ADMET study, spectroscopic characterization and effect of synthetic nitro chalcone in combination with norfloxacin, ciprofloxacin, and ethidium bromide against Staphylococcus aureus efflux pumps

Abstract

Chalcones are present in a wide variety of plants, having in their structure two aromatic rings that are linked together by a chain composed of three carbon atoms with α, β‐unsaturated to carbonyl system. Bacteria have several drug resistance mechanisms, among them the efflux pump; this mechanism, when active, is able to expel different compounds from inside bacterial cells. Several efflux pumps have already been identified for Staphylococcus aureus bacteria, including MepA and NorA. Many chalcones have been isolated and identified with various activities, such as antimicrobial. In view of this, this article aimed to evaluate the antibiotic modifying effect of chalcone (E)‐1‐(2‐hydroxyphenyl)‐3‐(3‐nitrophenyl)prop‐2‐en‐1‐one against S. aureus carrier of NorA and MepA efflux pump. Regarding the antibiotic, there was a synergism when associated with ciprofloxacin in SA‐K2068 strain, showing this chalcone as an alternative to reverse the resistance to this medicine. The physicochemical properties calculated were fundamental in the description of the predicted pharmacokinetic properties. Despite the mutagenic risk caused by the metabolic activation of nitrochalcone, it is possible to notice a pharmacological principle in a longer half‐life for the performance of biological activities. The compound has a good bioavailability, as it is highly absorbed in the intestine and easily transported by plasma proteins, in addition to not presenting neurotoxic, hepatotoxic, and cardiotoxic damage.

Synthesis, spectroscopic characterization, and antibacterial activity of chalcone (2E)‐1‐(3′‐aminophenyl)‐3‐(4‐dimethylaminophenyl)‐prop‐2‐en‐1‐one against multiresistant Staphylococcus aureus carrier of efflux pump mechanisms and β‐lactamase

“…Regarding the modification activity of antibiotics by chalcones, the work of Rocha et al [48] presents a nitrochalcone synthesized by the Claisen–Schmidt methodology that was able to potentiate the antibiotic activity of Ciprofloxacin on the K2068 strains of S. aureus carrying the MepA efflux pump and may reverse the resistance of bacteria to this drug. In addition, the authors point out that despite the mutagenic risk caused by the metabolic activation of nitrocalcone, ADMET studies have shown that the compound has good availability, is easily absorbed in the intestine, and shows no toxicity to heart, liver, and neural tissues.…”

Inhibition of Multidrug Efflux Pumps Belonging to the Major Facilitator Superfamily in Bacterial Pathogens

“…The NorA multidrug efflux pump system of S. aureus has been a good target for transport inhibition studies reviewed elsewhere [98]. In S. aureus, plant-derived chalcones showed synergistic activity with antimicrobial agents ciprofloxacin, norfloxacin, and ethidium bromide involving the MFS proteins NorA and MepA [99]. Molecular docking analysis of these chalcones showed close interactions with NorA residues Ser-337, Met-338, Gly-339, and Asn-340, implicating these residues as good molecular targets for transport studies and resistance modulation [99].…”

“…In S. aureus, plant-derived chalcones showed synergistic activity with antimicrobial agents ciprofloxacin, norfloxacin, and ethidium bromide involving the MFS proteins NorA and MepA [99]. Molecular docking analysis of these chalcones showed close interactions with NorA residues Ser-337, Met-338, Gly-339, and Asn-340, implicating these residues as good molecular targets for transport studies and resistance modulation [99]. The affected residues directly involve ciprofloxacin and norfloxacin binding and transport across the membrane through NorA.…”

Synthesis, molecular docking, ADMET, and evaluation of the anxiolytic effect in adult zebrafish of synthetic chalcone (E)‐3‐(4‐(dimethylamino)phenyl)‐1‐(2‐hydroxyphenyl)prop‐2‐en‐1‐one: An in vivo and in silico approach

“…Chemically, chalcones and their derivatives can undergo substitutions in their aromatic rings, being responsible for different spectra of activity. Thus, they have drawn attention for their simple structure associated with several pharmacological activities, such as anticancer [3], anti-inflammatory [4], antibacterial [5], antioxidant [6], antinociceptives [7], analgésicos [8], analgesics [9], antichagasic [10], and anxiolytics [11].…”