title: Synthesis and antileishmanial activity of new 1-(pyridin-2-yl)imidazolidin-2-ones derived from 2-amino-4,6-dimethylpyridine.
abstract: 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.
authors.affiliation: Department of Parasitology and Zoology, Faculty of Pharmacy, University of Nantes, France.
authors.forename: H
authors.initials: H
authors.lastname: Abdala
authors.forename: J M
authors.initials: JM
authors.lastname: Robert
authors.forename: P
authors.initials: P
authors.lastname: Le Pape
authors.forename: G
authors.initials: G
authors.lastname: Wielgosz
authors.forename: S
authors.initials: S
authors.lastname: Robert-Piessard
authors.forename: G
authors.initials: G
authors.lastname: Le Baut
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D007894:Leishmania mexicana / Q000187:drug effects / Q000201:enzymology; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000469:parasitology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D011725:Pyridines; D010741:Phospholipases A; D054467:Phospholipases A2