ABSTRACT
A new series of 3-(substituted-3,4-dihydronaphthyl)-2-propenoic acid amides has been prepared through convergent synthetic strategies and tested in combination with ciprofloxacin against NorA overexpressing Staphylococcus aureus 1199B as test strain for potentiating of the drug activity. Out of 24 compounds evaluated, 12 compounds potentiated the activity of ciprofloxacin and resulted in 2-16 fold reduction in the MIC (4-0.5 microg/mL) of the drug. The failure of these efflux pump inhibitors (EPIs) to potentiate the activity of ciprofloxacin when tested against NorA knock out S. aureus SA-K1758 established their identity as NorA inhibitors. The structure of all these newly synthesised compounds was confirmed by spectral data. The present communication describes the synthesis, bioevaluation, structure activity relationship and mechanism of action of these EPIs.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Membrane Transport Proteins/metabolism , Naphthalenes/chemistry , Naphthalenes/pharmacology , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Ciprofloxacin/pharmacology , Drug Synergism , Microbial Sensitivity Tests , Naphthalenes/chemical synthesis , Staphylococcus aureus/metabolism , Structure-Activity RelationshipABSTRACT
Based on our recent findings that piperine is a potent Staphylococcus aureus NorA efflux pump inhibitor (EPI), 38 piperine analogs were synthesized and bioevaluated for their EPI activity. Twenty-five of them were found active with potentiating activity equivalent or more than known EPIs like reserpine, carsonic acid and verapamil. The inhibitory mechanism of the compounds was confirmed by efflux inhibition assay using ethidium bromide as NorA substrate. The present communication describes the synthesis, bioevaluation and structure related activity of these efflux pump inhibitors.
