Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues.
ACTs
Chloroquine
DAQ
Malaria
Resistance
Journal
International journal for parasitology. Drugs and drug resistance
ISSN: 2211-3207
Titre abrégé: Int J Parasitol Drugs Drug Resist
Pays: Netherlands
ID NLM: 101576715
Informations de publication
Date de publication:
Dec 2022
Dec 2022
Historique:
received:
29
05
2022
revised:
17
10
2022
accepted:
18
10
2022
pubmed:
15
11
2022
medline:
15
12
2022
entrez:
14
11
2022
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 36375339
pii: S2211-3207(22)00024-0
doi: 10.1016/j.ijpddr.2022.10.003
pmc: PMC9771834
pii:
doi:
Substances chimiques
Chloroquine
886U3H6UFF
Acetylene
OC7TV75O83
Alkynes
0
Antimalarials
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
121-128Informations de copyright
Copyright © 2022. Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Declaration of competing interest WAC is currently employed at Novartis, however, all his efforts mentioned in this manuscript are a result of his work/collaboration with UCSF and collaborators in Brazil.
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