Activity of Bisphosphonates against Trypanosoma bruceirhodesiense

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 ∼3 orders of magnitude (minimum IC50 = 220 nM; maximum IC50 = 102 μM) yielded an R2 value of 0.87 with a cross-validated R2 value of 0.79. The predictive utility of this approach was tested for three sets of three compounds: the average pIC50 error was 0.23. For the nitrogen-containing bisphosphonates, in general, the activity was aromatic- \u3e\u3ealiphatic-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 μM for the n-C11 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 (≳200:1) as well as low IC50 values, suggesting their further investigation as antiparasitic agents against T. b. rhodesiense