forename: Bruna B
authors.initials: BB
authors.lastname: Drawanz
authors.affiliation: Laboratório de Química Aplicada à Bioativos, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, UFPel, Campus Universitário s/no, Pelotas, RS, 98001-970, Brazil.
authors.forename: Wilson
authors.initials: W
authors.lastname: Cunico
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD, 21205, USA.
authors.forename: Photini
authors.initials: P
authors.lastname: Sinnis
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD, 21205, USA.
authors.forename: Fidel
authors.initials: F
authors.lastname: Zavala
authors.affiliation: Centro de Pesquisas René Rachou-Fiocruz, Av. Augusto de Lima 1715, Belo Horizonte, MG, 30190-002, Brazil. akrettli@cpqrr.fiocruz.br.|Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Alfredo Balena, 190, Belo Horizonte, MG, 30130-100, Brazil. akrettli@cpqrr.fiocruz.br.
authors.forename: Antoniana U
authors.initials: AU
authors.lastname: Krettli
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002645:Chickens; D002522:Chlorocebus aethiops; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000635:transmission; D008289:Malaria, Avian / Q000188:drug therapy / Q000635:transmission; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010964:Plasmodium gallinaceum / Q000187:drug effects* / Q000254:growth & development; D011319:Primaquine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D005954:Glucosephosphate Dehydrogenase; D011319:Primaquine
keywords: Blocking malaria transmission; Exoerythrocytic stages, sporozoites; Malaria; Plasmodium berghei; Plasmodium gallinaceum; Sporogony; Thiazolidinones