Metalloantimalarials: Targeting of P. falciparum Strains with Novel Iron(III) and Gallium(III) Complexes of an Amine Phenol Ligand Scott E. Harpstrite, † Alicia A. Beatty, ‡ Silvia D. Collins, † Anna Oksman, §,| Daniel E. Goldberg, §,| and Vijay Sharma* ,† Mallinckrodt Institute of Radiology, Washington UniVersity Medical School, Box 8225, 510 S. Kingshighway BlVd., St. Louis, Missouri 63110, Department of Chemistry and Biochemistry, UniVersity of Notre Dame, Notre Dame, Indiana 46556-5670, Howard Hughes Medical Institute, and Departments of Medicine and Molecular Microbiology, Washington UniVersity Medical School, St. Louis, Missouri 63110 Received January 14, 2003 Emergence of chloroquine (CQ)-resistant Plasmodium falciparum strains necessitates discovery of potent and inexpensive antimalarial drugs. The high cost of new drugs negatively impacts their access and distribution in the regions of the world with scarce economic resources. While exploring structure-activity relationships, using gallium(III) as a surrogate marker for iron(III), we found cationic, and moderately hydrophobic, compounds, [ {1,12-bis(2- hydroxy-3-ethyl-benzyl)-1,5,8,12-tetraazadodecane}metal(III)] + (metal ) Fe(III) and Ga(III); [Fe-3-Eadd] + , 3; [Ga- 3-Eadd] + , 4), that possessed antimalarial activity. Crystal structure analyses revealed octahedral geometry for these complexes. The RP-HPLC analysis, after incubation in PBS or HEPES buffer (pH 7.4) at 37 °C for 3 days, detected only parental compounds thereby providing evidence for stability under physiological conditions. Both 3 and 4 demonstrated promising half-maximum inhibitory concentration (IC 50 ) values of ∼80 and 86 nM in the CQ-sensitive HB-3 line, respectively. However, both 3 and 4 were found to possess elevated IC 50 values of 2.5 and 0.8 µM, respectively, in the CQ-resistant Dd2 line, thus displaying preferential cytotoxicity toward the CQ-sensitive HB3 line. In cultured parasites, 3 and 4 targeted hemozoin formation. Thus, these compounds acted similarly to chloroquine with regard to action and resistance, despite the lack of structural similarity to quinolines. Finally, similarity in coordination chemistry, stability, and antimalarial cytotoxicity profiles indicated that gallium(III) ion can serve as a template for iron(III) in structure elucidation of active molecules in solution. Introduction Malarial parasites emerging from the genus Plasmodium infect 300-500 million people and result in the death of 1-3 million children each year. 1,2 Recently, interdisciplinary efforts involving a wide consortium of several laboratories have resulted in the genome sequencing of Plasmodium falciparum 3 and the mosquito vector Anopheles gambiae. 4 These genome discoveries will provide an enormous amount of information about the interaction of the parasite with its host and carrier, including the genes involved in parasite recognition by the human immune system. However, trans- lating this information into effective remedies will be an immensely challenging task due to the resistance pathways devised by the parasite. Resistance to chloroquine (CQ), an inexpensive and potent antimalarial, is becoming rampant. 5-7 New drugs exemplified by mefloquine 8-10 and halofantrine 11 * To whom correspondence should be addressed. E-mail: sharmav@ mir.wustl.edu. Phone: 314-362-9358. Fax: 314-362-0152. † Mallinckrodt Institute of Radiology, Washington University Medical School. ‡ University of Notre Dame. § Howard Hughes Medical Institute. | Departments of Medicine and Molecular Microbiology, Washington University Medical School. (1) Woster, P. Annu. Rep. Med. Chem. 2001, 36, 99. (2) Sturchler, D. Parasitol. Today 1989, 5, 39-40. (3) Gardner, M.; Hall, N.; Fung, E.; White, O.; Berriman, M.; Hyman, R.; Cariton, J.; Pain, A.; Nelson, K.; Bowman, S.; Paulsen, I.; James, K.; Eisen, J.; Rutherford, K.; Salzberg, S.; Craig, A.; Kyes, S.; Chan, M.; Nene, V.; Shallom, S.; Suh, B.; Peterson, J.; Angiouli, S.; Pertea, M.; Allen, J.; Selengut, J.; Haft, D.; Mather, M.; Vaidya, A.; Martin, D.; Fairlamb, A.; Fraunholz, M.; Roos, D.; Ralph, S.; Mcfadden, G.; Cummings, L.; Subramanian, G.; Mungall, C.; Venter, J.; Carucci, D.; Hoffman, S.; Newbold, C.; Davis, R.; Fraser, C.; Barrell, B. Nature 2002, 419, 498-511. (4) Holt, R.; Subramanian, G.; Halpern, A.; Sutton, G.; Charlab, R.; Nusskern, D.; Hoffman, S. Science 2002, 298, 129-149. Inorg. Chem. 2003, 42, 2294-2300 2294 Inorganic Chemistry, Vol. 42, No. 7, 2003 10.1021/ic034036e CCC: $25.00 © 2003 American Chemical Society Published on Web 03/01/2003