In vitro and in vivo activities of 1-hydroxy-2-alkyl-4(1H)quinolone derivatives against Toxoplasma gondii

Abstract

1-Hydroxy-2-dodecyl-4(1H)quinolone (HDQ) was recently identified as a Toxoplasma gondii inhibitor. We describe here two novel 1-hydroxyquinolones, which displayed 50% inhibitory concentrations 10- and 5-fold lower than that of HDQ. In a mouse model of acute toxoplasmosis, these two compounds and HDQ reduced the percentages of infected peritoneal cells and decreased the parasite loads in lungs and livers. Compound B showed a tendency toward lowering parasite loads in brains in a mouse model of toxoplasmic encephalitis.

FIG. 1.

Structures of HDQ and compounds A to D.

FIG. 2.

IC₅₀ determination. Confluent human foreskin fibroblasts monolayers were infected with RH strain tachyzoites and treated with either the indicated drug concentrations or a DMSO control. After 24 h of drug treatment, the average number of parasites per vacuole was determined by phase-contrast microscopy from at least two independent experiments and given as mean ± standard deviation; IC₅₀s were calculated by using the SigmaPlot software.

FIG. 3.

Flow cytometry analyses. Percentages of infected cells in peritoneal fluid 8 days after infection of NMRI mice i.p. with 10⁵ GFP-expressing RH tachyzoites and treatment. Atovaquone was used as a positive control. The results shown are pooled from three independent experiments; there were at least four mice in each group.

FIG. 4.

Quantitative PCR analysis of liver and lung samples. Four NMRI mice per group were infected i.p. with 10⁵ GFP-expressing RH tachyzoites and treated 3 days after infection daily for 5 days. On day 8 postinfection, organs were collected. The results are given as means ± standard deviations from three independent experiments. P values were determined by an unpaired Student t test.