Journal
PHARMACEUTICS
Volume 14, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics14061251
Keywords
malaria; Plasmodium; antimalarial drugs; quinolines; gold; heme detoxification; redox homeostasis; hemozoin; flavoenzymes
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Funding
- CAPES doctoral scholarship (Brazil)
- FAPEMIG, Brazil [APQ-01543-18]
- CNPq, Brazil [305732/2019-6]
- FAPESB, Brazil [APP0088/2016, IGM-002-FIO-20-2-25]
- FCT, Portugal [PTDC-SAU-INF- 29550-2017]
- Fondazione Cariplo, Italy [2017-0846]
- Ministero dell'Istruzione, dell'Universita e della Ricerca, Italy [PRIN 2015.4JRJPP_004]
- Ministero degli Affari Esteri e della Cooperazione Internazionale (Progetti di grande rilevanza, Italy) [00949-2018]
- US NIH/NIAID [R33AI12763]
- French Institute for Public Health Surveillance (Sante Publique France, grant CNR du Paludisme)
- Delegation Generale pour l'Armement [PDH-2-NRBC-4-B-4104]
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Hybrid-based drugs linked through a transition metal, such as the novel compound [AuAQPQ]PF6, show strong and effective antiplasmodial activity against multiple stages of the Plasmodium life cycle. The compound's mechanism involves inhibiting beta-hematin formation and enzymatic activity of thioredoxin reductases.
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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