A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis

Hybrid-based drugs linked through a transition metal constitute an emerging concept for Plasmodium intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine...

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Published in:Pharmaceutics 2022-06, Vol.14 (6), p.1251
Main Authors: De Souza Pereira, Caroline, Quadros, Helenita Costa, Aboagye, Samuel Yaw, Fontinha, Diana, D?Alessandro, Sarah, Byrne, Margaret Elizabeth, Gendrot, Mathieu, Fonta, Isabelle, Mosnier, Joel, Moreira, Diogo Rodrigo M, Basilico, Nicoletta, Williams, David L, Prudêncio, Miguel, Pradines, Bruno, Navarro, Maribel
Format: Article
Language:English
Subjects:
antimalarial drugs
Chemical properties
Drug therapy
Drug therapy, Combination
Drugs
Gold
Health aspects
heme detoxification
Insecticides
Life Sciences
Malaria
Methods
Organic chemicals
Parasites
Parasitic diseases
Physiological aspects
Plasmodium
Primaquine
quinolines
Solvents
Spectrum analysis
Vaccines
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Summary:Hybrid-based drugs linked through a transition metal constitute an emerging concept for Plasmodium intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine (PQ) linked by gold(I), named [AuAQPQ]PF6. This compound demonstrated potent and efficacious antiplasmodial activity against multiple stages of the Plasmodium life cycle. The source of this activity was thoroughly investigated by comparing parasite susceptibility to the hybrid’s components, the annotation of structure–activity relationships and studies of the mechanism of action. The activity of [AuAQPQ]PF6 for the parasite’s asexual blood stages was influenced by the presence of AQ, while its activity against gametocytes and pre-erythrocytic parasites was influenced by both quinolinic components. Moreover, the coordination of ligands to gold(I) was found to be essential for the enhancement of potency, as suggested by the observation that a combination of quinolinic ligands does not reproduce the antimalarial potency and efficacy as observed for the metallic hybrid. Our results indicate that this gold(I) hybrid compound presents a dual mechanism of action by inhibiting the beta-hematin formation and enzymatic activity of thioredoxin reductases. Overall, our findings support the potential of transition metals as a dual chemical linker and an antiplasmodial payload for the development of hybrid-based drugs.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics14061251