Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme
A new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to...
| 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/10.1080/14756366.2022.2086868 |
| _version_ | 1818553061279268864 |
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| author | Nada H. El-Dershaby Soad A. El-Hawash Shaymaa E. Kassab Hoda G. Dabees Ahmed E. Abdel Moneim Ibrahim A. Abdel Wahab Mohammad M. Abd-Alhaseeb Mostafa M. M. El-Miligy |
| author_facet | Nada H. El-Dershaby Soad A. El-Hawash Shaymaa E. Kassab Hoda G. Dabees Ahmed E. Abdel Moneim Ibrahim A. Abdel Wahab Mohammad M. Abd-Alhaseeb Mostafa M. M. El-Miligy |
| author_sort | Nada H. El-Dershaby |
| collection | DOAJ |
| description | A new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to enhance antibacterial activity for treatment of septicaemia. Compounds 5 b, 5j, 5n and 5o demonstrated potent in vitro COX-2 inhibitory activity comparable to celecoxib. 5j and 5o exhibited ED50 lower than celecoxib in carrageenan-induced paw edoema test with % PGE2 inhibition higher than celecoxib. Furthermore, 5 b, 5j and 5n showed gastric safety profile like celecoxib. Moreover, in vivo antibacterial screening revealed that, 5j showed activity against S.aureus and E.coli higher than sulfasalazine. While, 5o revealed activity against E.coli higher than sulfasalazine and against S.aureus comparable to sulfasalazine. Compound 5j achieved the target goal as potent inhibitor of COX-2/PGE2 axis and in vivo broad-spectrum antibacterial activity against induced septicaemia in mice. |
| first_indexed | 2024-12-12T09:21:07Z |
| format | Article |
| id | doaj.art-09f1914e14b8496fbcf7c84b641248cb |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-12T09:21:07Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-09f1914e14b8496fbcf7c84b641248cb2022-12-22T00:29:12ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013711737175110.1080/14756366.2022.2086868Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzymeNada H. El-Dershaby0Soad A. El-Hawash1Shaymaa E. Kassab2Hoda G. Dabees3Ahmed E. Abdel Moneim4Ibrahim A. Abdel Wahab5Mohammad M. Abd-Alhaseeb6Mostafa M. M. El-Miligy7Pharmaceutical Chemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, EgyptPharmaceutical Chemistry Department, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptPharmaceutical Chemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, EgyptPharmaceutical Chemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, EgyptDepartment of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, EgyptMicrobiology and Immunology Department, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhur University, Damanhour, EgyptPharmaceutical Chemistry Department, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptA new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to enhance antibacterial activity for treatment of septicaemia. Compounds 5 b, 5j, 5n and 5o demonstrated potent in vitro COX-2 inhibitory activity comparable to celecoxib. 5j and 5o exhibited ED50 lower than celecoxib in carrageenan-induced paw edoema test with % PGE2 inhibition higher than celecoxib. Furthermore, 5 b, 5j and 5n showed gastric safety profile like celecoxib. Moreover, in vivo antibacterial screening revealed that, 5j showed activity against S.aureus and E.coli higher than sulfasalazine. While, 5o revealed activity against E.coli higher than sulfasalazine and against S.aureus comparable to sulfasalazine. Compound 5j achieved the target goal as potent inhibitor of COX-2/PGE2 axis and in vivo broad-spectrum antibacterial activity against induced septicaemia in mice.https://www.tandfonline.com/doi/10.1080/14756366.2022.2086868SulphonamidessalicylamidesCOX-2 inhibitorsPGE2septicaemia |
| spellingShingle | Nada H. El-Dershaby Soad A. El-Hawash Shaymaa E. Kassab Hoda G. Dabees Ahmed E. Abdel Moneim Ibrahim A. Abdel Wahab Mohammad M. Abd-Alhaseeb Mostafa M. M. El-Miligy Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme Journal of Enzyme Inhibition and Medicinal Chemistry Sulphonamides salicylamides COX-2 inhibitors PGE2 septicaemia |
| title | Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme |
| title_full | Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme |
| title_fullStr | Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme |
| title_full_unstemmed | Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme |
| title_short | Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme |
| title_sort | rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of cox 2 pge2 axis and dhps enzyme |
| topic | Sulphonamides salicylamides COX-2 inhibitors PGE2 septicaemia |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2086868 |
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