Synthesis and antibacterial activity of C2 or C5 modified and D ring rejiggered canthin-6-one analogues

Thirty-one canthin-6-one analogues, mainly including C2 or C5 or D ring modified canthin-6-ones, were designed and synthesized in order to study their antibacterial activity and structure-activity relationships. The analogue 28 with the highest bioactivity had a peak minimum inhibitory concentration of 4 μg/ml and showed low cytotoxicity against L02 cells and good “drug-like” properties. The antibacterial effect of 28 was characterized further by scanning electron microscopy, cytoplasmic β-galactosidase leakage assay, molecular docking evaluation, UV-visible analysis and isothermal titration calorimetry (ITC) measurement. The results showed that 28 may exert its bactericidal effect by damaging bacterial cell membranes and disrupting the function of DNA topoisomerases, both of which could lead to rapid cell death.