posted on 2003-10-21, 00:00authored byJohn M. Sanders, Aurora Ortiz Gómez, Junhong Mao, Gary A. Meints, Erin M. Van Brussel, Agnieszka Burzynska, Pawel Kafarski, Dolores González-Pacanowska, Eric Oldfield
We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major
mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The
compounds investigated exhibit activities (IC50 values) ranging from ∼100 nM to ∼80 μM
(corresponding to Ki values as low as 10 nM). The most active compounds were found to be
zoledronate (whose single-crystal X-ray structure is reported), pyridinyl-ethane-1-hydroxy-1,1-bisphosphonates or picolyl aminomethylene bisphosphonates. However, N-alicyclic aminomethylene bisphosphonates, such as incadronate (N-cycloheptyl aminomethylene bisphosphonate), as well as aliphatic aminomethylene bisphosphonates containing short (n = 4, 5) alkyl
chains, were also active, with IC50 values in the 200−1700 nM range (corresponding to Ki values
of ∼20−170 nM). Bisphosphonates containing longer or multiple (N,N-) alkyl substitutions
were inactive, as were aromatic species lacking an o- or m-nitrogen atom in the ring, or
possessing multiple halogen substitutions or a p-amino group. To put these observations on a
more quantitative structural basis, we used three-dimensional quantitative structure−activity
relationship techniques: comparative molecular field analysis (CoMFA) and comparative
molecular similarity index analysis (CoMSIA), to investigate which structural features
correlated with high activity. Training set results (N = 62 compounds) yielded good correlations
with each technique (R2 = 0.87 and 0.88, respectively), and were further validated by using a
training/test set approach. Test set results (N = 24 compounds) indicated that IC50 values
could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods,
respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate side
chain and a hydrophobic feature contributed significantly to activity. Overall, these results
are of general interest since they represent the first detailed quantitative structure−activity
relationship study of the inhibition of an expressed farnesyl pyrophosphate synthase enzyme
by bisphosphonate inhibitors and that the activity of these inhibitors can be predicted within
about a factor of 3 by using 3D-QSAR techniques.