Derivatives of 2-amino-4,6-dimethylpyridine resulting from the integration of the amino function into a 2-imidazolidinone were synthesized 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 μmol/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 μmol/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.
- 1-(4,6-dimethylpyridin-2- yl)imidazolidin-2-ones
- 2-Amino-4,6-dimethylpiridine derivatives
- Anti-leishmania activity
- PLA inhibition
ASJC Scopus subject areas
- Drug Discovery