This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Malaria remains one of the world''s most devastating infectious diseases, afflicting several hundred million people and killing close to two million children each year. Plasmodium falciparum, the most deadly species, has become widely resistant to most available antimalarial therapies. Chloroquine, the mainstay of treatment and prophylaxis of malaria, disrupts polymerization of heme released during catabolism of host hemoglobin within the causative organism, but the mechanisms of chloroquine resistance remain unknown. New antimalarials that attack chloroquine resistance mechanisms, but not susceptible to the same resistance modes would be highly desirable and furthermore, would help in understanding the mechanism(s) of chloroquine resistance. Towards this objective, we have synthesized and characterized a series of organic scaffolds that are capable of coordinating metals, including a bio-compatible iron (III) to generate stable compounds that possess a delocalize d c ationic charge for penetration in the intracellular compartments. The lead compounds have demonstrated reciprocal cytotoxic activity against chloroquine-sensitive (HB3) and chloroquine-resistant (Dd2) strains. In addition to other spectroscopic techniques, mass spectrometry (FAB) has been used to analyze the molecular weight of these metallopharmaceuticals. Further, the compounds that bind irreversibly to the target protein, will be evaluated through matrix-assisted laser desorption ionization (MALDI) at Washington University resource for biomedical and bioorganic mass spectrometry. The results will be beneficial to identify gene(s) targeted by these metallopharmaceuticals.
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