First identification of xanthone sulfonamides as potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors

Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) would be useful anti-atherogenic agents, since an absence of ACAT affects the absorption and transformation of cholesterol, indirectly resulting in the reduction of cholesteryl ester accumulation in blood vessels. This report discloses xanthone sulfonamides as novel class small molecule inhibitors of ACAT. A series of xanthone sulfonamides were synthesized and evaluated to result in the identification of several potent ACAT inhibitors, among which 2n proved to be more potent than the positive control Sandoz58-35. Moreover, a molecular model for the binding between 2n and the active site of ACAT-2 was provided based computational docking results.

A series of xanthone sulfonamides were identified by HTS as inhibitors of the ACAT. Compound 2n shows 64.8% inhibition to ACAT at 10 μg/mL concentration.Figure optionsDownload as PowerPoint slide