Synthesis of a novel series of 2-alkylthio substituted naphthoquinones as potent acyl-CoA: Cholesterol acyltransferase (ACAT) inhibitors

We report a new series of naphthoquinone derivatives as potent ACAT inhibitors, which were obtained through structural variations of previously disclosed lead 1. Several analogs represented by 3i–l, 4k–m, 6a–n, 7a, and 7i demonstrated potent human macrophage ACAT inhibitory activity by a cell-based reporter assay with human HepG2 cell lines. In particular, compounds 4l and 6j emerged as highly potent inhibitors, exhibiting significantly high inhibitory potencies with IC50 values of 0.44 μM and 0.6 μM, respectively. Moreover, compound 4l significantly reduced the accumulation of cellular cholesterol in HepG2 cell lines.

A series of naphthoquinone derivatives as potent ACAT inhibitors were synthesized based on compound 1. Compound 4l exhibited potent inhibitory activity against ACAT with IC50 values of 0.44 μM.Figure optionsDownload as PowerPoint slideHighlights
► A new series of naphthoquinone derivatives was synthesized as ACAT inhibitors.
► Several analogs exhibited potent ACAT inhibitory activity.
►  Compound 4l emerged as a highly potent inhibitor with IC50 values of 0.44 μM.
► Compound 4l significantly reduced cellular cholesterol in HepG2 cell lines.