Synthesis, characterization, and molecular structure of a gallium(III) complex of an amine-phenol ligand with activity against chloroquine-sensitive Plasmodium falciparum strains.
Emergence of chloroquine-resistant Plasmodium falciparum strains necessitates discovery of novel antimalarial drugs, especially if the agents can be synthesized from commercially available, inexpensive precursors via short synthetic routes. While exploring structure-activity relationships, we found a gallium(III) complex, [(1,12-bis(2-hydroxy-5-methoxybenzyl)-1,5,8,12-tetraazadodecane)-gallium(III)](+) [Ga-5-Madd](+), 1, that possessed antimalarial efficacy. Like previously reported complexes, the crystal structure of 1 revealed gallium(III) in a symmetrical octahedral environment surrounded by four secondary amine nitrogen atoms in equatorial plane and two axial oxygen atoms. In contrast to a previously reported complex, [Ga-3-Madd](+), this novel metallo-antimalarial 1 possessed modest efficacy against chloroquine-sensitive HB3 Plasmodium lines. Thus, slight variation in the positions of methoxy functionalities on the aromatic rings of the organic scaffold dramatically altered specificity thereby suggesting a targeted (e.g., transporter- or receptor-mediated) rather than non-specific (e.g., pH or other gradient-mediated) mechanism of action for these agents.
Ocheskey
Joseph A
JA
Mallinckrodt Institute of Radiology, Washington University Medical School, St. Louis, MO 63110, USA.
Polyakov
Valery R
VR
Harpstrite
Scott E
SE
Oksman
Anna
A
Goldberg
Daniel E
DE
Piwnica-Worms
David
D
Sharma
Vijay
V
D000588:Amines; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005708:Gallium / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019800:Phenol; D010963:Plasmodium falciparum / Q000187:drug effects*
D000588:Amines; D000962:Antimalarials; D008024:Ligands; D009942:Organometallic Compounds; D019800:Phenol; D002738:Chloroquine; D005708:Gallium