Synthesis, anti-ferroptosis, anti-quorum sensing, antibacterial and DNA interaction studies of chromene-hydrazone derivatives.

Nineteen chromene-hydrazone derivatives containing a variety of structural modifications on the hydrazone moiety were synthesized. Structure-activity correlations were investigated to determine the influence of structural variations on anti-ferroptosis, anti-quorum sensing, antibacterial, DNA cleavage and DNA binding properties. Ferroptosis inhibitory activity was determined by measuring the ability of the derivatives to reverse erastin-induced ferroptosis. Several of the derivatives were more effective than fisetin at inhibiting ferroptosis, with the thiosemicarbazone derivative being the most effective. Quorum sensing inhibition was evaluated using Vibrio harveyi, and both V. harveyi and Staphylococcus aureus were used to determine antibacterial activity. The semicarbazone and benzensulfonyl hydrazone derivatives showed moderate quorum sensing inhibition with IC50 values of 27 µM and 22 µM, respectively, while a few aryl hydrazone and pyridyl hydrazone derivatives showed bacterial growth inhibition, with MIC values ranging from 3.9 to 125 µM. In addition, the interaction of the hydrazone derivatives with DNA was investigated by gel electrophoresis, UV-Vis spectroscopy and molecular docking. All of the derivatives cleaved plasmid DNA and showed favorable interaction with B-DNA through minor groove binding. Overall, this work highlights a broad range of pharmacological applications for chromene-hydrazone derivatives.

Antagonism of Quorum Sensing Phenotypes by Analogs of the Marine Bacterial Secondary Metabolite 3-Methyl-N-(2'-Phenylethyl)-Butyramide.

Quorum sensing (QS) antagonists have been proposed as novel therapeutic agents to combat bacterial infections. We previously reported that the secondary metabolite 3-methyl-N-(2'-phenylethyl)-butyramide, produced by a marine bacterium identified as Halobacillus salinus, inhibits QS controlled phenotypes in multiple Gram-negative reporter strains. Here we report that N-phenethyl hexanamide, a structurally-related compound produced by the marine bacterium Vibrio neptunius, similarly demonstrates QS inhibitory properties. To more fully explore structure-activity relationships within this new class of QS inhibitors, a panel of twenty analogs was synthesized and biologically evaluated. Several compounds were identified with increased attenuation of QS-regulated phenotypes, most notably N-(4-fluorophenyl)-3-phenylpropanamide against the marine pathogen Vibrio harveyi (IC50 = 1.1 µM). These findings support the opportunity to further develop substituted phenethylamides as QS inhibitors.