(Aminomethylene)phosphonate Analogues as Zn^II Chelators: Synthesis and Characterization

A series of (aminomethylene)phosphonate (AMP) analogues, 8–14, bearing one or two heterocyclic moieties (imidazolyl, pyridyl, and thiazolyl) on the aminomethylene group, were synthesized as potential Zn^II chelators. The complexes of analogues 8–14 with Zn^II ions were characterized by their stoichiometry, geometry, coordination sites, acid/base equilibria, and stability constants. Analogues 8–14 form stable water-soluble 2:1 L/Zn^II complexes, as established by Zn^II titration, monitored by UV/Vis spectrophotometry 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, 8, 10, and 12, exhibit high log β values (17.68, 16.92, and 16.65, respectively), while for the AMP-thiazolyl (14) complex with Zn^II, log β is 12.53. Generally, ligands 9, 11, and 13, bearing two heterocyclic moieties, present higher log β values (22.25, 21.00, and 18.28, respectively) vs. analogues bearing one heterocyclic moiety. Additionally, based on ¹H, ¹³C, and ³¹P NMR spectroscopic data, we propose a structure of the 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 new family of water-soluble high-affinity Zn^II chelators, in particular AMP-(Im)₂, which forms the most stable complex (log β 22).