A new tripodal ligand, tris[2-(((2-thiazolyl)methylidene)amino)ethyl]amine (Tatren), has been synthesized and characterized by NMR, IR, and UV-visible absorbance spectroscopy and elemental analysis. Tatren forms stable complexes with transition metal ions (Zn2+, 1; Mn2+, 2; Co2+, 3) and the alkaline earth metal ions (Ca2+, 4; Mg2+, 5). Single-crystal X-ray structures of 1, 2, and 5 revealed six-coordinate chelate complexes with formula [M(Tatren)]- (ClO4)(2) in which the metal centers are coordinated by three thiazolyl N atoms and three acyclic imine N atoms. Crystals of 1, 2, and 5 are monoclinic, P2(1)/c space group. Crystals of 4 are triclinic, P (1) over bar space group. The Ca2+ complex is eight-coordinate with all N atoms of Tatren and one water molecule coordinated to the metal ion. Spectrophotometric titrations show that formation constants for the chelates of metal ions are much greater than1 in methanol. Free Tatren inhibits the catalytic domain of matrix metalloproteinase-13 (MMP-13, collagenase-3) with K-i = 3.5 +/- 0.6 muM. Molecular mechanics-based docking calculations suggest that one leg of Tatren coordinates to the catalytic Zn2+ in MMPs-2, -9, and -13 with significant hydrogen bonding to backbone amide groups. High-level DFT calculations suggest that, in the absence of nonbonded interactions between Tatren and the enzyme, the most stable first coordination sphere of the catalytic Zn2+ is achieved with three imidazolyl groups from His residues and two imine N atoms from one leg of Tatren. While complexes (1-3) do not inhibit MMP-13 to a significant extent, 4 does (Ki = 30 +/- 10 muM). Hence, this study shows that tripodal chelating ligands of this class and their Ca2+ complexes have potential as active-site inhibitors for MMPs.