Synthesis and Characterization of Antiplasmodial Gallium (III) and Iron (III) Complexes of Aminochloroquinoline-3, 4-Hydroxypyridinone Conjugates: Preliminary Studies.

Metallation is a drug optimization strategy that has been used to enhance efficacy as well as pharmacokinetic and pharmacodynamic PK/PD properties in antimalarials. In our earlier studies antiplasmodial aminochloroquinoline-3,4-hydroxypyridinone ACQ-HPO conjugates/hybrid compounds were reported to have remarkable in vitro activity against chloroquine resistant Plasmodia but poor in vivo activity thus the need for their optimization. Herein we report the synthesis of iron (III) and gallium (III) complexes of the ACQ-HPOs which were characterized then evaluated for in vitro antiplasmodial activity. From the preliminary structural elucidation data, the structures of five complexes were found to be ML3 type while one was a ML2+. However, these structural findings remain tentative pending crystallographic analyses. The metal complexation enhanced antiplasmodial activity significantly in the chloroquine resistant CQR strain Dd2. Generally, the metal complexes were more active in resistant strain Dd2 than in the sensitive strain D10. Both the ACQ-HPO ligands and complexes had a lower antiplasmodial activity in both strains than CQ, however the resistance indices, Dd2/D10, of the complexes were 10-fold lower than that of CQ indicating their potential to combat antimalarial drug resistance. Future studies will focus on cytotoxicity tests and crystallography to enable accurate determination of the therapeutic indices of these metallodrugs.