Influence of Amodiaquine on the Antimalarial Activity of Ellagic Acid: Crystallographic and Biological Studies

• Published in: Chemical biology & drug design 2014-12, Vol.84 (6), p.669-675
• Main Authors: Żesławska, Ewa, Oleksyn, Barbara, Fabre, Aude, Benoit-Vical, Françoise
• Format: Article
• Language: English
• Subjects: Amodiaquine - chemistry; Antimalarials - chemistry; Antimalarials - pharmacology; antiplasmodial activity; Chemical Sciences; Coordination chemistry; crystal structure; Crystallography, X-Ray; Ellagic Acid - chemistry; hybrid complex; Hydrogen Bonding; intermolecular interactions; mode of action; Molecular Conformation; Plasmodium falciparum - drug effects; X-ray diffraction
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12359

In the search for new antimalarial drugs, design of hybrid molecules is recommended to improve biological activity and to decrease the risk of parasite resistance development. Ellagic acid, as an inhibitor of Plasmodium glutathione, presents an original mode of action and thus appears as a promising antiplasmodial compound. A new complex (AQ–EA) consisting of the well‐known antimalarial drug, amodiaquine, and ellagic acid was obtained. The studied crystal structure of AQ–EA showed that the triclinic centrosymmetrical unit cell of the crystal contains two molecules of amodiaquine (AQ) and two symmetrically independent molecules of ellagic acid (EA). The packing of the molecules in the crystal is dominated by hydrogen bonds between AQ and EA. The antiplasmodial activity of the hybrid complex AQ–EA was also determined and compared with the values of IC50 for AQ and EA separately. Potentiation assays between both molecules were conducted to understand the pharmacological interactions between AQ and EA against Plasmodium falciparum in vitro. The hybrid complex AQ–EA (IC50 of 47 nm) showed improved antiplasmodial activity in comparison with EA alone. A new hybrid complex of antimalarial amodiaquine and ellagic acid was obtained and its crystal structure was determined. The antiplasmodial activity of the complex was also examined and compared with the values of IC50 for the components separately. The hybrid complex showed improved antiplasmodial activity in comparison with ellagic acid alone.