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

Jérome Bouquet,Marion Rivaud,Eric Deharo,Séverine Chevalley,Valérie Jullian,Alexis Valentin

doi:10.1186/1475-2875-11-67

Abstract

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.

Highlights

Nitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world
The resistance index (RI) of nitidine was lower than the RI of chloroquine (1.55 and 0.95 for F32/FcB1 and F32/FcM29, respectively, versus more than 4 for chloroquine, Table 1)
At concentrations ranging from one tenth to ten times the IC50, the highest inhibition of P. falciparum growth was obtained during the two first thirds of the cycle, with a maximum inhibition between hours 8 and 24 (Figure 2)

Summary

Introduction

Nitidine is thought to be the main active ingredient in several traditional anti-malarial remedies used in different parts of the world. Recent estimates indicate that more than 200 million clinical episodes of malaria and approximately about 1 million deaths due to Plasmodium falciparum occur worldwide annually. Resistance of this parasite to virtually all of the currently available anti-malarial drugs is of great concern; new, inexpensive drugs are urgently needed to address the global burden of malaria. The widespread use of nitidine stresses the importance of this molecule in the field of malaria control. Cytotoxic and anti-cancerous properties were reported [8], including nitidine-mediated inhibition of topoisomerase I [9], which may indicate potentially important toxicity and could rule out this molecule’s use as an anti-malarial drug

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