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 t o 900 ng/ml, while several derivatives were not active at a concentration o f 100 mug/ml. In a structure activity relationship study, modification of t he 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 incre ase in activity but does not entirely control it. Pyrrolidine substituents at position R7 generally were more active than other substituents at this p osition. Tetracyclic quinolone derivatives were amongst the most active com pounds with IC50 values in the range of 0.3-8.8 mug/ml. The in vitro cytoto xicity on HT-29 cells was determined for active compounds with IC50 values below 1 mug/ml. In addition, six drugs with an IC50 below 1 mug/ml and a se lectivity index of more than 10 were chosen for in vivo experiments. Dose e scalation experiments with a maximum dose of 100 mg/kg/bid were performed i n a mouse model without central nervous system involvement. For unknown rea sons the in vitro effect of the drugs could not be confirmed in vivo, but t he 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.