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

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 microM, 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-substituted derivatives showed IC50 values of 13 +/- 0.5 and 7 +/- 3 microM in intracellular amastigotes constituting new promising compounds for further studies.

Synthesis and antileishmanial activity of new 1-(pyridin-2-yl)imidazolidin-2-ones derived from 2-amino-4,6-dimethylpyridine.

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.

A glycoprotein isolated from the sponge, Pachymatisma johnstonii, has anti-leishmanial activity.

A high anti-leishmanial activity was observed in an aqueous extract from the marine sponge Pachymatisma johnstonii, Bowerbank 1842 (Demospongiae, Geodiidae). Pachymatismin, a glycoprotein, was purified and shown to be a cytotoxic agent, which acts on promastigote and clinical-like amastigote stages with IC50 about 1 microg protein/ml and induces changes in the cell shape, phospholipase A2 activity and invasion capacity of the parasite. We believe pachymatismin is the first reported substance from a marine organism with anti-leishmanial activity.