Planta Med 2016; 82(S 01): S1-S381
DOI: 10.1055/s-0036-1596768
Abstracts
Georg Thieme Verlag KG Stuttgart · New York

Flavone derivatives: a promising tool in the fight against malaria

F Nardella
1  Equipe Chimie Biologie Intégrative – Laboratoire d'Innovation Thérapeutique, UMR CNRS-Unistra 7200, Faculté de Pharmacie, 74 route du Rhin, CS60024, 67401 Illkirch Cedex, France
2  Institut de Parasitologie et de Pathologie Tropicale de Strasbourg, Faculté de Médecine, 3 rue Koeberlé, 67000 Strasbourg, France
,
S Stiebing
3  Centre d'Etudes et de Recherches sur le Médicament en Normandie, Université de Caen Basse-Normandie, Boulevard Becquerel, 14032 Caen Cedex, France
,
P Wagner
1  Equipe Chimie Biologie Intégrative – Laboratoire d'Innovation Thérapeutique, UMR CNRS-Unistra 7200, Faculté de Pharmacie, 74 route du Rhin, CS60024, 67401 Illkirch Cedex, France
,
V Collot
3  Centre d'Etudes et de Recherches sur le Médicament en Normandie, Université de Caen Basse-Normandie, Boulevard Becquerel, 14032 Caen Cedex, France
,
M Kaiser
4  Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland
,
B Witkowski
5  Unité d'Epidémiologie Moléculaire du Paludisme, Institut Pasteur du Cambodge, 5 Boulevard Monivong, Phnom Penh, Cambodia
,
D Menard
5  Unité d'Epidémiologie Moléculaire du Paludisme, Institut Pasteur du Cambodge, 5 Boulevard Monivong, Phnom Penh, Cambodia
,
M Schmitt
1  Equipe Chimie Biologie Intégrative – Laboratoire d'Innovation Thérapeutique, UMR CNRS-Unistra 7200, Faculté de Pharmacie, 74 route du Rhin, CS60024, 67401 Illkirch Cedex, France
,
E Candolfi
2  Institut de Parasitologie et de Pathologie Tropicale de Strasbourg, Faculté de Médecine, 3 rue Koeberlé, 67000 Strasbourg, France
,
C Vonthron-Sénécheau
1  Equipe Chimie Biologie Intégrative – Laboratoire d'Innovation Thérapeutique, UMR CNRS-Unistra 7200, Faculté de Pharmacie, 74 route du Rhin, CS60024, 67401 Illkirch Cedex, France
› Author Affiliations
Further Information

Publication History

Publication Date:
14 December 2016 (online)

 

P. falciparum malaria is the deadliest parasitic disease with 438.000 deaths every year [1]. The increasing resistance of Plasmodium to antimalarials, notably to the first line treatment, artemisinins [2], is a major threat and fast acting drugs with new mechanisms of action are needed. We isolated an active biflavonoid from Campnosperma panamense (Anacardiaceae, IC50= 480 nM in vitro on P. falciparum K1 multi-resistant strain) [3], and developed novel simplified synthetic analogs (MR series) with improved pharmacological and pharmacokinetic profiles. One of these analogs, MR70 is parasiticidal on early blood stages of P. falciparum in less than 6 hours. Moreover, MR70 and its analog MR87 exhibit a partial in vivo antimalarial activity, reducing parasitemia by 35% to 70%, respectively, on day 4 in a murine model (P. berghei ANKA, 100 mg/kg for 4 days). But these compounds showed no significant improvement in terms of survival. A structure-activity relationship study is still ongoing to further improve these results. MR70 is a fast acting drug. To our knowledge, it is the only compound targeting specifically these stages, suggesting a potential new mechanism of action. Interestingly, this stage is specifically the one that is resistant to artemisinins [4] and we are currently assessing MR70 efficacy on resistant isolates. Further investigation is needed to optimize MR70 activity and to understand its underlying mechanism(s) of action.

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Acknowledgements: Fondation Groupe Pasteur Mutualité, Fondation Pierre Ledoux Jeunesse Internationale, Réseau International des Instituts Pasteur.

Keywords: Plasmodium, flavone, in vivo, artemisinin, resistance, fast acting drug.

References:

[1] World malaria report, 2015, WHO. http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/

[2] Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008; 24: 2619 – 2620

[3] Weniger B, Vonthron-Sénécheau C, Arango GJ, Kaiser M, Brun R, Anton R. A bioactive biflavonoid from Campnosperma panamense. Fitoterapia 2004; 7: 764 – 767

[4] Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P, Kim S, Lim P, Mao S, Sopha C, Sam B, Anderson J, Duong S, Chuor CM, Taylor WRJ, Suon S, Mercereau-Puijalon O, Fairhurst RM, Menard D. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis 2013; 12: 1043 – 1049