title: Antileishmanial activities and mechanisms of action of indole-based azoles.
abstract: 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.
authors.affiliation: Department of Parasitology and Medical Mycology, BioCiT UPRES EA 1155, Faculty of Pharmacy, Nantes University, 1 rue Gaston Veil, 44035 Nantes cedex 01, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pagniez
authors.forename: Hiam
authors.initials: H
authors.lastname: Abdala-Valencia
authors.forename: Pascal
authors.initials: P
authors.lastname: Marchand
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.forename: Guillaume
authors.initials: G
authors.lastname: Le Baut
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robert-Piessard
authors.forename: Patrice
authors.initials: P
authors.lastname: Le Pape
mesh_terms: 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*
chemical_list: 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