Antileishmanial activities and mechanisms of action of indole-based azoles.
Two 3-(alpha-azolylbenzyl)indoles were evaluated against Leishmania amastigotes. Both compounds proved to be very active against intracellular and axenic amastigotes. The IC50 values of the imidazole derivative, PM17, and the triazole analogue, PM19, against L. mexicana axenic amastigotes, were 4.4 +/- 0.1 and 6.4 +/- 0.1 microM, respectively. Against intracellular amastigotes, PM17 produced a 66% decrease of leishmanial burden at 1 microM and PM19 had an IC50 of 1.3 microM. In a Balb/c mice model of L. major leishmaniasis, administration of PM17 led to a clear-cut parasite burden reduction: 98.9% in the spleen, 79.0% in the liver and 49.9% in the popliteal node draining the cutaneous lesion. As anticipated, it was brought to the fore that PM17 decreases ergosterol biosynthesis leading to membrane fungal cell alterations. Moreover it was proved that this imidazole antifungal agent induces a parasite burden-correlated decrease in interleukine-4 production both in the splenocyte and the popliteal node of the mouse.
Pagniez
Fabrice
F
Department of Parasitology and Medical Mycology, BioCiT UPRES EA 1155, Faculty of Pharmacy, Nantes University, 1 rue Gaston Veil, 44035 Nantes cedex 01, France.
Abdala-Valencia
Hiam
H
Marchand
Pascal
P
Le Borgne
Marc
M
Le Baut
Guillaume
G
Robert-Piessard
Sylvie
S
Le Pape
Patrice
P
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001393:Azoles / Q000138:chemical synthesis / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004875:Ergosterol / Q000096:biosynthesis; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D008099:Liver / Q000187:drug effects / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D012680:Sensitivity and Specificity; D013154:Spleen / Q000187:drug effects / Q000469:parasitology; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
C513742:5-bromo-3-((2,4-dichlorophenyl)(1H-imidazol-1-yl)methyl)-1-ethylindole; C513743:5-bromo-3-((2,4-dichlorophenyl)(1H-triazol-1-yl)methyl)-1-ethylindole; D000981:Antiprotozoal Agents; D001393:Azoles; D007093:Imidazoles; D007211:Indoles; D014230:Triazoles; D015847:Interleukin-4; D010741:Phospholipases A; D004875:Ergosterol