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

TY - JOUR

T1 - Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

AU - Hubin, Timothy J.

AU - Amoyaw, Prince N.A.

AU - Roewe, Kimberly D.

AU - Simpson, Natalie C.

AU - Maples, Randall D.

AU - Carder Freeman, Tarynn N.

AU - Cain, Amy N.

AU - Le, Justin G.

AU - Archibald, Stephen J.

AU - Khan, Shabana I.

AU - Tekwani, Babu L.

AU - Khan, M. O.Faruk

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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 Mn 2+ 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 anti-malarial 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.

AB - 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 Mn 2+ 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 anti-malarial 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.

KW - Antimalarial agents

KW - Biological activity

KW - Cross-bridged tetraazamacrocycles

KW - Metal complexes

KW - Synthesis

KW - Tetraazamacrocycles

UR - http://www.scopus.com/inward/record.url?scp=84901939621&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2014.05.003

DO - 10.1016/j.bmc.2014.05.003

M3 - Article

C2 - 24857776

AN - SCOPUS:84901939621

SN - 0968-0896

VL - 22

SP - 3239

EP - 3244

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 13

ER -