Synthesis, characterization, and molecular structure of a gallium(III) complex of an amine-phenol ligand with activity against chloroquine-sensitive Plasmodium falciparum strains

Abstract

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.