Synthesis and Evaluation of 2‐Azetidinone and 1H‐Pyrrole‐2,5‐dione Derivatives as Cholesterol Absorption Inhibitors for Reducing Inflammation Response and Oxidative Stress

Excess lipid accumulation can initiate the development and progression of atherosclerotic lesions, thus eventually leading to cardiovascular disease. Lipid‐lowering medication therapy is one of the cornerstones of cardiovascular disease therapy. On the basis of the cholesterol absorption inhibitor ezetimibe, we successfully synthesized seven 2‐azetidinone derivatives and eighteen 1H‐pyrrole‐2,5‐dione derivatives. Most of the new compounds significantly inhibited cholesterol uptake in vitro. In addition, one of the most active inhibitors, 3‐(4‐fluorophenyl)‐1‐(3S)‐3‐hydroxy‐3‐(4‐hydroxyphenyl)propyl]‐4‐(4‐hydroxyphenyl)‐1H‐pyrrole‐2,5‐dione ( 14q ), showed no cytotoxicity in L02 and HEK293T cell lines. Further evaluation indicated that 14q inhibited considerably the amount of TNF‐α, ROS, MDA, and LDH in vitro. Therefore, 14q might be a novel cholesterol absorption inhibitor.