Biological activities of nitidine, a potential anti-malarial lead compound

Malaria Journal

Research

Eric Deharo¹  Marion Rivaud¹  Séverine Chevalley¹  Jérome Bouquet¹  Valérie Jullian¹  Alexis Valentin¹ 

[1] Université de Toulouse; UPS; UMR 152 (Laboratoire Pharmadev), Faculté de Pharmacie, 35 Chemin des maraîchers, F-31062, Toulouse cedex 9, France;Institut de Recherche pour le Développement (IRD); UMR 152 (Laboratoire Pharmadev), 118, rte de Narbonne, F-31062, Toulouse cedex 9, France;

关键词: Malaria;    Chloroquine;    Vero Cell;    Selectivity Index;    Food Vacuole;   

DOI  :  10.1186/1475-2875-11-67

 received in 2011-11-08, accepted in 2012-03-09,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundNitidine 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.MethodsIn 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.ResultsNitidine 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.ConclusionNitidine 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.

【 授权许可】

Unknown   
© Bouquet et al; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.