New antiprotozoal drugs refered as antimicrotubular haloacetamidobenzoates
Abstract number: 1733_1174
Fellous A., Valentin A., Andrade S., Kalil J., Veauvy M., Le Borgne M., Le Pape P.
Objectives: Protozoal diseases constitute a major world public health problem. Malaria conveyed in the yearly deaths of 2,000,000 children and there would be 300 millions of new cases per year. Concerning leishmaniasis, it is estimated that approximately up to 2030 million people in 88 countries are infected. Chagas' disease is an anthropozoonosis due to Trypanosoma cruzi. Chagas' disease is widespread in Latin America where it strikes 20 millions of people. The growing problem of drug resistance has greatly complicated the treatment for these parasitic diseases. There is still a real need for active new compounds that would provide therapeutic benefits with less side effects and a defined cell target.
Methods: A new family of patented antimicrotubule drugs named haloacetamidobenzoates (MF and GR derivatives) was designed and evaluated against three protozoa, Plasmodium, Leishmania and Trypanosoma. In vitro and in vivo models were developed. Mechanism of action was studied by scanning electron microscopy, immunocytochemistry and microtubule assembly assay.
Results: MF29 and GR37 were found to be cytotoxic in vitro on chloroquine resistant Plasmodium falciparum strains, Leishmania spp. and Trypanosoma with IC50 values about 0.1 mM. These compounds were shown to be very poor inhibitors of in vitro mammal brain microtubule assembly indicating parasite specificity. Parasite MAP2-like proteins may increase strongly the sensitivity of parasite tubulins to the drug. Concerning Plasmodium, the in vitro data have been confirmed in an in vivo murine model using Plasmodium berghei showing a high reduction in mortality percentage and a moderate activity on parasitaemia. In the visceral and cutaneous murine leishmaniasis models, the reference drug antimoniate meglumine (Glucantime) showed a less marked reduction in parasite organ load that the MF 29 compound. Moreover a significant reduction of mortality was observed when infected mice by Trypanosoma cruzi are treated by MF 29 compound.
Conclusion: These data demonstrated the high level of antiprotozoal activity of MF derivatives compared to other antimicrotubule agents or other antileshmanial drugs. An interesting point of our work is related to the fact that we have established the mechanism of action of haloacetamidobenzoates with the precise identification of the cellular target.
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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