title: Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.
abstract: Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.
authors: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors: Paloma F
authors: PF
authors: Salas
authors: Christoph
authors: C
authors: Herrmann
authors: Jacqueline F
authors: JF
authors: Cawthray
authors: Corinna
authors: C
authors: Nimphius
authors: Alexander
authors: A
authors: Kenkel
authors: Jessie
authors: J
authors: Chen
authors: Carmen
authors: C
authors: de Kock
authors: Peter J
authors: PJ
authors: Smith
authors: Brian O
authors: BO
authors: Patrick
authors: Michael J
authors: MJ
authors: Adam
authors: Chris
authors: C
authors: Orvig
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006427:Hemin / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D000075163:Metallocenes; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D000075163:Metallocenes; D006427:Hemin; D002738:Chloroquine; C479230:ferroquine; C004998:ferrocene