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  • NMR analyses support the above statement Compound is an


    NMR analyses support the above statement. Compound 32 is an interesting example of an isosteric analog of compounds 12–14. It has been demonstrated that 32 forms a rather stable six-membered ring via a hydrogen bond based on the chemical shift of the phosphorus YM 58483 at the C-3 position as illustrated in Figure 5. In addition, proton NMR data of 28 and the n-propyl derivative of 12–14 (compound 33), performed in anhydrous deuterated DMSO, indicated the occurrence of this conformational restriction on these compounds. Two signals of protons bonded to heteroatoms were observed in the 1H NMR spectrum of 33 at 7.70ppm and 8.95ppm, respectively. The first signal moved upfield (5.40ppm) when 1 equiv of Mg2+ was added. A similar behavior was observed from the proton NMR spectrum of 28. Once again, two signals that appeared at 6.69ppm and 9.11ppm. The first one moved upfield (4.41ppm) when one equivalent of Mg2+ was added. In summary, it can be concluded that the activity against T. cruzi of compounds of type 12–14 can be attributed due to these compounds adapt a restricted conformation having no tension of torsion that would be benefit for molecular recognition, whereas the 1-hydroxy derivatives 27–31 present a manifold of conformations that would not lead to a successful interaction with the target enzyme. Nevertheless, these bisphophonate derivatives exhibited a selective and potent inhibitory action towards TgFPPS. Efforts in optimizing lead structures 12–14 are currently being pursued in our laboratory.
    Experimental section
    Drug screening
    Computational methods All the DFT calculations were performed using the gaussian09 program, the B3LYP functional and the 6-311+G(d,p) basis set. Calculations were carried out with full geometry optimization, using standard termination conditions, and including in all cases the effect of the solvent (water) through the Tomasi’s polarized continuum model (PCM) as implemented in gaussian09. Several different input geometries were used in order to find the most important conformers; the Mg atom always appeared coordinated to two oxygen atoms, and the hydrogen bonding usually drove the energy minimization processes.
    Introduction Bisphosphonates are currently used to treat post-menopausal and steroid-induced osteoporosis, Paget’s disease, hypercalcemia and osteolysis associated with multiple myeloma and metastatic cancers [1], [2], [3], [4]. Due to their ability to bind calcium ions in a multidentate manner, bisphosphonates rapidly accumulate in bone [5] where they inhibit the activity of bone-destroying osteoclasts. The antiresorptive activity of the potent nitrogen-containing bisphosphonates (N-BPs) results from two key properties [6], their affinity for bone mineral, and their potency for inhibiting a molecular target in osteoclasts. It has recently been demonstrated [7] that the relative mineral affinity of several clinically utilized bisphosphonates increases in the order etidronate