Abstract
Six 2'-hydroxychalcones were synthesized and characterized by NMR,
FT-Raman, ATR-FTIR, and UV-Vis. These chalcones alone and in combination
with the ciprofloxacin, penicillin, and erythromycin antibiotics were
tested against multiresistant strains of Staphylococcus aureus. It was
also verified by in vitro and in silico studeis the capacity of these
chalcones to inhibit the NorA efflux pump. The MICs values of
ciprofloxacin were reduced in the presence of all tested chalcones. For
norfloxacin antibiotic, the chalcones A1, A4, A5 and A6 promoted the
reduced in the MIC values. The A2 chalcone was the only one to reduce
the MIC values when associated with penicillin. Any chalcones were not
able to reduce MIC values when associated with erythromycin. These
results indicate that the synergistic effects demonstrated for the
synthesized chalcones were influenced by the introduction of a furanic
ring (A1), a chlorine atom and a methoxy group at the C4 position (A2
and A4), a second double bond (A5), and a fluorine atom at the C2
position (A6). The ADMET analysis predicts that the chalcones A2, A3, A5
and A6 have easier cell permeation. The nucleophilic region makes the A5
chalcone capable of covalently bonding with plasma proteins, and the
presence of oxygenated aromatic substitutions makes the chalcones A1 and
A4 more water-soluble and consequently easier to excrete. On the other
hand, the substitution of the methoxy group of the A4 chalcone makes it
more susceptible to O-demethylation reactions by the CYP3A4 isoenzyme.
The molecular docking revealed that all six chalcones could hinder the
binding of norfloxacin to the NorA efflux pump.
(c) 2021 Elsevier B.V. All rights reserved.
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