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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320722000240 |
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| author | Wilian A. Cortopassi Emma Gunderson Yasmin Annunciato Antony.E.S. Silva Amália dos Santos Ferreira Carolina Bioni Garcia Teles Andre S. Pimentel Roopa Ramamoorthi Marcos L Gazarini Mario R. Meneghetti Rafael.V.C. Guido Dhelio B. Pereira Matthew P. Jacobson Antoniana U. Krettli Anna Caroline C Aguiar |
| author_facet | Wilian A. Cortopassi Emma Gunderson Yasmin Annunciato Antony.E.S. Silva Amália dos Santos Ferreira Carolina Bioni Garcia Teles Andre S. Pimentel Roopa Ramamoorthi Marcos L Gazarini Mario R. Meneghetti Rafael.V.C. Guido Dhelio B. Pereira Matthew P. Jacobson Antoniana U. Krettli Anna Caroline C Aguiar |
| author_sort | Wilian A. Cortopassi |
| collection | DOAJ |
| 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 (DAQM), 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. |
| first_indexed | 2024-04-11T14:01:06Z |
| format | Article |
| id | doaj.art-0b9cbb46649a4e53a7ef050c9041a6cc |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-04-11T14:01:06Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-0b9cbb46649a4e53a7ef050c9041a6cc2022-12-22T04:20:08ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072022-12-0120121128Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analoguesWilian A. Cortopassi0Emma Gunderson1Yasmin Annunciato2Antony.E.S. Silva3Amália dos Santos Ferreira4Carolina Bioni Garcia Teles5Andre S. Pimentel6Roopa Ramamoorthi7Marcos L Gazarini8Mario R. Meneghetti9Rafael.V.C. Guido10Dhelio B. Pereira11Matthew P. Jacobson12Antoniana U. Krettli13Anna Caroline C Aguiar14Department of Pharmaceutical Chemistry, University of California, San Francisco, USADepartment of Pharmaceutical Chemistry, University of California, San Francisco, USADepartment of Biosciences, Federal University of São Paulo, Santos, SP, BrazilGroup of Catalysis and Chemical Reactivity Group, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió, AL, BrazilOswaldo Cruz Foundation, Leishmaniasis and Malaria Bioassay Platform, Porto Velho, Rondônia, BrazilOswaldo Cruz Foundation, Leishmaniasis and Malaria Bioassay Platform, Porto Velho, Rondônia, BrazilDepartment of Chemistry, Pontifical Catholic University of Rio de Janeiro, RJ, BrazilCatalyst Program, University of California, San Francisco, USADepartment of Biosciences, Federal University of São Paulo, Santos, SP, BrazilGroup of Catalysis and Chemical Reactivity Group, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió, AL, BrazilSão Carlos Institute of Physics, University of Sao Paulo, Av. João Dagnone, 1100 - Santa Angelina, São Carlos, SP, 13563-120, BrazilResearch Center in Tropical Medicine of Rondônia, Porto Velho, Rondônia, BrazilDepartment of Pharmaceutical Chemistry, University of California, San Francisco, USAMalaria Laboratory, René Rachou Research Center, FIOCRUZ, Belo Horizonte, MG, Brazil; Corresponding author.Department of Biosciences, Federal University of São Paulo, Santos, SP, Brazil; São Carlos Institute of Physics, University of Sao Paulo, Av. João Dagnone, 1100 - Santa Angelina, São Carlos, SP, 13563-120, Brazil; Corresponding author.Department of Biosciences, Federal University of São Paulo, Santos, SP, Brazil.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 (DAQM), 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.http://www.sciencedirect.com/science/article/pii/S2211320722000240MalariaChloroquineResistanceACTsDAQ |
| spellingShingle | Wilian A. Cortopassi Emma Gunderson Yasmin Annunciato Antony.E.S. Silva Amália dos Santos Ferreira Carolina Bioni Garcia Teles Andre S. Pimentel Roopa Ramamoorthi Marcos L Gazarini Mario R. Meneghetti Rafael.V.C. Guido Dhelio B. Pereira Matthew P. Jacobson Antoniana U. Krettli Anna Caroline C Aguiar Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues International Journal for Parasitology: Drugs and Drug Resistance Malaria Chloroquine Resistance ACTs DAQ |
| 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 | Malaria Chloroquine Resistance ACTs DAQ |
| url | http://www.sciencedirect.com/science/article/pii/S2211320722000240 |
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