Design, synthesis, and biological evaluation of chrysin derivatives as potential FabH inhibitors

New series of chrysin derivatives (4a-4t) were designed and synthesized by introducing different substituted piperazines at C-7 position. Their inhibitory effects on FabH were evaluated using two Gram-negative bacterial strains, Escherichia coli and Pseudomonas aeruginosa, and two Gram-positive bacterial strains, Bacillus subtilis and Staphylococcus aureus. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with the control positive drugs. Among them, compound 4s exhibited the most potent inhibitory activity with IC50 values of 5.78 +/- 0.24m inhibiting E.coli FabH and potent antibacterial activity against S.aureus and E.coli with MIC of 1.25 +/- 0.01, 1.15 +/- 0.12g/mL, respectively, comparing to the control positive drugs penicillin G (7.56 +/- 0.30m). Docking simulation was performed to position compound 4s into the FabH active site, and the result showed that compound 4s could bind well with the FabH as potent FabH inhibitor.