Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins
Inspired by the remarkable bioactivities exhibited by the natural products, piperine and piperlongumine, we synthesised eight natural product-inspired analogues to further investigate their structures. For the first time, we confirmed the structure of the key cyclised dihydropyrazolecarbothioamide p...
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MDPI AG
2020-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/12/2841 |
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| author | Gabriel Zazeri Ana Paula R. Povinelli Cécile S. Le Duff Bridget Tang Marinonio L. Cornelio Alan M. Jones |
| author_facet | Gabriel Zazeri Ana Paula R. Povinelli Cécile S. Le Duff Bridget Tang Marinonio L. Cornelio Alan M. Jones |
| author_sort | Gabriel Zazeri |
| collection | DOAJ |
| description | Inspired by the remarkable bioactivities exhibited by the natural products, piperine and piperlongumine, we synthesised eight natural product-inspired analogues to further investigate their structures. For the first time, we confirmed the structure of the key cyclised dihydropyrazolecarbothioamide piperine analogues including the use of two-dimensional (2D) <sup>15</sup>N-based spectroscopy nuclear magnetic resonance (NMR) spectroscopy. Prior investigations demonstrated promising results from these scaffolds for the inhibition of inflammatory response via downregulation of the IL-1β and NF-κB pathway. However, the molecular interaction of these molecules with their protein targets remains unknown. Ab initio calculations revealed the electronic density function map of the molecules, showing the effects of structural modification in the electronic structure. Finally, molecular interactions between the synthesized molecules and the proteins IL-1β and NF-κB were achieved. Docking results showed that all the analogues interact in the DNA binding site of NF-κB with higher affinity compared to the natural products and, with the exception of <b>9a</b> and <b>9b,</b> have higher affinity than the natural products for the binding site of IL-1β. Specificity for the molecular recognition of <b>3a</b>, <b>3c</b> and <b>9b</b> with IL-1β through cation–π interactions was determined. These results revealed <b>3a</b>, <b>3c</b>, <b>4a</b>, <b>4c</b> and <b>10</b> as the most promising molecules to be evaluated as IL-1β and NF-κB inhibitors. |
| first_indexed | 2024-03-10T19:01:22Z |
| format | Article |
| id | doaj.art-8f1194ec44164803834fada3d0f18fbb |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T19:01:22Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-8f1194ec44164803834fada3d0f18fbb2023-11-20T04:24:26ZengMDPI AGMolecules1420-30492020-06-012512284110.3390/molecules25122841Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB ProteinsGabriel Zazeri0Ana Paula R. Povinelli1Cécile S. Le Duff2Bridget Tang3Marinonio L. Cornelio4Alan M. Jones5Departamento de Física–IBILCE, Rua Cristovão Colombo, 2265 CEP 15054-000 São José do Rio Preto–São Paulo, BrazilDepartamento de Física–IBILCE, Rua Cristovão Colombo, 2265 CEP 15054-000 São José do Rio Preto–São Paulo, BrazilSchool of Chemistry, University of Birmingham, Edgbaston B15 2TT, UKSchool of Chemistry, University of Birmingham, Edgbaston B15 2TT, UKDepartamento de Física–IBILCE, Rua Cristovão Colombo, 2265 CEP 15054-000 São José do Rio Preto–São Paulo, BrazilSchool of Pharmacy, University of Birmingham, Edgbaston B15 2TT, UKInspired by the remarkable bioactivities exhibited by the natural products, piperine and piperlongumine, we synthesised eight natural product-inspired analogues to further investigate their structures. For the first time, we confirmed the structure of the key cyclised dihydropyrazolecarbothioamide piperine analogues including the use of two-dimensional (2D) <sup>15</sup>N-based spectroscopy nuclear magnetic resonance (NMR) spectroscopy. Prior investigations demonstrated promising results from these scaffolds for the inhibition of inflammatory response via downregulation of the IL-1β and NF-κB pathway. However, the molecular interaction of these molecules with their protein targets remains unknown. Ab initio calculations revealed the electronic density function map of the molecules, showing the effects of structural modification in the electronic structure. Finally, molecular interactions between the synthesized molecules and the proteins IL-1β and NF-κB were achieved. Docking results showed that all the analogues interact in the DNA binding site of NF-κB with higher affinity compared to the natural products and, with the exception of <b>9a</b> and <b>9b,</b> have higher affinity than the natural products for the binding site of IL-1β. Specificity for the molecular recognition of <b>3a</b>, <b>3c</b> and <b>9b</b> with IL-1β through cation–π interactions was determined. These results revealed <b>3a</b>, <b>3c</b>, <b>4a</b>, <b>4c</b> and <b>10</b> as the most promising molecules to be evaluated as IL-1β and NF-κB inhibitors.https://www.mdpi.com/1420-3049/25/12/2841molecular dockingpiperinepiperlongumine |
| spellingShingle | Gabriel Zazeri Ana Paula R. Povinelli Cécile S. Le Duff Bridget Tang Marinonio L. Cornelio Alan M. Jones Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins Molecules molecular docking piperine piperlongumine |
| title | Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins |
| title_full | Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins |
| title_fullStr | Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins |
| title_full_unstemmed | Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins |
| title_short | Synthesis and Spectroscopic Analysis of Piperine- and Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins |
| title_sort | synthesis and spectroscopic analysis of piperine and piperlongumine inspired natural product scaffolds and their molecular docking with il 1β and nf κb proteins |
| topic | molecular docking piperine piperlongumine |
| url | https://www.mdpi.com/1420-3049/25/12/2841 |
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