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Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues
- Source :
- Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP
- Publication Year :
- 2022
-
Abstract
- 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.
- Subjects :
- Falciparum
Plasmodium
Plasmodium falciparum
Resistance
Drug Resistance
Vivax
Vaccine Related
Antimalarials
Rare Diseases
Biodefense
Humans
2.1 Biological and endogenous factors
Pharmacology (medical)
Aetiology
Child
Pharmacology
Acetylene
PLANEJAMENTO DE FÁRMACOS
Prevention
Chloroquine
Malaria
DAQ
Vector-Borne Diseases
Orphan Drug
Good Health and Well Being
Infectious Diseases
5.1 Pharmaceuticals
Medical Microbiology
Alkynes
Parasitology
ACTs
Antimicrobial Resistance
Development of treatments and therapeutic interventions
Infection
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP
- Accession number :
- edsair.doi.dedup.....90a9b6c4b4f4ef2f1131d295b7f4af99