Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

Abstract

Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn2+ complex of this ligand was the most potent with IC50s of 0.127 and 0.157 µM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better antimalarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn2+. Few of the Cu2+ and Fe2+ complexes also showed improvement in activity but Ni2+, Co2+ and Zn2+ complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development.

N,N′-diethyl and N-ethyl,N′-methyl glyoxal-bridged cyclams: synthesis, characterization, and bleaching activities of the corresponding Mn(II) complexes

“…These macrocycles can be easily N-functionalized with various groups, allowing the preparation of a wide range of ligands suitable for important applications such as for catalysis [4,8], and the development of metal-based imaging and therapeutic agents in medicine [10].…”

Antiplasmodial activity of targeted zinc(II)-dipicolylamine complexes

“…[21] Manganese complexes of cross-bridged tetraazamacrocyclic ligands are highly potent against P. Falciparum strains resistant to chloroquine. [22] A number of zinc complexes with ligands such as quinine and arginine have displayed unique activity against iRBCs. [23, 24] One complex in particular, zinc-desferrioxamine, was found to be more permeative into iRBCs than the desferrioxamine ligand alone as the former exchanges its bound zinc for ferric ions which enhanced uptake.…”

Synthesis and structural studies of two pyridine-armed reinforced cyclen chelators and their transition metal complexes

“…[1] Depending on the chelated metal, tetraazamacrocyclic complexes have found use in a range of applications, including medical imaging, [2] [3] [4] [5] protein binding agents, [6] [7] and as anti-malarial drugs. [8] [9] Recently we have been interested in the use of this complex type as oxidation catalysts. [10] [11] [12] A recent papers by Que, et al, has shown that addition of a pyridyl pendant arm to a tetraazamacrocycle can result in new and improved oxidation catalysis.…”