Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity
This work proposes the design of β-keto esters as antibacterial compounds. The design was based on the structure of the autoinducer of bacterial quorum sensing, <i>N</i>-(3-oxo-hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL). Eight β-keto ester analogues were synthesised with good yields a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/10/1339 |
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| author | Maximiliano Martínez-Cifuentes Emmanuel Soto-Tapia Camila Linares-Pipón Ben Bradshaw Paulina Valenzuela-Hormazabal David Ramírez Patricio Muñoz-Torres Claudio Parra |
| author_facet | Maximiliano Martínez-Cifuentes Emmanuel Soto-Tapia Camila Linares-Pipón Ben Bradshaw Paulina Valenzuela-Hormazabal David Ramírez Patricio Muñoz-Torres Claudio Parra |
| author_sort | Maximiliano Martínez-Cifuentes |
| collection | DOAJ |
| description | This work proposes the design of β-keto esters as antibacterial compounds. The design was based on the structure of the autoinducer of bacterial quorum sensing, <i>N</i>-(3-oxo-hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL). Eight β-keto ester analogues were synthesised with good yields and were spectroscopically characterised, showing that the compounds were only present in their β-keto ester tautomer form. We carried out a computational analysis of the reactivity and ADME (absorption, distribution, metabolism, and excretion) properties of the compounds as well as molecular docking and molecular dynamics calculations with the LasR and LuxS quorum-sensing (QS) proteins, which are involved in bacterial resistance to antibiotics. The results show that all the compounds exhibit reliable ADME properties and that only compound <b>7</b> can present electrophile toxicity. The theoretical reactivity study shows that compounds <b>6</b> and <b>8</b> present a differential local reactivity regarding the rest of the series. Compound <b>8</b> presents the most promising potential in terms of its ability to interact with the LasR and LuxS QS proteins efficiently according to its molecular docking and molecular dynamics calculations. An initial in vitro antimicrobial screening was performed against the human pathogenic bacteria <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i> as well as the phytopathogenic bacteria <i>Pseudomonas syringae</i> and <i>Agrobacterium tumefaciens</i>. Compounds <b>6</b> and <b>8</b> exhibit the most promising results in the in vitro antimicrobial screening against the panel of bacteria studied. |
| first_indexed | 2024-03-10T20:58:31Z |
| format | Article |
| id | doaj.art-3a8fe336900a4e60ac4efa03d5c88dac |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T20:58:31Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-3a8fe336900a4e60ac4efa03d5c88dac2023-11-19T17:41:03ZengMDPI AGPharmaceuticals1424-82472023-09-011610133910.3390/ph16101339Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition CapacityMaximiliano Martínez-Cifuentes0Emmanuel Soto-Tapia1Camila Linares-Pipón2Ben Bradshaw3Paulina Valenzuela-Hormazabal4David Ramírez5Patricio Muñoz-Torres6Claudio Parra7Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Concepción, Edmundo Larenas 129, Concepción 4070371, ChileDepartamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Concepción, Edmundo Larenas 129, Concepción 4070371, ChileDepartamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Concepción, Edmundo Larenas 129, Concepción 4070371, ChileLaboratori de Química Orgánica, Facultat de Farmàcia, IBUB, Universitat de Barcelona, Av. Joan XXIII, s/n, 08028 Barcelona, SpainDepartamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, ChileDepartamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4030000, ChileLaboratorio de Patología Vegetal y Bioproductos, Facultad de Ciencias Agronómicas, Universidad de Tarapacá, Av. General Velásquez 1775, Arica 1000000, ChileDepartamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Concepción, Edmundo Larenas 129, Concepción 4070371, ChileThis work proposes the design of β-keto esters as antibacterial compounds. The design was based on the structure of the autoinducer of bacterial quorum sensing, <i>N</i>-(3-oxo-hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL). Eight β-keto ester analogues were synthesised with good yields and were spectroscopically characterised, showing that the compounds were only present in their β-keto ester tautomer form. We carried out a computational analysis of the reactivity and ADME (absorption, distribution, metabolism, and excretion) properties of the compounds as well as molecular docking and molecular dynamics calculations with the LasR and LuxS quorum-sensing (QS) proteins, which are involved in bacterial resistance to antibiotics. The results show that all the compounds exhibit reliable ADME properties and that only compound <b>7</b> can present electrophile toxicity. The theoretical reactivity study shows that compounds <b>6</b> and <b>8</b> present a differential local reactivity regarding the rest of the series. Compound <b>8</b> presents the most promising potential in terms of its ability to interact with the LasR and LuxS QS proteins efficiently according to its molecular docking and molecular dynamics calculations. An initial in vitro antimicrobial screening was performed against the human pathogenic bacteria <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i> as well as the phytopathogenic bacteria <i>Pseudomonas syringae</i> and <i>Agrobacterium tumefaciens</i>. Compounds <b>6</b> and <b>8</b> exhibit the most promising results in the in vitro antimicrobial screening against the panel of bacteria studied.https://www.mdpi.com/1424-8247/16/10/1339β-keto estersDFTdockingLasR and LuxSquorum sensing |
| spellingShingle | Maximiliano Martínez-Cifuentes Emmanuel Soto-Tapia Camila Linares-Pipón Ben Bradshaw Paulina Valenzuela-Hormazabal David Ramírez Patricio Muñoz-Torres Claudio Parra Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity Pharmaceuticals β-keto esters DFT docking LasR and LuxS quorum sensing |
| title | Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity |
| title_full | Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity |
| title_fullStr | Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity |
| title_full_unstemmed | Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity |
| title_short | Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity |
| title_sort | design of β keto esters with antibacterial activity synthesis in vitro evaluation and theoretical assessment of their reactivity and quorum sensing inhibition capacity |
| topic | β-keto esters DFT docking LasR and LuxS quorum sensing |
| url | https://www.mdpi.com/1424-8247/16/10/1339 |
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