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https://www.arca.fiocruz.br/handle/icict/62696
ANTIMALARIAL AGENTS DERIVED FROM METAL-AMODIAQUINE COMPLEXES WITH ACTIVITY IN MULTIPLE STAGES OF THE PLASMODIUM LIFE CYCLE
Author
Affilliation
Universidade Federal do Rio Grande do Sul. Instituto de Química. Porto Alegre, RS Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Universidade Federal de Juiz de Fora. Departamento de Química. Juiz de Fora, MG Brasil.
Universidade Federal de Mato Grosso. Departamento de Solos e Engenharia Rural. Cuiabá, MT, Brasil.
Universidade Federal de São Carlos. Departamento de Química. São Carlos, SP, Brasil.
Universidade Federal de Juiz de Fora. Departamento de Química. Juiz de Fora, MG Brasil.
Swiss Tropical & Public Health Institute. Allschwil, Switzerland / University of Basel. Basel, Switzerland.
Dipartimento di Scienze Farmacologiche e Biomolecolari. Università degli Studi di Milano. Milan, Italy.
Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche. Universitá degli Studi di Milano. Milan, Italy.
Universidade Federal de São Carlos. Departamento de Química. São Carlos, SP, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Universidade Federal de Juiz de Fora. Departamento de Química. Juiz de Fora, MG Brasil.
Universidade Federal de Mato Grosso. Departamento de Solos e Engenharia Rural. Cuiabá, MT, Brasil.
Universidade Federal de São Carlos. Departamento de Química. São Carlos, SP, Brasil.
Universidade Federal de Juiz de Fora. Departamento de Química. Juiz de Fora, MG Brasil.
Swiss Tropical & Public Health Institute. Allschwil, Switzerland / University of Basel. Basel, Switzerland.
Dipartimento di Scienze Farmacologiche e Biomolecolari. Università degli Studi di Milano. Milan, Italy.
Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche. Universitá degli Studi di Milano. Milan, Italy.
Universidade Federal de São Carlos. Departamento de Química. São Carlos, SP, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Abstract
Malaria is the one of the deadliest infectious diseases worldwide. Chemically, quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of ruthenium(II)- and gold(I)-containing amodiaquine (AQ) were synthesized, and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in solution was investigated, demonstrating the stability of the quinoline-metal bond. RuII- and AuI-AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle as assayed in vitro and in vivo. These properties could be attributed to the ability of the metal-AQ complexes to reproduce the suppression of heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle; this can be attributed to the action of the metallic species. Altogether, these findings indicate that metal coordination with antimalarial quinolines is a potential chemical tool for drug design and discovery in malaria and other infectious diseases susceptible to quinoline treatment.
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