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Antimicrobial Agents and Chemotherapy, October 2000, p. 2771-2776, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Anti-Toxoplasma Activities of 24 Quinolones and Fluoroquinolones In Vitro: Prediction of Activity by Molecular Topology and Virtual Computational Techniques

Rafael Gozalbes,1,2 Monique Brun-Pascaud,3 Ramon Garcia-Domenech,4 Jorge Galvez,4 Pierre-Marie Girard,5 Jean-Pierre Doucet,2 and Francis Derouin1,*

Laboratoire de Parasitologie-Mycologie, Faculté de Médecine Lariboisière Saint-Louis, Université Paris 7, 75006 Paris,1 Institut de Topologie et de Dynamique des Systèmes (ITODYS), Université Paris 7, 75005 Paris,2 Inserm E9933, Hôpital Bichat, 75018 Paris,3 and Service des Maladies Infectieuses, Hôpital Rothschild, 75571 Paris Cedex 12,5 France, and Unidad de Investigación en Diseño de Fármacos y Conectividad Molecular, Departamento de Química-Física, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot (Valencia), Spain4

Received 26 June 2000/Returned for modification 21 July 2000/Accepted 26 July 2000

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 (IC50s) 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 IC50s 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 IC50s (r2 = 0.87, cross-validation r2 = 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.

* Corresponding author. Mailing address: Laboratoire de Parasitologie-Mycologie, Lariboisière St-Louis, Faculté de Médecine, 15 rue de l'Ecole de Médecine, 75006 Paris, France. Phone: 33 1 43 29 65 25. Fax: 33 1 43 29 51 92. E-mail: paracord{at}wanadoo.fr.

Antimicrobial Agents and Chemotherapy, October 2000, p. 2771-2776, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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