Three prototype tridentate ligands (i.e., pyrazinecarboxaldehyde thiosemicarbazone, sodium pyrazinecarboxaldehyde dithiocarbazonate, and pyrazinecarboxaldehyde 2'-pyrazinylhydrazone) were prepared and evaluated for their relative abilities to remove iron from model systems designed to mimic particular aspects of chronic transfusional iron overload. These compounds were synthesized by condensation of pyrazinecarboxaldehyde with the appropriate substituted hydrazide. Iron-binding properties were determined, and the ability to remove iron from the proteins transferrin and ferritin was ascertained. An in vivo model system employing iron-loaded mice was used to demonstrate that all three compounds were effective at reducing tissue iron levels.