RESUMO
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Eritrócitos/parasitologia , Glucosefosfato Desidrogenase/metabolismo , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium gallinaceum/efeitos dos fármacos , Primaquina/análogos & derivados , Primaquina/farmacologia , Animais , Linhagem Celular Tumoral , Galinhas , Chlorocebus aethiops , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Células Hep G2 , Humanos , Malária/transmissão , Malária Aviária/tratamento farmacológico , Malária Aviária/transmissão , Camundongos , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium gallinaceum/crescimento & desenvolvimentoRESUMO
The efficient synthesis of sixteen 5-arylidene-2,4-thiazolidinediones by aldol condensation reaction of 2,4-thiazolidinedione, mono- and di-substituted arenealdehydes and KOH using ultrasound irradiation is reported. The desired compounds were obtained in a few min (10-30 min) with moderate to good yields (25-81%).
Assuntos
Tiazolidinedionas/síntese química , Tiazolidinedionas/efeitos da radiação , Ultrassom/métodos , Catálise , Hidróxidos/química , Hidróxidos/efeitos da radiação , Indicadores e Reagentes , Compostos de Potássio/química , Compostos de Potássio/efeitos da radiaçãoRESUMO
The efficient multicomponent synthesis of thiazolidinones from the reaction of arenealdehydes, mercaptoacetic acid and 2-picolilamine or 2-aminopyridine under ultrasound irradiation are reported. The reaction with 2-aminopyridine needs a Lewis acid catalysis to afford the corresponding 2-aryl-3-(pyridin-2-yl)-1,3-thiazolidin-4-ones. All novel compounds were identified and characterized by (1)H and (13)C NMR spectra. Applying the sonochemical methodology, two series of heterocyclic thiazolidinones were synthesized in good yields after short reaction times.
Assuntos
Aminopiridinas/química , Ácidos Picolínicos/química , Tiazolidinas/síntese química , Ultrassom , Estrutura Molecular , Tiazolidinas/químicaRESUMO
An efficient multicomponent reaction of arenealdehydes, mercaptoacetic acid and piperonilamine under ultrasound irradiation to afford 2-aryl-3-(piperonylmethyl)-1,3-thiazolidin-4-ones is reported. Applying this methodology, eleven heterocycles were synthesized and isolated in good yields after short reaction times.