A hybrid of amodiaquine and primaquine linked by gold(I) Is a multistage antimalarial agent targeting heme detoxification and thiol redox homeostasis

Universidade Federal de Juiz de Fora. Departamento de Química. Laboratório de Química Bioinorgânica e Catálise. Juiz de Fora, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Rush University Medical Center. Department of Microbial Pathogens and Immunity. Chicago, USA.
Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Lisboa, Portugal.
Dipartimento di Scienze Farmacologiche e Biomolecolari. Università degli Studi di Milano. Milan, Italy.
Rush University Medical Center. Department of Microbial Pathogens and Immunity. Chicago, USA.
Unité Parasitologie et Entomologie. Institut de Recherche Biomédicale des Armées. Marseille, France / Aix-Marseille Université, VITROME. Marseille, France / IHU Méditerranée Infection. Marseille, France / Centre National de Référence du Paludisme. Marseille, France.
Unité Parasitologie et Entomologie. Institut de Recherche Biomédicale des Armées. Marseille, France / Aix-Marseille Université, VITROME. Marseille, France / IHU Méditerranée Infection. Marseille, France / Centre National de Référence du Paludisme. Marseille, France.
Unité Parasitologie et Entomologie. Institut de Recherche Biomédicale des Armées. Marseille, France / Aix-Marseille Université, VITROME. Marseille, France / IHU Méditerranée Infection. Marseille, France / Centre National de Référence du Paludisme. Marseille, France.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche. Universitá Degli Studi di Milano. Milan, Italy.
Rush University Medical Center. Department of Microbial Pathogens and Immunity. Chicago, USA.
Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Lisboa, Portugal.
Unité Parasitologie et Entomologie. Institut de Recherche Biomédicale des Armées. Marseille, France / Aix-Marseille Université, VITROME. Marseille, France / IHU Méditerranée Infection. Marseille, France / Centre National de Référence du Paludisme. Marseille, France.
Universidade Federal de Juiz de Fora. Departamento de Química. Laboratório de Química Bioinorgânica e Catálise. Juiz de Fora, MG, Brasil.

Abstract

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.

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MDPI

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PEREIRA, Caroline de Souza et al. A hybrid of amodiaquine and primaquine linked by gold (I) is a multistage antimalarial agent targeting heme detoxification and thiol redox homeostasis. Pharmaceutics, v.14, n.6, p. 1-20, 2022.

DOI

10.3390/ pharmaceutics14061251

ISSN

1999-4923

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/55132

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