Activity of bisphosphonates against Trypanosoma brucei rhodesiense

J Med Chem. 2002 Jul 4;45(14):2904-14. doi: 10.1021/jm0102809.


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 approximately 3 orders of magnitude (minimum IC(50) = 220 nM; maximum IC(50) = 102 microM) 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 IC(50) values decreased nearly monotonically with increasing chain length (down to IC(50) = 2.0 microM 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 LD(50) values of bisphosphonates in a mammalian cell general toxicity screen and present a comparison between the therapeutic indices and the IC(50) values in the T. b. rhodesiense growth inhibition assay. Several bisphosphonates were found to have large therapeutic indices (> or =200:1) as well as low IC(50) values, suggesting their further investigation as antiparasitic agents against T. b. rhodesiense.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Diphosphonates / chemistry
  • Diphosphonates / pharmacology*
  • Diphosphonates / toxicity
  • Humans
  • Lethal Dose 50
  • Models, Molecular
  • Quantitative Structure-Activity Relationship
  • Quantum Theory
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanocidal Agents / toxicity
  • Trypanosoma brucei rhodesiense / drug effects*
  • Tumor Cells, Cultured


  • Diphosphonates
  • Trypanocidal Agents