title: 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 Mn(2+) complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM 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 Mn(2+). Few of the Cu(2+) and Fe(2+) complexes also showed improvement in activity but Ni(2+), Co(2+) and Zn(2+) complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development.
authors.affiliation: Department of Chemistry, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hubin
authors.affiliation: College of Pharmacy, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States.
authors.forename: Prince N-A
authors.initials: PN
authors.lastname: Amoyaw
authors.affiliation: Department of Chemistry, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Roewe
authors.affiliation: Department of Chemistry, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States.
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Simpson
authors.affiliation: Department of Chemistry, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States.
authors.forename: Randall D
authors.initials: RD
authors.lastname: Maples
authors.affiliation: Department of Chemistry, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States.
authors.forename: TaRynn N
authors.initials: TN
authors.lastname: Carder Freeman
authors.affiliation: Department of Chemistry, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Cain
authors.affiliation: Department of Chemistry, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Le
authors.affiliation: Department of Chemistry, University of Hull, Cottingham Road, Kingston Upon Hull HU6 7RX, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Archibald
authors.affiliation: National Center for Natural Products Research, University of Mississippi, University, MS 38677, United States.
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.affiliation: National Center for Natural Products Research, University of Mississippi, University, MS 38677, United States.
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.affiliation: College of Pharmacy, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096, United States. Electronic address: faruk.khan@swosu.edu.
authors.forename: M O Faruk
authors.initials: MO
authors.lastname: Khan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002738:Chloroquine / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014131:Trace Elements / Q000737:chemistry; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D001372:Aza Compounds; D056831:Coordination Complexes; D008024:Ligands; D047028:Macrocyclic Compounds; D014131:Trace Elements; D002738:Chloroquine
keywords: Antimalarial agents; Biological activity; Cross-bridged tetraazamacrocycles; Metal complexes; Synthesis; Tetraazamacrocycles