A zinc(II) containing configurationally restricted analogue of bismacrocyclic cyclam-type CXCR4 chemokine receptor antagonists has been synthesized and shown to adopt only one configuration in solution. The single crystal X-ray structure reveals favorable binding to acetate via a bidentate chelation that can be related to the proposed interaction with aspartate on the receptor protein surface. The zinc(II) complex is highly active against HIV infection in vitro. AMD3100 (the octa HCl salt of 1-1′-[1,4-phenylenebis-(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane)), Figure 1c, is a drug that interacts with a cell surface protein (CXCR4) via hydrogen bonding interactions or more effectively as the metal complex via coordinate bonds with aspartate residues. 1 On metal complex formation, the tetra-aza macrocyclic rings in AMD3100 show multiple configurations in solution. 2 Configurationally fixed analogues would have the advantage of presenting only one configuration in solution for coordinate bond formation on binding to the protein. Our study aims to produce a series of configurationally fixed complexes and show the key importance of the coordination interaction for drug binding. We also wish to validate the general strategy of configurational fixing as a route to improve the activity of metal-containing drugs.The CXCR4 chemokine receptor is a seven-helix transmembrane G-protein coupled receptor with multiple critical functions in both normal and pathological physiology. It is a member of the family of 18 recognized chemokine receptors and has a sole natural ligand (CXCL12). 3 Synthetic small molecule antagonists exist, including AMD3100, and have been shown to have both a high binding specificity and an effective inhibitory action against a number of disease states. 4,5 For example, in vitro assays show that AMD3100 inhibits infection by the human immunodeficiency virus (HIV-1 and HIV-2) at micromolar concentrations. 6 It has been demonstrated that formation of metal complexes and aza-macrocyclic ring configuration may have major effects on AMD3100-protein interactions. 1,2,[7][8][9] In particular, it has been suggested that zinc(II) could play a key role in the biological activity of the bicyclam derivatives. 10,11 In an attempt to rationalize the effects of cyclam configuration and to produce new specific antagonists for CXCR4, we have successfully synthesized a configurationally fixed bismacrocyclic compound and its zinc(II) complex. The solution and solid-state properties of the zinc(II) complex were investigated via high field NMR (800 MHz) and X-ray crystallography. The inhibitory effect on infection by HIV-1 and HIV-2 in MT-4 cells is also presented for both the chelator, 4 ((5-5′-[1,4-phenylenebis(methylene)]-bis (1,5,8,12-tetraazabicyclo[10.2.2]hexadecane)), and the complex Zn 2 4(OAc) 4 .There are six possible configurations that a cyclam ring can adopt on complexation to a metal ion, as defined by Bosnich and co-workers and shown in Figure 1b, where trans-III is generally the most thermodyn...