Antileishmanial activities and mechanisms of action of indole-based azoles

Abstract

Two 3-(α-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 μM, respectively. Against intracellular amastigotes, PM17 produced a 66% decrease of leishmanial burden at 1 μM and PM19 had an IC₅₀ of 1.3 μM. 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.

Keywords::

• Leishmania
• antileishmanials
• azole derivatives
• interleukine-4
• ergosterol