Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.
Acridones
/ chemistry
Administration, Oral
Animals
Antimalarials
/ chemistry
Cell Survival
/ drug effects
Disease Models, Animal
Female
Half-Life
Hep G2 Cells
Humans
Life Cycle Stages
/ drug effects
Malaria
/ drug therapy
Male
Mice
Mice, Inbred C57BL
Plasmodium falciparum
/ drug effects
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
11 06 2020
11 06 2020
Historique:
pubmed:
12
5
2020
medline:
13
11
2020
entrez:
12
5
2020
Statut:
ppublish
Résumé
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.
Identifiants
pubmed: 32390431
doi: 10.1021/acs.jmedchem.0c00539
pmc: PMC7354843
mid: NIHMS1593349
doi:
Substances chimiques
Acridones
0
Antimalarials
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
6179-6202Subventions
Organisme : NIAID NIH HHS
ID : R01 AI093784
Pays : United States
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