Aminomethylene-Phosphonate Analogues as Zn(II)-Chelators: Synthesis and Characterization

series of aminomethylene(ethylene)-phosphonate (AMP, 1, AEP, 2) analogues, 3-9, bearing one or two eterocyclic moieties (imidazolyl, pyridyl, and thiazolyl) on the aminomethylene group, were synthesized aspotential agents for Zn(II)-chelation therapy. The complexes of analogues 3-9 with Zn(II)-ions were characterized by their stoichiometry, geometry, coordination-sites, acid-base equilibria, and stability constants. Analogues 3-9 form stable water-soluble 2:1 L:Zn(II) complexes, as established by Zn(II)-titration, monitored by UV and by ¹H- and ³¹P-NMR spectroscopy. Acidity and stability constants were established for each derivative by potentiometric pH-titrations. ML₂-type Zn(II)-complexes of AMP, bearing either an imidazolyl or pyridyl moiety, 3, 4, and 5, exhibit high logb values – 17.68, 16.92, and 16.65, respectively, while for the AMP-thiazolyl, 6, -Zn(II) complex, logb is 12.53. Generally, ligands 7, 8, and 9, bearing two heterocyclic moieties, present higher logb values (22.25, 21.00, and 18.28, respectively) vs. analogues bearing one heterocyclic moiety. Additionally, based on ¹H-,¹³C-, and ³¹P-NMR data, we propose a structure of AMP-(Im)₂-Zn(II) complex in solution, where the Zn(II)-coordination sites involve the phosphonate moiety and both imidazolyl rings of the two binding molecules, forming an octahedral geometry around the Zn(II)-ion. In summary, we propose a novel family of water-soluble high-affinity Zn(II)-chelators, potentially useful for Zn(II)-chelation therapy, and in particular we suggest using AMP-(Im)₂.