Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activity
A structure-guided modelling approach using COX-2 as a template was used to investigate the effect of replacing the chloro atom located at the chlorophenyl ring of amide-linked bipyrazole moieties, aiming at attaining better anti-inflammatory effect with a good safety profile. Bromo, fluoro, nitro,...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2109025 |
| _version_ | 1798040238645313536 |
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| author | Souraya A. Domiati Khaled H. Abd El Galil Mohammed A. S. Abourehab Tamer M. Ibrahim Hanan M. Ragab |
| author_facet | Souraya A. Domiati Khaled H. Abd El Galil Mohammed A. S. Abourehab Tamer M. Ibrahim Hanan M. Ragab |
| author_sort | Souraya A. Domiati |
| collection | DOAJ |
| description | A structure-guided modelling approach using COX-2 as a template was used to investigate the effect of replacing the chloro atom located at the chlorophenyl ring of amide-linked bipyrazole moieties, aiming at attaining better anti-inflammatory effect with a good safety profile. Bromo, fluoro, nitro, and methyl groups were revealed to be ideal candidates. Consequently, new bipyrazole derivatives were synthesised. The in vitro inhibitory COX-1/COX-2 activity of the synthesised compounds exhibited promising selectivity. The fluoro and methyl derivatives were the most active candidates. The in vivo formalin-induced paw edoema model confirmed the anti-inflammatory activity of the synthesised compounds. All the tested derivatives had a good ulcerogenic safety profile except for the methyl substituted compound. In silico molecular dynamics simulations of the fluoro and methyl poses complexed with COX-2 for 50 ns indicated stable binding to COX-2. Generally, our approach delivers a fruitful matrix for the development of further amide-linked bipyrazole anti-inflammatory candidates. |
| first_indexed | 2024-04-11T22:04:42Z |
| format | Article |
| id | doaj.art-0059908b01c2425ca1e9b5923f422ca4 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-11T22:04:42Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-0059908b01c2425ca1e9b5923f422ca42022-12-22T04:00:44ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013712179219010.1080/14756366.2022.2109025Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activitySouraya A. Domiati0Khaled H. Abd El Galil1Mohammed A. S. Abourehab2Tamer M. Ibrahim3Hanan M. Ragab4Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, LebanonDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, Beirut Arab University, Beirut, LebanonDepartment of Pharmaceutics College of Pharmacy, Umm Al-Qura University, Makkah, Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptA structure-guided modelling approach using COX-2 as a template was used to investigate the effect of replacing the chloro atom located at the chlorophenyl ring of amide-linked bipyrazole moieties, aiming at attaining better anti-inflammatory effect with a good safety profile. Bromo, fluoro, nitro, and methyl groups were revealed to be ideal candidates. Consequently, new bipyrazole derivatives were synthesised. The in vitro inhibitory COX-1/COX-2 activity of the synthesised compounds exhibited promising selectivity. The fluoro and methyl derivatives were the most active candidates. The in vivo formalin-induced paw edoema model confirmed the anti-inflammatory activity of the synthesised compounds. All the tested derivatives had a good ulcerogenic safety profile except for the methyl substituted compound. In silico molecular dynamics simulations of the fluoro and methyl poses complexed with COX-2 for 50 ns indicated stable binding to COX-2. Generally, our approach delivers a fruitful matrix for the development of further amide-linked bipyrazole anti-inflammatory candidates.https://www.tandfonline.com/doi/10.1080/14756366.2022.2109025Inflammationstructure-guidedamide-linked bipyrazolesCOX-2 selective inhibitorsdocking |
| spellingShingle | Souraya A. Domiati Khaled H. Abd El Galil Mohammed A. S. Abourehab Tamer M. Ibrahim Hanan M. Ragab Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activity Journal of Enzyme Inhibition and Medicinal Chemistry Inflammation structure-guided amide-linked bipyrazoles COX-2 selective inhibitors docking |
| title | Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activity |
| title_full | Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activity |
| title_fullStr | Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activity |
| title_full_unstemmed | Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activity |
| title_short | Structure-guided approach on the role of substitution on amide-linked bipyrazoles and its effect on their anti-inflammatory activity |
| title_sort | structure guided approach on the role of substitution on amide linked bipyrazoles and its effect on their anti inflammatory activity |
| topic | Inflammation structure-guided amide-linked bipyrazoles COX-2 selective inhibitors docking |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2109025 |
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