The chemokine receptor CXCR4 is a member of the seven transmembrane GPCR family, which is implicated in multiple diseases, including HIV infection, cancers, and rheumatoid arthritis. Low-molecular-weight nonpeptidic compounds, including AMD3100 and various pyridyl macrocyclic zinc(II) complexes, have been identified as selective antagonists of CXCR4. In the present study, structure-activity relationship studies were performed by combining the common structural features of alkylamino and pyridiyl macrocyclic antagonists. Several new zinc(II) or copper(II) complexes demonstrated potent anti-HIV activity, strong CXCR4-binding activity, and significant inhibitory activity against Ca2+ mobilization induced by CXCL12 stimulation. These results may prove useful in the design of novel CXCR4 antagonists, and the compounds described could potentially be developed as therapeutics against CXCR4-relevant diseases or chemical probes to study the biological activity of CXCR4. To chelate or not to chelate? Low-molecular-weight nonpeptidic compounds were designed by combining common structural motifs of alkylamino and pyridyl macrocyclic antagonists of the chemokine receptor CXCR4. Several new zinc(II) or copper(II) complexes exhibited potent anti-HIV activity, strong CXCR4 binding activity, and significant inhibitory activity against Ca2+ mobilization induced by CXCL12 stimulation.