Evaluation of quinolone derivatives for antitrypanosomal activity.

About 160 fluoroquinolones and derivatives were tested for antitrypanosomal activity in a drug sensitivity assay followed by fluorometric evaluation. The most active quinolone compounds had IC50 values in the range from 100 to 900 ng/ml, while several derivatives were not active at a concentration of 100 microg/ml. In a structure activity relationship study, modification of the quinolones at position R1, R2, R3 and R8 did not influence trypanocidal activity. An exchange of the fluor at position 6 may contribute to an increase in activity but does not entirely control it. Pyrrolidine substituents at position R7 generally were more active than other substituents at this position. Tetracyclic quinolone derivatives were amongst the most active compounds with IC50 values in the range of 0.3-8.8 microg/ml. The in vitro cytotoxicity on HT-29 cells was determined for active compounds with IC50 values below 1 microg/ml. In addition, six drugs with an IC50 below 1 microg/ml and a selectivity index of more than 10 were chosen for in vivo experiments. Dose escalation experiments with a maximum dose of 100 mg/kg/bid were performed in a mouse model without central nervous system involvement. For unknown reasons the in vitro effect of the drugs could not be confirmed in vivo, but the class of compound remains of interest for their mode of action, the low toxicity, pharmacological properties and the availability of a large number of synthesized compounds.