Synthesis and biological evaluation of 4-phenoxy-phenyl isoxazoles as novel acetyl-CoA carboxylase inhibitors

Acetyl-CoA carboxylase (ACC) is a crucial enzyme in fatty acid metabolism, which plays major role the occurrence and development of certain tumours. Herein, one potential ACC inhibitor (6a) was identified through high-throughput virtual screening (HTVS), series 4-phenoxy-phenyl isoxazoles were synthesised for structure-activity relationship (SAR) studies. Among these compounds, 6g exhibited most potent inhibitory activity (IC50=99.8 nM), comparable to that CP-640186. Moreover, antiproliferation assay revealed compound 6l strongest cytotoxicity, with IC50 values 0.22 µM (A549), 0.26 (HepG2), 0.21 (MDA-MB-231), respectively. The preliminary mechanistic studies on suggested compounds decreased malonyl-CoA levels, arrested cell cycle at G0/G1 phase, induced apoptosis MDA-MB-231 cells. Overall, results indicated are further study cancer therapeutics as inhibitors.