Indole-3-ethylsulfamoylphenylacrylamides: Potent histone deacetylase inhibitors with anti-inflammatory activity

• LBH589–PXD101 core model based compounds have been synthesized.
• These synthetics were evaluated for their HDAC inhibitory and anti-inflammatory activity.
• Compounds 9–12 show up to 1.7-fold improved IL-6 suppression compared to LBH589·HCl (1·HCl).
• Compound 9 exhibited potent activity to reduce inflammation in an animal model.

A series of 2-methyl-1H-indol-3-ethylsulfamoylphenylacrylamides based on LBH589–PXD101 core have been synthesized and evaluated for their histone deacetylase (HDAC) inhibitory and anti-inflammatory activity. In vitro, compounds 9–12 show 2.6-fold better HDAC inhibition and 3-fold better IL-6 suppression compared to LBH589·HCl (1·HCl). Furthermore, these compounds did not show apparent cell viability suppression on macrophages while in contrast, treatment with 1·HCl resulted in significant reduction in cell viability as demonstrated by an MTT assay. Repressed expression of iNOS, COX-2 and reduced phosphorylation of p65 revealed the inhibitory effect of these analogues on inflammatory mediator release which is related to inhibited NF-ĸB signals. (N-Hydroxy-3-{3-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide) (9), exhibited ability superior to that of 1·HCl, was able to reduce carrageenan-induced acute inflammation in an animal model. Compounds 9–12 have potential anti-inflammatory activity and compound 9 can serve as lead compound for further development.

LBH589–PXD101 core model based compounds have been synthesized and evaluated for their HDAC inhibitory and anti-inflammatory activity.Figure optionsDownload as PowerPoint slide