3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance.
ACS Infect Dis
; 10(7): 2419-2442, 2024 Jul 12.
Article
em En
| MEDLINE
| ID: mdl-38862127
ABSTRACT
ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331, exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596, a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598, a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
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Quinolonas
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Antimaláricos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
ACS Infect Dis
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos