title: Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Martin
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Kate
authors.initials: K
authors.lastname: de Luca-Fradley
authors.forename: Jared C
authors.initials: JC
authors.lastname: Lewis
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Grimley
authors.forename: Erin M
authors.initials: EM
authors.lastname: Van Brussel
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Olsen
authors.forename: Gary A
authors.initials: GA
authors.lastname: Meints
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Burzynska
authors.forename: Pawel
authors.initials: P
authors.lastname: Kafarski
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007928:Lethal Dose 50; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D004164:Diphosphonates; D014344:Trypanocidal Agents