Activity of bisphosphonates against Trypanosoma brucei rhodesiense

We report the results of a comparative molecular field analysis (CoMFA) investigation of the growth inhibition of the bloodstream form of Trypanosoma brucei rhodesiense trypomastigotes by bisphosphonates. A quantitative three-dimensional structure-activity relationship CoMFA model for a set of 26 bisphosphonates having a range of activity spanning similar to3 orders of magnitude (minimum IC50 = 220 nM; maximum IC50 = 102 muM) yielded an R-2 value of 0.87 with a cross-validated R-2 value of 0.79. The predictive utility of this approach was tested for three sets of three compounds: the average pIC(50) error was 0.23. For the nitrogen-containing bisphosphonates, in general, the activity was aromatic- >> aliphatic-containing side chains. The activity of aromatic species lacking an alkyl ring substitution decreased from ortho to meta to para substitution; halogen substitutions also reduced activity. For the aliphatic bisphosphonates, the IC50 values decreased nearly monotonically with increasing chain length (down to IC50 = 2.0 muM for the n-C-11 alkyl side chain species). We also show, using a "rescue" experiment, that the molecular target of the nitrogen-containing bisphosphonate, risedronate, in T. b. rhodesiense is the enzyme farnesyl pyrophosphate synthase. In addition, we report the LD50 values of bisphosphonates in a mammalian cell general toxicity screen and present a comparison between the therapeutic indices and the IC50 values in the T. b. rhodesiense growth inhibition assay. Several bisphosphonates were found to have large therapeutic indices (greater than or similar to200:1) as well as low IC50 values, suggesting their further investigation as antiparasitic agents against T b. rhodesiense.