No abstract

The protein kinase C (PKC) family of isoenzymes mediate a wide range of signal transduction pathways in many different cells lines. Little is known regarding the presence and functional roles of PKC in Leishmania spp. Here we report the inhibition of parasite PKC by new imidazolidinone compounds. The most active derivative 7 showed an important activity (IC50 = 9.9 microM) against the clinical relevant stage of parasites in comparison with Glucantime (IC50 = 464.5 microM), without inducing toxicity on human fibroblast cells (IC50 = 102 microM). Pretreatment of intact parasites with 10 microM of compound 7 inhibited 80% of PKC activity. At the same concentration, this compound inhibited 70% of the parasite-host cell invasion process. An in vivo model showed that compound 7 reduced the liver parasite burden by 25% and spleen parasite burden by 44%. These results provide the first evidence that PKC plays a critical role in the invasion process. Thus Leishmania PKC activity could be a relevant therapeutic target and the imidazolidinones novel antileishmanial candidates.

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Derivatives of 2-amino-4,6-dimethylpyridine resulting from the integration of the amino function into a 2-imidazolidinone were synthetized via the corresponding 2-chloroethylurea. N3-benzylation, acylation or sulfonylation afforded the target compounds 6-14 which were evaluated for their in vitro and in vivo antileishmanial activity. Two compounds, the N3-benzyl derivative 7 and the N3-tolylsulfonyl derivative 14, exhibited potent inhibition against cultured extracellular promastigotes of Leishmania mexicana with IC50 comparable to that of the previously studied N-(4,6-dimethylpyridin-2-yl) furan-2-carboxamide 2: 32.4, 46 and 69 mumol/l, respectively. Experimentation of their activity against mice macrophage amastigotes pointed out that IC50 of imidazolidones 7 and 14 were 7 and 13-fold lower than that of amide 2: 13.7 and 89 mumol/l. In vivo evaluation in Balb/c mice, intradermally infested with Leishmania mexicana, confirmed that, in the lesion site, compound 14 was able to significantly reduce the parasite burden at a daily i.p. dose of 10 mg/kg. It was demonstrated that these N-pyridinylimidazolidinones could act by interference with the parasite PLA2 activity.

Summary: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 teduction 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 seties, two of the N-substitued derivatives showed IC50 values of 1 3 ± 0.5 and 7 ± 3 μM in intracellular amastigotes constituting new promising compounds for further studies.KEY WORDS : leishmania mexicana, antileishmanial activity, 2-amino-4,6-dimethylpyridine, flow cytometry. Résumé