Metalloantimalarials: targeting of P. falciparum strains with novel iron(III) and gallium(III) complexes of an amine phenol ligand.
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 degrees 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 approximately 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 microM, 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.
Harpstrite
Scott E
SE
Mallinckrodt Institute of Radiology, Washington University Medical School, Box 8225, 510 S. Kingshighway Blvd., St. Louis, Missouri 63110, USA.
Beatty
Alicia A
AA
Collins
Silvia D
SD
Oksman
Anna
A
Goldberg
Daniel E
DE
Sharma
Vijay
V
D000588:Amines / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000191:economics / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance; D005290:Ferric Compounds / Q000138:chemical synthesis* / Q000191:economics / Q000494:pharmacology*; D005708:Gallium / Q000737:chemistry / Q000191:economics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000191:economics / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D019800:Phenol / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000588:Amines; D000962:Antimalarials; D005290:Ferric Compounds; D008024:Ligands; D009942:Organometallic Compounds; D019800:Phenol; D002738:Chloroquine; D005708:Gallium