Structural Characteristicsof Chloroquine-Bridged Ferrocenophane Analogues of Ferroquine MayObviate Malaria Drug-Resistance Mechanisms.

Five compounds displaying an unprecedented binding modeof chloroquine to ferrocene through the bridging of the cyclopentadienylrings were studied alongside their monosubstituted ferrocene analoguesand organic fragments. The antiplasmodial activity was evaluated againststrains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were lessactive than their five monosubstituted ferrocenyl analogues, theyretained activity in the drug-resistant strains. The biological andphysical properties were correlated to antiplasmodial activity. Intramolecularhydrogen bonding was associated with increased antiplasmodial action,but it is not the determining factor. Instead, balance between lipophilicityand hydrophilicity had a greater influence. It was found that calculatedpartition coefficient (log P) values of 4.5–5.0and topological polar surfaces area (tPSA) values of ∼26.0Å2give the best balance. The particular conformation,compact size, and lipophilicity/hydrophilicity balance observed inthe bridged compounds provide them with the structural characteristicsneeded to escape the mechanisms responsible for resistance. [ABSTRACT FROM AUTHOR]