Activity of Bisphosphonates against Trypanosoma brucei rhodesiense

• Published in: Journal of medicinal chemistry Vol. 45; no. 14; pp. 2904 - 2914
• Main Authors: 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, Kafarski, Pawel, Croft, Simon L, Oldfield, Eric
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.07.2002; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Chemistry, Medicinal; Crystallography, X-Ray; Diphosphonates - chemistry; Diphosphonates - pharmacology; Diphosphonates - toxicity; Humans; Lethal Dose 50; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Quantum Theory; Science & Technology; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanocidal Agents - toxicity; Trypanosoma brucei rhodesiense - drug effects; Tumor Cells, Cultured; POTENTIAL ROUTE; CHARGE-DENSITY; INHIBITION; IN-VIVO; DIPHOSPHATE SYNTHASE; DICTYOSTELIUM-DISCOIDEUM; ENTAMOEBA-HISTOLYTICA; LEISHMANIA-DONOVANI; PYROPHOSPHATE-DEPENDENT PHOSPHOFRUCTOKINASE; BONE-RESORPTION; Kinetoplastida; Protozoa; Toxicity; Prediction; Cytotoxicity; Diphosphonic acid derivatives; Bisphosphonates; X ray diffraction; In vitro; Modeling; Pyridine derivatives; Antiprotozoal agent; Three dimensional model; Structure activity relation; Aminoacid; KB cell line; Parasiticid; Molecular model; Comparative molecular field analysis method; Trypomastigote; Trypanosoma brucei; Electrostatic model
• ISSN: 0022-2623; 1520-4804
• 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 ∼3 orders of magnitude (minimum IC50 = 220 nM; maximum IC50 = 102 μM) 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 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.