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: Paloma F Salas, Christoph Herrmann, Jacqueline F Cawthray, Corinna Nimphius, Alexander Kenkel, Jessie Chen, Carmen de Kock, Peter J Smith, Brian O Patrick, Michael J Adam, Chris Orvig
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 4 Pg. 1596-613 (Feb 28 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23327489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoquinolines
• Antimalarials
• Antineoplastic Agents
• Ferrous Compounds
• Metallocenes
• Hemin
• Chloroquine
• ferroquine
• ferrocene

Topics

• Aminoquinolines (chemical synthesis, chemistry, pharmacology)
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Chloroquine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Crystallography, X-Ray
• Drug Resistance
• Drug Screening Assays, Antitumor
• Ferrous Compounds (chemical synthesis, chemistry, pharmacology)
• Hemin (chemistry)
• Humans
• Hydrogen Bonding
• Hydrophobic and Hydrophilic Interactions
• Metallocenes
• Models, Molecular
• Molecular Structure
• Parasitic Sensitivity Tests
• Plasmodium falciparum
• Structure-Activity Relationship