Synthesis and biological activity of chloroquine ferrocenyl conjugates for the treatment of malaria

Malaria is one of the main causes of mortality and morbidity in the world, endangering billions and affecting millions of people each year. Resistance to common antimalarial drugs has proven to be a challenging problem in malaria control. In an attempt to develop an effective and affordable treatment for malaria, ferrocenyl conjugates incorporating a common antimalarial drug such as chloroquine have been developed. Based on the previous successes of organometallic derivatives of classical pharmacophores, a series of chloroquine-bridged ferrocenyl derivatives was synthesized. These novel compounds present an unprecedented binding mode of chloroquine to the ferrocene moiety, through the bridging of the two Cp rings. The structural effects of this type of conjugation of chloroquine and ferrocene were studied by NMR spectroscopy and crystal structure determination. These compounds were studied along with the monosubstituted ferrocenyl analogs and the organic components in order to compare the effects of the substitution on their biological response. The antiplasmodial activity of these sets of compounds was evaluated against the chloroquine-sensitive (D10) and the chloroquine-resistant (D2d and K1) malaria parasite (Plasmodium falciparum) strains. Additionally, their biological activity was assessed using a number of in vitro assays. Biological and physical properties were correlated to the antimalarial activity. All compounds were active against the tested parasite strains. The presence of the ferrocene significantly improved the antiplasmodial action, when compared to chloroquine, against the drug-resistant parasite strains. While the chloroquine-bridged ferrocenyl derivatives were in general less active than the monosubstituted ferrocenyl analogs, they retained activity in the drug-resistant strain to a greater extent. Their particular conformation, compact size and lipophilicity/hydrophilicity balance could be providing them with the structural characteristics needed to escape the mechanisms responsible for resistance. Additionally, two strategies for drug design were applied: multiple-loading and multifunctional therapy approaches. Ferrocenyl compounds loaded with two molecules of chloroquine and mefloquine were synthesized and characterized. Similarly, ferrocenyl derivatives of chloroquine and mefloquine were further derivatized with a monossacharide molecule. The double-loaded compounds are the first few examples of their kind. The multifunctional conjugates improved the antimalarial action of the ferrocenyl quinoline derivatives.Science, Faculty ofChemistry, Department ofGraduat