Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of <i>Pseudomonas aeruginosa</i> Quorum Sensing Signal as New Anti-Biofilm Agents
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. <i>P...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/4/417 |
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| author | Jeanne Trognon Gonzalo Vera Maya Rima Jean-Luc Stigliani Laurent Amielet Salomé El Hage Barbora Lajoie Christine Roques Fatima El Garah |
| author_facet | Jeanne Trognon Gonzalo Vera Maya Rima Jean-Luc Stigliani Laurent Amielet Salomé El Hage Barbora Lajoie Christine Roques Fatima El Garah |
| author_sort | Jeanne Trognon |
| collection | DOAJ |
| description | 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. <i>Pseudomonas aeruginosa</i>, 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 <i>P. aeruginosa</i> in vitro. Overall, results showed several chromone 2-carboxamides of the retro series are potent inhibitors of the formation of <i>P. aeruginosa</i> biofilms (16/25 compound with % inhibition ≥ 50% at 50 μM), without cytotoxicity on Vero cells (IC<sub>50</sub> > 1.0 mM). The 2,4-dinitro-N-(4-oxo-4H-chromen-2-yl) benzamide (<b>6n</b>) was the most promising antibiofilm compound, with potential for hit to lead optimization. |
| first_indexed | 2024-03-09T13:10:57Z |
| format | Article |
| id | doaj.art-c3ae9fd1c30244b2837250f9a0421635 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T13:10:57Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-c3ae9fd1c30244b2837250f9a04216352023-11-30T21:42:52ZengMDPI AGPharmaceuticals1424-82472022-03-0115441710.3390/ph15040417Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of <i>Pseudomonas aeruginosa</i> Quorum Sensing Signal as New Anti-Biofilm AgentsJeanne Trognon0Gonzalo Vera1Maya Rima2Jean-Luc Stigliani3Laurent Amielet4Salomé El Hage5Barbora Lajoie6Christine Roques7Fatima El Garah8Laboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceLaboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceLaboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceLaboratoire de Chimie de Coordination, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceLaboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceLaboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceLaboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceLaboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceLaboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, 31062 Toulouse, FranceBiofilm 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. <i>Pseudomonas aeruginosa</i>, 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 <i>P. aeruginosa</i> in vitro. Overall, results showed several chromone 2-carboxamides of the retro series are potent inhibitors of the formation of <i>P. aeruginosa</i> biofilms (16/25 compound with % inhibition ≥ 50% at 50 μM), without cytotoxicity on Vero cells (IC<sub>50</sub> > 1.0 mM). The 2,4-dinitro-N-(4-oxo-4H-chromen-2-yl) benzamide (<b>6n</b>) was the most promising antibiofilm compound, with potential for hit to lead optimization.https://www.mdpi.com/1424-8247/15/4/417<i>Pseudomonas aeruginosa</i>Quorum Sensing inhibitionchromone carboxamidesPqsR<i>Pseudomonas</i> Quinolone Signal (PQS)biofilms |
| spellingShingle | Jeanne Trognon Gonzalo Vera Maya Rima Jean-Luc Stigliani Laurent Amielet Salomé El Hage Barbora Lajoie Christine Roques Fatima El Garah Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of <i>Pseudomonas aeruginosa</i> Quorum Sensing Signal as New Anti-Biofilm Agents Pharmaceuticals <i>Pseudomonas aeruginosa</i> Quorum Sensing inhibition chromone carboxamides PqsR <i>Pseudomonas</i> Quinolone Signal (PQS) biofilms |
| title | Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of <i>Pseudomonas aeruginosa</i> Quorum Sensing Signal as New Anti-Biofilm Agents |
| title_full | Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of <i>Pseudomonas aeruginosa</i> Quorum Sensing Signal as New Anti-Biofilm Agents |
| title_fullStr | Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of <i>Pseudomonas aeruginosa</i> Quorum Sensing Signal as New Anti-Biofilm Agents |
| title_full_unstemmed | Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of <i>Pseudomonas aeruginosa</i> Quorum Sensing Signal as New Anti-Biofilm Agents |
| title_short | Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of <i>Pseudomonas aeruginosa</i> Quorum Sensing Signal as New Anti-Biofilm Agents |
| title_sort | investigation of direct and retro chromone 2 carboxamides based analogs of i pseudomonas aeruginosa i quorum sensing signal as new anti biofilm agents |
| topic | <i>Pseudomonas aeruginosa</i> Quorum Sensing inhibition chromone carboxamides PqsR <i>Pseudomonas</i> Quinolone Signal (PQS) biofilms |
| url | https://www.mdpi.com/1424-8247/15/4/417 |
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