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.
Abdala
H
H
Service de Parasitologie, UPRES EA 1155, Faculté de Pharmacie, Université de Nantes.
Alvarez
N
N
Delmas
F
F
Di Giorgio
C
C
Robert
J M
JM
Le Baut
G
G
Le Pape
P
P
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005434:Flow Cytometry / Q000662:veterinary; D007274:Injections, Intraperitoneal / Q000662:veterinary; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000662:veterinary*; D007928:Lethal Dose 50; D008099:Liver / Q000469:parasitology; D008198:Lymph Nodes / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013154:Spleen / Q000469:parasitology
C464526:2-amino-4,6-dimethyl pyrimidine; D000981:Antiprotozoal Agents; D011743:Pyrimidines