Powerful methodologies for drug design and drug database screening and selection are presently available. Studies relating the structure of molecules to a property or a biological activity by means of statistical tools (QSPR and QSAR studies, respectively) are particularly relevant. An important point for this methodology is the use of good structural descriptors that are representative of the molecular features res- ponsible for the relevant activity. Topological indices (TIs) are two-dimensional descriptors which take into account the internal atomic arrangement of compounds, and which encode in numerical form information about molecular size, shape, branching, presence of heteroatoms and multiple bonds. The usefulness of TIs in QSPR and QSAR studies has been extensively demonstrated, and they have also been used as a measure of structural similarity or diversity by their application to databases virtually generated by computer. In this article we will briefly review the history of TIs, their advantages and limitations with respect to other descriptors, and their possibilities in drug design and database selection. These applications rely on new computational techniques such as virtual combinatorial synthesis, virtual computational screening or inverse QSAR.

The apicoplast, a plastid-like organelle of Toxoplasma gondii , is thought to be a unique drug target for quinolones. In this study, we assessed the in vitro activity of quinolones against T. gondii and developed new quantitative structure-activity relationship models able to predict this activity. The anti- Toxoplasma activities of 24 quinolones were examined by means of linear discriminant analysis (LDA) using topological indices as structural descriptors. In parallel, in vitro 50% inhibitory concentrations (IC ₅₀ s) were determined in tissue culture. A multilinear regression (MLR) analysis was 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 would be active against T. gondii . This was confirmed in vitro for most of the 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 correlation was found between measured and predicted IC ₅₀ s ( r ² = 0.87, cross-validation r ² = 0.74). MLR analysis showed that the carboxylic group at position C-3 of the quinolone ring was not essential for anti- Toxoplasma activity. In contrast, activity was totally dependent on the presence of a fluorine 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 essential for the activity of gatifloxacin and moxifloxacin.