title: Biological activities of nitidine, a potential anti-malarial lead compound.
abstract: BACKGROUND
  Nitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world. The widespread use of these therapies stresses the importance of studying this molecule in the context of malaria control. However, little is known about its potential as an anti-plasmodial drug, as well as its mechanism of action.
  
  
  METHODS
  In this study, the anti-malarial potential of nitidine was evaluated in vitro on CQ-sensitive and -resistant strains. The nitidine's selectivity index compared with cancerous and non-cancerous cell lines was then determined. In vivo assays were then performed, using the four-day Peter's test methodology. To gain information about nitidine's possible mode of action, its moment of action on the parasite cell cycle was studied, and its localization inside the parasite was determined using confocal microscopy. The in vitro abilities of nitidine to bind haem and to inhibit β-haematin formation were also demonstrated.
  
  
  RESULTS
  Nitidine showed similar in vitro activity in CQ-sensitive and resistant strains, and also a satisfying selectivity index (> 10) when compared with a non-cancerous cells line. Its in vivo activity was moderate; however, no sign of acute toxicity was observed during treatment. Nitidine's moment of action on the parasite cycle showed that it could not interfere with DNA replication; this was consistent with the observation that nitidine did not localize in the nucleus, but rather in the cytoplasm of the parasite. Nitidine was able to form a 1-1 complex with haem in vitro and also inhibited β-haematin formation with the same potency as chloroquine.
  
  
  CONCLUSIONS
  Nitidine can be considered a potential anti-malarial lead compound. Its ability to complex haem and inhibit β-haematin formation suggests a mechanism of action similar to that of chloroquine. The anti-malarial activity of nitidine could therefore be improved by structural modification of this molecule to increase its penetration of the digestive vacuole in the parasite, where haemoglobin metabolization takes place.
authors.affiliation: Université de Toulouse, UPS, UMR 152 (Laboratoire Pharmadev), Faculté de Pharmacie, 35 Chemin des maraîchers, F-31062 Toulouse cedex 9, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Bouquet
authors.forename: Marion
authors.initials: M
authors.lastname: Rivaud
authors.forename: Séverine
authors.initials: S
authors.lastname: Chevalley
authors.forename: Eric
authors.initials: E
authors.lastname: Deharo
authors.forename: Valérie
authors.initials: V
authors.lastname: Jullian
authors.forename: Alexis
authors.initials: A
authors.lastname: Valentin
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000302:isolation & purification / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000187:drug effects / Q000469:parasitology; D004351:Drug Resistance; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006367:HeLa Cells; D006418:Heme / Q000378:metabolism; D006420:Hemeproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria; D051379:Mice; D018613:Microscopy, Confocal; D010961:Plasmodium / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D014709:Vero Cells; D032106:Zanthoxylum / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D053119:Benzophenanthridines; D006420:Hemeproteins; C020753:hemozoin; D006418:Heme; C013615:nitidine