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https://www.arca.fiocruz.br/handle/icict/50256
STUDIES OF POTENCY AND EFFICACY OF AN OPTIMIZED ARTEMISININ-QUINOLINE HYBRID AGAINST MULTIPLE STAGES OF THE PLASMODIUM LIFE CYCLE
Autor(es)
Afiliação
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
University of Erlangen-Nürnberg. Center for Molecular Materials Friedrich-Alexander. Organic Chemistry Chair I and Interdisciplinary. Nikolaus Fiebiger-Straße. Erlangen, Germany.
University of Erlangen-Nürnberg. Center for Molecular Materials Friedrich-Alexander. Organic Chemistry Chair I and Interdisciplinary. Nikolaus Fiebiger-Straße. Erlangen, Germany.
Università degli Studi di Milano. Dipartimento di Scienze Farmacologiche e Biomolecolari. Milan, Italy.
Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Lisboa, Portugal.
Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Lisboa, Portugal.
,Universidade Federal do Rio Grande do Sul. Instituto de Química. Grupo de Química Inorgânica Medicinal e Reações Aplicadas. Porto Alegre, RS, Brasil.
Universitá degli Studi di Milano. Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche. Milan, Italy.
Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Lisboa, Portugal.
University of Erlangen-Nürnberg. Center for Molecular Materials Friedrich-Alexander. Organic Chemistry Chair I and Interdisciplinary. Nikolaus Fiebiger-Straße. Erlangen, Germany.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
University of Erlangen-Nürnberg. Center for Molecular Materials Friedrich-Alexander. Organic Chemistry Chair I and Interdisciplinary. Nikolaus Fiebiger-Straße. Erlangen, Germany.
University of Erlangen-Nürnberg. Center for Molecular Materials Friedrich-Alexander. Organic Chemistry Chair I and Interdisciplinary. Nikolaus Fiebiger-Straße. Erlangen, Germany.
Università degli Studi di Milano. Dipartimento di Scienze Farmacologiche e Biomolecolari. Milan, Italy.
Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Lisboa, Portugal.
Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Lisboa, Portugal.
,Universidade Federal do Rio Grande do Sul. Instituto de Química. Grupo de Química Inorgânica Medicinal e Reações Aplicadas. Porto Alegre, RS, Brasil.
Universitá degli Studi di Milano. Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche. Milan, Italy.
Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Lisboa, Portugal.
University of Erlangen-Nürnberg. Center for Molecular Materials Friedrich-Alexander. Organic Chemistry Chair I and Interdisciplinary. Nikolaus Fiebiger-Straße. Erlangen, Germany.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Resumo em Inglês
A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to
display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this
study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei
hepatic infection and to decrease the viability of P. falciparum gametocytes, in addition to determining
whether the drug exhibits efficacy of a P. berghei infection in mice. This hybrid compound has
a low level of cytotoxicity to mammalian cells and, conversely, a high level of selectivity. It is
potent in the prevention of hepatic stage development as well as in killing gametocytes, denoting
a potential blockage of malaria transmission. The hybrid presents a potent inhibitory activity
for beta-hematin crystal formation, in which subsequent assays revealed that its endoperoxide
component undergoes bioactivation by reductive reaction with ferrous heme towards the formation
of heme-drug adducts; in parallel, the 7-chloroquinoline component has binding affinity for ferric
hemin. Both structural components of the hybrid co-operate to enhance the inhibition of betahematin,
and this bitopic ligand property is essential for arresting the growth of asexual blood
parasites. We demonstrated the in vivo efficacy of the hybrid as an erythrocytic schizonticide agent
in comparison to a chloroquine/artemisinin combination therapy. Collectively, the findings suggest
that the bitopic property of the hybrid is highly operative on heme detoxification suppression, and
this provides compelling evidence for explaining the action of the hybrid on the asexual blood
stage. For sporozoite and gametocyte stages, the hybrid conserves the potency typically observed
for endoperoxide drugs, and this is possibly achieved due to the redox chemistry of endoperoxide
components with ferrous heme.
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