Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of Pseudomonas aeruginosa Quorum Sensing Signal as New Anti-Biofilm Agents

Abstract

Biofilm formation is considered a major cause of therapeutic failure because bacteria in biofilms have higher protection against antimicrobials. Thus, biofilm-related infections are extremely challenging to treat and pose major concerns for public health, along with huge economic impacts. Pseudomonas aeruginosa, in particular, is a “critical priority” pathogen, responsible for severe infections, especially in cystic fibrosis patients because of its capacity to form resistant biofilms. Therefore, new therapeutic approaches are needed to complete the pipeline of molecules offering new targets and modes of action. Biofilm formation is mainly controlled by Quorum Sensing (QS), a communication system based on signaling molecules. In the present study, we employed a molecular docking approach (Autodock Vina) to assess two series of chromones-based compounds as possible ligands for PqsR, a LuxR-type receptor. Most compounds showed good predicted affinities for PqsR, higher than the PQS native ligand. Encouraged by these docking results, we synthesized a library of 34 direct and 25 retro chromone carboxamides using two optimized routes from 2-chromone carboxylic acid as starting material for both series. We evaluated the synthesized carboxamides for their ability to inhibit the biofilm formation of P. aeruginosa in vitro. Overall, results showed several chromone 2-carboxamides of the retro series are potent inhibitors of the formation of P. aeruginosa biofilms (16/25 compound with % inhibition ≥ 50% at 50 μM), without cytotoxicity on Vero cells (IC50 > 1.0 mM). The 2,4-dinitro-N-(4-oxo-4H-chromen-2-yl) benzamide (6n) was the most promising antibiofilm compound, with potential for hit to lead optimization.

Discovery of potent 1,1-diarylthiogalactoside glycomimetic inhibitors of Pseudomonas aeruginosa LecA with antibiofilm properties

“…Finally, to exclude any unwanted antibiotic effect on biofilm formation, the MICs (the concentration at which no bacterial growth was visible after 24 h of incubation at 37°C) and MBCs (minimal bactericidal concentration; the concentration at which the number of CFU was reduced by 99.9%) of compounds 8a and 9a against P. aeruginosa PAO1 were recorded as previously described. [34] The MICs and MBCs were higher than 5 mM (the highest concentration tested) for both compounds which demonstrated clearly the absence of classical antibacterial effect (on planktonic cells) for the tested compounds.…”

Antibacterial Activity of Quinoline‐Based Derivatives against Methicillin‐Resistant Staphylococcus aureus and Pseudomonas aeruginosa: Design, Synthesis, DFT and Molecular Dynamic Simulations

“…In the Conceptual DFT (CDFT), quantum descriptors including chemical hardness (η), chemical potential (V), and electronegativity (χ) are determined by the molecule response to changes in the electron number (N) at constant external potential, v(r). [54,58]…”

“…In the Conceptual DFT ( CDFT ), quantum descriptors including chemical hardness ( η ), chemical potential ( V ), and electronegativity ( χ ) are determined by the molecule response to changes in the electron number (N) at constant external potential, v(r) [54,58] $$$\vcenter{\openup.5em\halign{$\displaystyle{#}$\cr V={\left({{\partial E}\over{\partial N}}\right)}_{v\left(r\right)}\hfill\cr}}$$$ $$$\vcenter{\openup.5em\halign{$\displaystyle{#}$\cr \eta ={{1}\over{2}}{\left({{{\partial }^{2}E}\over{{\partial N}^{2}}}\right)}_{v\left(r\right)}={{{1}\over{2}}\left({{\partial \mu }\over{\partial N}}\right)}_{v\left(r\right)}\hfill\cr}}$$$ …”

“…As demonstrated in Figure 7 and Table S12 (see supplementary data), the moiety of quinoline derivatives is tightly bound to the pocket of PqsR . The outward appearance A pocket is hidden in the PqsR hinge region between two subdomains connected by sheet regions via hydrogen bonds (HBs) [54] . Compounds 3 , 5 , 8 , 9 , 12 and Ciprofloxacin formed HBs with the ILE236.…”

The Molecular Architecture of Pseudomonas aeruginosa Quorum-Sensing Inhibitors

“…Two series of chromones-based compounds were synthesized with the help of molecular docking. Based on the bioactive results, 3 2 ( Figure 11 a) was the most potent inhibitor of biofilm; it showed good predicted affinities for PqsR and may be a promising QS inhibitor targeting pqs [ 73 ]. Many compounds containing amide bonds or ureido motifs can act as inhibitors.…”