Discovery and evaluation of thiazinoquinones as anti-protozoal agents.
Mar Drugs
; 11(9): 3472-99, 2013 Sep 09.
Article
em En
| MEDLINE
| ID: mdl-24022732
ABSTRACT
Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC50 3.1 µM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 3.3 µM) while exhibiting low levels of cytotoxicity (L6, IC50 167 µM). A series of C-7 amide and Δ²(³) analogues were prepared that explored the influence of lipophilicity and oxidation state on observed anti-protozoal activity and selectivity. Little variation in anti-malarial potency was observed (IC50 0.62-6.5 µM), and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and Δ²(³)-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while Δ²(³)-phenethylamide 8e (IC50 0.67 µM, SI 78) exhibited improved potency and selectivity towards T. brucei rhodesiense compared to the natural product hit. A second series of analogues were prepared that replaced the quinoline ring of 2 with benzofuran or benzothiophene moieties. While esters 10a/10b and 15 were once again found to exhibit cytotoxicity, carboxylic acid analogues exhibited potent anti-Pf activity (IC50 0.34-0.035 µM) combined with excellent selectivity (SI 560-4000). In vivo evaluation of a furan carboxylic acid analogue against P. berghei was undertaken, demonstrating 85.7% and 47% reductions in parasitaemia with ip or oral dosing respectively.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinonas
/
Antimaláricos
Idioma:
En
Revista:
Mar Drugs
Assunto da revista:
BIOLOGIA
/
FARMACOLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Nova Zelândia