Aminoguanidine hydrazones (AGH's) as modulators of norfloxacin resistance in Staphylococcus aureus that overexpress NorA efflux pump

Abstract

One of the promising fields for improving the effectiveness of antimicrobial agents is their combination with efflux pump inhibitors (EPIs), which besides expanding the use of existing antibiotics. The goal of this research was to evaluate a series of aminoguanidine hydrazones (AGH's, 1-19) as antibacterial agents and NorA efflux pump inhibitors in Staphylococcus aureus strain SA-1199B. Molecular modeling and docking studies were also performed in order to explain at the molecular level the interactions of the compounds with the generated NorA efflux pump model. The MICs of the antibiotic and ethidium bromide were determined by microdilution assay in absence or presence of a subinhibitory concentration of aminoguanidine hydrazones and macrophages viability was determined through MTT assay. Bioinformatic software Swiss-Model and AutoDock 4.2 were used to perform modeling and docking studies, respectively. As results, all AGH's were able to potentiate the action for the antibiotic norfloxacin, causing MIC's reduction of 16-fold and 32-fold to ethidium bromide. In the cell viability test, the concentration of 10 μg/mL showed better results than 90% and the concentration of 1000 μg/mL showed the lowest viability, reaching a maximum of 50% for the analyzed aminoguanidine hydrazones. Molecular docking studies showed that both norfloxacin and derivative 13 were recognized by the same binding site of NorA pump, suggesting a competitive mechanism. The present work demonstrated for the first time that AGH derivatives have potential to be putative inhibitors of NorA efflux pump, showing a promising activity as an antibacterial drug development.

Biological Activity of Some Newly Synthesized Hydrazone Derivatives Derived From (Dicyclopropylmethylene)hydrazone

“…Compound 1 was reacted with cyanoacetic acid hydrazide in ethanol as a solvent given a mixture of cyanoacetohydrazone and pyrazole derivatives (12 and 13) which can exist in two tautomeric ketone-enol forms), respectively and these products were separated easily from ethanol by cooling. Treatment of dicyclopropyl ketone with thiourea derivative (14) in boiling ethanol gave the corresponding quinazoline derivative (15).…”

“…13 Aminoguanidine hydrazones (AGH's) have potential important towards developing focused adjuvants for antibiotic drug therapies against bacterial multidrug resistance. 14 These compounds also evaluated for their in vitro α-glucosidase inhibitory activity. 15 Hydrazones have been used to design materials that are used for pH-responsive drug delivery systems and these hydrazones were characterized by different spectral methods.…”

Synthesis and evaluation of antimicrobial and anticancer activities of 3‐phenyl‐1‐phenylsulfonyl pyrazoles containing an aminoguanidine moiety

“…Aminoguanidine derivatives, a kind of good metal anticancer and antiviral coordination complexes with low toxicity, have recently been investigated as antimicrobial agents. [ 17–24 ] In our previous work, a series of aminoguanidine derivatives containing N ‐arylsulfonyl indoles were prepared as new antimicrobial agents. Most compounds in this series showed potent inhibitory activity against the tested bacterial strains, including multidrug‐resistant strains, with minimum inhibitory concentration (MIC) values in the range of 0.5–8 μg/ml.…”

“…Aminoguanidine derivatives, a kind of good metal anticancer and antiviral coordination complexes with low toxicity, have recently been investigated as antimicrobial agents. [17][18][19][20][21][22][23][24] In our previous work, a values in the range of 1.51-15.1 µmol/l. [20] So, it is valuable to further investigate this skeleton to discover new antimicrobial and anticancer molecules with better performances.…”

Electrochemical Evaluation of Aminoguanidine Hydrazone Derivative with Potential Anticancer Activity: Studies of Glassy Carbon/CNT and Gold Electrodes Both Modified with PAMAM

“…Aminoguanidine hydrazine derivatives are bioactive compounds that have been intensively studied for their different (and interesting) biological activities, such as in the treatment of hypertension (Guanabenz) [1] [2] [3], or antiarrhythmic [4] [5]; nonpeptide NPFF1 Receptor Antagonists reverse opioid-induced hyperalgesia [6]; as modulators of norfloxacin resistance in S. aureus that overexpress the efflux pump of NorA [7]; and anticancer [8].…”