Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study.
Bioorg Med Chem Lett
; 26(1): 94-9, 2016 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-26602278
ABSTRACT
Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC50=5700nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent optimization led to the identification of the potent lead compound 8n with IC50 values of 4.5 and 6.9nM, respectively, against LPS-induced PGE2 production and NO production in RAW 264.7 macrophage cells. In addition, 8n was about 30- and >150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC50=70nM) than MK-886 and hit compound 1, respectively. Molecular docking suggests that compound 8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 enzyme.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Compuestos de Sulfhidrilo
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Dinoprostona
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Oxidorreductasas Intramoleculares
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Inhibidores Enzimáticos
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Simulación del Acoplamiento Molecular
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Hidrazinas
Límite:
Humans
Idioma:
En
Año:
2016
Tipo del documento:
Article