New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets
Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and sy...
| Published in: | Molecules |
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| Main Authors: | , , , , , , , |
| Format: | Article |
| Language: | English |
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MDPI AG
2020-02-01
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| Online Access: | https://www.mdpi.com/1420-3049/25/4/899 |
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| author | Chiara Brullo Matteo Massa Federica Rapetti Silvana Alfei Maria B. Bertolotto Fabrizio Montecucco Maria Grazia Signorello Olga Bruno |
| author_facet | Chiara Brullo Matteo Massa Federica Rapetti Silvana Alfei Maria B. Bertolotto Fabrizio Montecucco Maria Grazia Signorello Olga Bruno |
| author_sort | Chiara Brullo |
| collection | DOAJ |
| container_title | Molecules |
| description | Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and synthesized a series of hybrid compounds by linking pyrazole and imidazo-pyrazole scaffolds to differently decorated catechol moieties through an acylhydrazone chain. Some compounds showed antioxidant activity, inhibiting reactive oxygen species (ROS) elevation in neutrophils, and a good inhibition of phosphodiesterases type 4D and, particularly, type 4B, the isoform most involved in inflammation. In addition, most compounds inhibited ROS production also in platelets, confirming their ability to exert an antiinflammatory response by two independent mechanism. Structure−activity relationship (SAR) analyses evidenced that both heterocyclic scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds, characterized by a strong antioxidant activity in different biological targets. |
| format | Article |
| id | doaj-art-e7c6db4d1b4f4eabb71ca1df7b4c98b6 |
| institution | Directory of Open Access Journals |
| issn | 1420-3049 |
| language | English |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| spelling | doaj-art-e7c6db4d1b4f4eabb71ca1df7b4c98b62025-08-19T19:41:08ZengMDPI AGMolecules1420-30492020-02-0125489910.3390/molecules25040899molecules25040899New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological TargetsChiara Brullo0Matteo Massa1Federica Rapetti2Silvana Alfei3Maria B. Bertolotto4Fabrizio Montecucco5Maria Grazia Signorello6Olga Bruno7Department of Pharmacy, Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV 3, I-16132 Genova, ItalyDepartment of Pharmacy, Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV 3, I-16132 Genova, ItalyDepartment of Pharmacy, Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV 3, I-16132 Genova, ItalyDepartment of Pharmacy, Section of Chemistry and Pharmaceutical and Food Technologies, University of Genoa, Viale Cembrano 4, I-16148 Genova, ItalyFirst Clinic of Internal Medicine, Department of Internal Medicine, and IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Largo R. Benzi 10, I-16132 Genoa, ItalyFirst Clinic of Internal Medicine, Department of Internal Medicine, and IRCCS Ospedale Policlinico San Martino Genova-Italian Cardiovascular Network, Largo R. Benzi 10, I-16132 Genoa, ItalyDepartment of Pharmacy, Biochemistry Lab., University of Genoa, Viale Benedetto XV 3, I-16132 Genova, ItalyDepartment of Pharmacy, Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV 3, I-16132 Genova, ItalySeveral anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and synthesized a series of hybrid compounds by linking pyrazole and imidazo-pyrazole scaffolds to differently decorated catechol moieties through an acylhydrazone chain. Some compounds showed antioxidant activity, inhibiting reactive oxygen species (ROS) elevation in neutrophils, and a good inhibition of phosphodiesterases type 4D and, particularly, type 4B, the isoform most involved in inflammation. In addition, most compounds inhibited ROS production also in platelets, confirming their ability to exert an antiinflammatory response by two independent mechanism. Structure−activity relationship (SAR) analyses evidenced that both heterocyclic scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds, characterized by a strong antioxidant activity in different biological targets.https://www.mdpi.com/1420-3049/25/4/899pyrazole-4-carbohydrazidesimidazopyrazole-7-carbohydrazidesreactive oxygen production inhibitionplateletsneutrophilsphosphodiesterase inhibitors |
| spellingShingle | Chiara Brullo Matteo Massa Federica Rapetti Silvana Alfei Maria B. Bertolotto Fabrizio Montecucco Maria Grazia Signorello Olga Bruno New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets pyrazole-4-carbohydrazides imidazopyrazole-7-carbohydrazides reactive oxygen production inhibition platelets neutrophils phosphodiesterase inhibitors |
| title | New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets |
| title_full | New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets |
| title_fullStr | New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets |
| title_full_unstemmed | New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets |
| title_short | New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets |
| title_sort | new hybrid pyrazole and imidazopyrazole antinflammatory agents able to reduce ros production in different biological targets |
| topic | pyrazole-4-carbohydrazides imidazopyrazole-7-carbohydrazides reactive oxygen production inhibition platelets neutrophils phosphodiesterase inhibitors |
| url | https://www.mdpi.com/1420-3049/25/4/899 |
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