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Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues

Malaria is among the tropical diseases that cause the most deaths in Africa. Around 500,000 malaria deaths are reported yearly among African children under the age of five. Chloroquine (CQ) is a low-cost antimalarial used worldwide for the treatment of Plasmodium vivax malaria. Due to resistance mec...

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Autores principales: Cortopassi, Wilian A., Gunderson, Emma, Annunciato, Yasmin, Silva, Antony.E.S., dos Santos Ferreira, Amália, Garcia Teles, Carolina Bioni, Pimentel, Andre S., Ramamoorthi, Roopa, Gazarini, Marcos L, Meneghetti, Mario R., Guido, Rafael.V.C., Pereira, Dhelio B., Jacobson, Matthew P., Krettli, Antoniana U., Caroline C Aguiar, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771834/
https://www.ncbi.nlm.nih.gov/pubmed/36375339
http://dx.doi.org/10.1016/j.ijpddr.2022.10.003
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author Cortopassi, Wilian A.
Gunderson, Emma
Annunciato, Yasmin
Silva, Antony.E.S.
dos Santos Ferreira, Amália
Garcia Teles, Carolina Bioni
Pimentel, Andre S.
Ramamoorthi, Roopa
Gazarini, Marcos L
Meneghetti, Mario R.
Guido, Rafael.V.C.
Pereira, Dhelio B.
Jacobson, Matthew P.
Krettli, Antoniana U.
Caroline C Aguiar, Anna
author_facet Cortopassi, Wilian A.
Gunderson, Emma
Annunciato, Yasmin
Silva, Antony.E.S.
dos Santos Ferreira, Amália
Garcia Teles, Carolina Bioni
Pimentel, Andre S.
Ramamoorthi, Roopa
Gazarini, Marcos L
Meneghetti, Mario R.
Guido, Rafael.V.C.
Pereira, Dhelio B.
Jacobson, Matthew P.
Krettli, Antoniana U.
Caroline C Aguiar, Anna
author_sort Cortopassi, Wilian A.
collection PubMed
description Malaria is among the tropical diseases that cause the most deaths in Africa. Around 500,000 malaria deaths are reported yearly among African children under the age of five. Chloroquine (CQ) is a low-cost antimalarial used worldwide for the treatment of Plasmodium vivax malaria. Due to resistance mechanisms, CQ is no longer effective against most malaria cases caused by P. falciparum. The World Health Organization recommends artemisinin combination therapies for P. falciparum malaria, but resistance is emerging in Southeast Asia and some parts of Africa. Therefore, new medicines for treating malaria are urgently needed. Previously, our group identified the 4-aminoquinoline DAQ, a CQ analog containing an acetylenic bond in its side chain, which overcomes CQ resistance in K1 P. falciparum strains. In this work, the antiplasmodial profile, drug-like properties, and pharmacokinetics of DAQ were further investigated. DAQ showed no cross-resistance against standard CQ-resistant strains (e.g., Dd2, IPC 4912, RF12) nor against P. falciparum and P. vivax isolates from patients in the Brazilian Amazon. Using drug pressure assays, DAQ showed a low propensity to generate resistance. DAQ showed considerable solubility but low metabolic stability. The main metabolite was identified as a mono N-deethylated derivative (DAQ(M)), which also showed significant inhibitory activity against CQ-resistant P. falciparum strains. Our findings indicated that the presence of a triple bond in CQ-analogues may represent a low-cost opportunity to overcome known mechanisms of resistance in the malaria parasite.
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spelling pubmed-97718342022-12-23 Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues Cortopassi, Wilian A. Gunderson, Emma Annunciato, Yasmin Silva, Antony.E.S. dos Santos Ferreira, Amália Garcia Teles, Carolina Bioni Pimentel, Andre S. Ramamoorthi, Roopa Gazarini, Marcos L Meneghetti, Mario R. Guido, Rafael.V.C. Pereira, Dhelio B. Jacobson, Matthew P. Krettli, Antoniana U. Caroline C Aguiar, Anna Int J Parasitol Drugs Drug Resist Regular article Malaria is among the tropical diseases that cause the most deaths in Africa. Around 500,000 malaria deaths are reported yearly among African children under the age of five. Chloroquine (CQ) is a low-cost antimalarial used worldwide for the treatment of Plasmodium vivax malaria. Due to resistance mechanisms, CQ is no longer effective against most malaria cases caused by P. falciparum. The World Health Organization recommends artemisinin combination therapies for P. falciparum malaria, but resistance is emerging in Southeast Asia and some parts of Africa. Therefore, new medicines for treating malaria are urgently needed. Previously, our group identified the 4-aminoquinoline DAQ, a CQ analog containing an acetylenic bond in its side chain, which overcomes CQ resistance in K1 P. falciparum strains. In this work, the antiplasmodial profile, drug-like properties, and pharmacokinetics of DAQ were further investigated. DAQ showed no cross-resistance against standard CQ-resistant strains (e.g., Dd2, IPC 4912, RF12) nor against P. falciparum and P. vivax isolates from patients in the Brazilian Amazon. Using drug pressure assays, DAQ showed a low propensity to generate resistance. DAQ showed considerable solubility but low metabolic stability. The main metabolite was identified as a mono N-deethylated derivative (DAQ(M)), which also showed significant inhibitory activity against CQ-resistant P. falciparum strains. Our findings indicated that the presence of a triple bond in CQ-analogues may represent a low-cost opportunity to overcome known mechanisms of resistance in the malaria parasite. Elsevier 2022-10-31 /pmc/articles/PMC9771834/ /pubmed/36375339 http://dx.doi.org/10.1016/j.ijpddr.2022.10.003 Text en © 2022 Published by Elsevier Ltd on behalf of Australian Society for Parasitology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Regular article
Cortopassi, Wilian A.
Gunderson, Emma
Annunciato, Yasmin
Silva, Antony.E.S.
dos Santos Ferreira, Amália
Garcia Teles, Carolina Bioni
Pimentel, Andre S.
Ramamoorthi, Roopa
Gazarini, Marcos L
Meneghetti, Mario R.
Guido, Rafael.V.C.
Pereira, Dhelio B.
Jacobson, Matthew P.
Krettli, Antoniana U.
Caroline C Aguiar, Anna
Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues
title Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues
title_full Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues
title_fullStr Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues
title_full_unstemmed Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues
title_short Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues
title_sort fighting plasmodium chloroquine resistance with acetylenic chloroquine analogues
topic Regular article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771834/
https://www.ncbi.nlm.nih.gov/pubmed/36375339
http://dx.doi.org/10.1016/j.ijpddr.2022.10.003
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