Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
Martin, Michael B;
Sanders, John M;
Kendrick, Howard;
de Luca-Fradley, Kate;
Lewis, Jared C;
Grimley, Joshua S;
Van Brussel, Erin M;
Olsen, Jeffrey R;
Meints, Gary A;
Burzynska, Agnieszka;
+3 more...Kafarski, Pawel;
Croft, Simon L;
Oldfield, Eric;
(2002)
Activity of bisphosphonates against Trypanosoma brucei rhodesiense.
Journal of medicinal chemistry, 45 (14).
pp. 2904-2914.
ISSN 0022-2623
DOI: https://doi.org/10.1021/jm0102809
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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.