Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum.
J Med Chem
; 64(5): 2739-2761, 2021 03 11.
Article
em En
| MEDLINE
| ID: mdl-33620219
ABSTRACT
Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
2_ODS3
/
3_ND
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Tetrazóis
/
Hemoglobinas
/
Amidas
/
Antimaláricos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2021
Tipo de documento:
Article