Aminophenyl chalcones potentiating antibiotic activity and inhibiting bacterial efflux pump.

Chalcones and their derivatives are substances of great interest for medicinal chemistry due to their antibacterial activities. As the bacterial resistance to clinically available antibiotics has become a worldwide public health problem, it is essential to search for compounds capable of reverting the bacterial resistance. As a possibility, the chalcone class could be an interesting answer to this problem. The chalcones (2E)-1-(4'-aminophenyl)-3-(phenyl)­prop-2-en-1-one (APCHAL), and (2E)-1-(4'-aminophenyl)-3-(4-chlorophenyl)­prop-2-en-1-one (ACLOPHENYL) were synthesized by the Claisen-Schmidt condensation and characterized by 1H and 13C nuclear magnetic resonance (NMR), Fourier-transform infrared (FT-IR), and mass spectrometry (MS), In addition, microbiological tests were performed to investigate the antibacterial activity, modulatory potential, and efflux pump inhibition against Staphylococcus aureus (S. aureus) multi-resistant strains. Regarding the S. aureus Gram-positive model, the APCHAL presented synergism with gentamicin and antagonism with penicillin. APCHAL reduced the Minimum inhibitory concentration (MIC) of gentamicin by almost 70%. When comparing the effects of the antibiotic modifying activity of ACLOPHENYL and APCHAL, a loss of synergism is noted with gentamicin due to the addition of a chlorine to the substance structure. For Escherichia coli (E. coli) a total lack of effect, synergistic or antagonistic, was observed between ACLOPHENYL and the antibiotics. In the evaluation of inhibition of the efflux pump, both chalcones presented a synergistic effect with norfloxacin and ciprofloxacin against S. aureus, although the effect is much less pronounced with ACLOPHENYL. The effect of APCHAL is particularly notable against the K2068 (MepA overexpresser) strain, with synergistic effects with both ciprofloxacin and ethidium bromide. The docking results also show that both compounds bind to roughly the same region of the binding site of 1199B (NorA overexpresser), and that this region overlaps with the preferred binding region of norfloxacin. The APCHAL chalcone may contribute to the prevention or treatment of infectious diseases caused by multidrug-resistant S. aureus.

Direct antibacterial and antibiotic resistance modulatory activity of chalcones synthesized from the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone.

Antibiotic for clinical use lose its effectiveness over time due to bacterial resistance. In this work, four chalcones with modifications in their ligands were synthesized from the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone, characterized by nuclear magnetic resonance (NMR) and infrared spectroscopy, and tested in bacterial models to investigate the direct and modifiers effects of the antibiotic activity of these four novel chalcones. The tests followed the broth microdilution methodology to obtain the Minimum Inhibitory Concentration (MIC). The MIC/8 of the products were used in the resistance reversion test. The chalcone 2 showed the best result in terms of direct activity, with MIC 645 µg/mL for Staphylococcus aureus and 812 µg/mL for Escherichia coli. While, for the bacterial resistance reversal test, the chalcones presented several synergistic interactions, being that chalcone 4 had the best interaction with the tested antibiotics. It was found that the type of ligand, as well as its position in the ring, interferes in the modulation of the antibiotic activity. Our results show that chalcones are strong candidates to be used as antibacterial drug or in combination with antibiotics for the treatment of infections caused by multidrug-resistant (MDR) strains.