In vitro and in vivo antileishmanial activity of 2-amino-4,6-dimethylpyridine derivatives against Leishmania mexicana

Abstract

Leishmania mexicana promastigote and intracellular amastigote growths were inhibited by the water-soluble furan-2-carboxamide issued from the pharmacophore 2-amino-4,6-dimethylpyridine with IC50 values of 69 ± 2 and 89 ± 9 µM, respectively. This compound was also tested against established L. mexicana infection in susceptible BALB/c mice; an intraperitoneal administration of 10 mg/Kg/day during five consecutive days induced a high reduction in the amastigote burden of the poplitea lymph node (81 ± 6.4 %), the spleen (80 ± 1.6 %) and the liver (73 ± 9 %). Approach of the mechanism of antileishmanial activity of this compound, assessed by the flow cytometry, showed a reduction in the protein and DNA synthesis. Finally, an actual increase of the in vitro antileishmanial activity was obtained by replacement of the amidic function by an imidazolidin-2-one moiety. In this new series, two of the N-substitued derivatives showed IC50 values of 13 ± 0.5 and 7 ± 3 µM in intracellular amastigotes constituting new promising compounds for further studies.

Keywords

• Leishmania mexicana
• antileishmanial activity
• 2-amino-4,6-dimethylpyridine
• flow cytometry