Recherche de nouveaux antipaludiques actifs sur les souches sauvages et résistantes de Plasmodium vivax et Plasmodium falciparum

TL;DRAbstract

In this study, because Plasmodium vivax cannot be cultured in vivo, we used a DHFR-deficient yeast strain expressing heterologous P. Vivax dhfr gene for the screening of 25 antifolate derivatives to evaluate promising antifolate drugs. DHFR inhibitors function mainly as a competitive inhibitor of the parasite enzyme. This yeast mutant strain was transformed with plasmids containing either a P. Vivax dhfr gene wild-type (S58+S117+I173), or the double (S58R+S117N) or triple mutant (S58R+S117N+I173L) and as controls the human and the own yeast dhfr gene. Pyrimethamine and methotrexate were used as control drugs. The screening allow us to select 6 of 25 compounds, that selectively inhibit both P. Vivax wild-type and mutant DHFR enzymes in vivo in yeast. The inhibitory concentration (IC50) of these 6 quinazoline compounds derivatives were determined on in vitro cultures of P. Falciparum field isolates. The sequenced dhfr gene of isolates confirms that a correlation exists between the dhfr g

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