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 ∼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- ≫ 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 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.