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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1755-6) contains supplementary material, which is available to authorized users.

Synthetic strategies and medicinal perspectives of 4‐thiazolidinones: Recent developments and structure–activity relationship studies

“…The compounds showed no hemolytic activity on normal erythrocytes or on G6PD‐deficient erythrocytes compared to the standard primaquine. Compound 236a was discovered to have potent antimalarial activity, reducing exoerythrocytic forms of Plasmodium berghei [59].…”

“…The compounds showed no hemolytic activity on normal erythrocytes or on G6PD-deficient erythrocytes compared to the standard primaquine. Compound 236a was discovered to have potent antimalarial activity, reducing exoerythrocytic forms of Plasmodium berghei[59].2.5.5 | Anti-Alzheimer's derivativesBilgicli et al made new piperonyl-based 4-thiazolidinone derivatives and tested them for their ability to stop enzymes like acetylcholinesterase, human carbonic anhydrase I and II, and -glycosidase. The target compounds were prepared through the reaction of piperonylamine 237 with appropriate aromatic aldehydes to give the intermediates 238, which underwent cyclization in the presence of mercaptoacetic acid in ethyl alcohol to yield the desired piperonyl-based 4-thiazolidinone derivatives 239 (Scheme 52).…”

Tafenoquine: A Step toward Malaria Elimination

“…As one example, a cohort of primaquine-thiazolidinones were generated and shown to suppress rodent and avian malaria transmission (Figure ). Despite the slightly lower activity against P. berghei liver-stage schizonts in vitro and in vivo , the cytotoxicity and hemolytic toxicity were greatly reduced in different cell types as well as G6PD-deficient human RBCs . Perhaps similar modifications to tafenoquine or NPC1161B would facilitate the search for safer substitutes for treating G6PD-deficient individuals while retaining their long-acting, antirelapse, and broad-spectrum activities.…”

Primaquine derivatives: Modifications of the terminal amino group

“…Primaquine-thiazolidinones 191e205 were recently prepared by multicomponent one-pot reactions from primaquine, mercaptoacetic acid and aromatic aldehyde bearing halogen, nitro, methoxy, methyl or cyano substituents at various positions (Scheme 14) [131].…”