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 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.
Martin
Michael B
MB
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
Sanders
John M
JM
Kendrick
Howard
H
de Luca-Fradley
Kate
K
Lewis
Jared C
JC
Grimley
Joshua S
JS
Van Brussel
Erin M
EM
Olsen
Jeffrey R
JR
Meints
Gary A
GA
Burzynska
Agnieszka
A
Kafarski
Pawel
P
Croft
Simon L
SL
Oldfield
Eric
E
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
D004164:Diphosphonates; D014344:Trypanocidal Agents