Synthesis and antileishmanial activities of novel 3-substituted quinolines

Abstract

The antileishmanial efficacy of four novel quinoline derivatives was determined in vitro against Leishmania chagasi, using extracellular and intracellular parasite models. When tested against L. chagasi-infected macrophages, compound 3b demonstrated 8.3-fold greater activity than did the standard pentavalent antimony. No significant activity was found for compounds 3a, 4a, and 4b. The antilesihmanial effect of compound 3b was independent of host cell activation, as demonstrated by nitric oxide production. Ultrastructural studies of promastigotes treated with compound 3b showed mainly enlarged mitochondria, with matrix swelling and reduction in the number of cristae. Synthetic analogues based on the quinoline ring structure, already an established template for antiparasitic drugs, could provide further useful compounds.

FIG. 1.

Determination of the IC₅₀ of compound 3b against L. chagasi-infected macrophages. Pentavalent antimony was used as a standard drug. Macrophages were treated for 120 h at 37°C with drugs, and the number of infected macrophages in Giemsa-stained glass coverslips was determined by light microscopy. Dose-response curves were obtained in GraphPad Prism 3.0 software. Data are mean and standard deviation.

FIG. 2.

Ultrastructural effects of compound 3b on Leishmania promastigotes. (B and C) Promastigotes were incubated with compound 3b at 10 μg ml⁻¹ for 30 (B) and 60 min (C) at 24°C and subsequently observed under a transmission electron microscope. (A) Untreated cells were used as parasite controls. m, mitochondria; n, nucleus; g, granules; v, vacuoles.

FIG. 3.

Synthesis of quinolines 3a through 4b.