Planta Med 2013; 79 - PA26
DOI: 10.1055/s-0033-1351930

Synthetic flavone derivatives as potential new in vivo antimalarial agents

F Nardella 1, V Collot 2, B Weniger 1, M Kaiser 3, M Schmitt 1, E Candolfi 4, C Vonthron 1
  • 1Université de Strasbourg, Faculté de Pharmacie, Laboratoire d'Innovation Thérapeutique – UMR CNRS 7200. CS60024, 67401 Illkirch Cedex, France
  • 2Université de Caen Basse Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie – UPRES EA 4258 – FR CNRS 3038 INC3 M, Boulevard Becquerel, 14032 CAEN Cedex, France
  • 3Swiss Tropical and Public Health Institution. Socinstrasse 57, CH-4002 Basel Switzerland
  • 4Université de Strasbourg, Faculté de Médecine, Institut de Parasitologie et de Pathologie Tropicale, EA-7292 DHPI, 3 rue Koeberlé, 67000 Strasbourg, France

Malaria is a burden causes approximately 660.000 deaths every year, mostly among African children. Since 2000, mortality rates have fallen by more than 25%, indicating that the WHO Global Malaria Program is efficient1. However, the emergence of resistance to artemisinin could reverse the trend of decreasing mortality2. Consequently, there is an urgent need of discovering new treatments associated with the exploration of novel targets. Thus, we are developing new synthetic antimalarial agents with an original structure inspired by nature. The isolation of an active biflavonoid from Campnosperma panamense (Anacadiaceae) led us to the development of simplified synthetic analogs. Structure Activity Relationship (SAR) study is still in progress, but several active compounds have already been synthesized. Nevertheless, the most active compounds in vitro are poorly bioavailable and were inactive in vivo on the murine model Plasmodium berghei ANKA. One compound, MR70, is less active than others (IC50= 1.9µM, P. falciparum strain K1) but exhibits an interesting bioavailability that could potentially induce an in vivo activity (plasma level of 8.1µM two hours after an intraperitoneal injection of 100 mg/kg). Indeed, in preliminary studies conducted on mice infected intraperitoneally by an inoculum of 2.106 parasites (P. berghei ANKA), MR70 enabled to reverse the parasitemia of infected mice by 50% when administered intraperitoneally one hour after parasites inoculation and for 3 more days (4 × 100 mg/kg). Within this context, the SAR study should be pursued in order to increase the antimalarial activity and the bioavailability. Once an active molecule will be satisfactory, we will try to elucidate its mechanism of action, with the hope of discovering a new target.

References:

[1] World Malaria Report, 2012

[2] Phyo, A. P. et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet 379, 1960 – 1966 (2012).