Anti-Toxoplasma activities of 24 quinolones and fluoroquinolones in vitro:Prediction of activity by molecular topology and virtual computational techniques

The apicoplast, a plastid-like organelle of Toxoplasma gondii, is thought t o be a unique drug target for quinolones. In this study, we assessed the in vitro activity of quinolones against T. gondii and developed new quantitat ive structure-activity relationship models able to predict this activity, T he anti-Toxoplasma activities of 24 quinolones were examined by means of li near discriminant analysis (LDA) using topological indices as structural de scriptors. In parallel, in vitro 50% inhibitory concentrations (IC(50)s) we re determined in tissue culture. A multilinear regression (MLR) analysis wa s then performed to establish a model capable of classifying quinolones by in vitro activity. LDA and MLR analysis were applied to virtual structures to identify the influence of each atom or substituent of the quinolone ring on anti-Toxoplasma activity. LDA predicted that 20 of the 24 quinolones wo uld be active against T, gondii, This was confirmed in vitro for most of th e quinolones. Trovafloxacin, grepafloxacin, gatifloxacin, and moxifloxacin were the quinolones most potent against T,gondii, with IC(50)s of 0.4, 2.4, 4.1, and 5.1 mg/liter, respectively. Using MLR analysis, a good correlatio n was found between measured and predicted IC(50)s (r(2) = 0.87, cross-vali dation r(2) = 0.74). MLR analysis showed that the carboxylic group at posit ion C-3 of the quinolone ring was not essential for anti-Toxoplasma activit y. In contrast, activity was totally dependent on the presence of a fluorin e at position C-6 and was enhanced by the presence of a methyl group at C-5 or an azabicyclohexane at C-7, A nucleophilic substituent at C-8 was essen tial for the activity of gatifloxacin and moxifloxacin.