Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation
A hybrid pharmacophore model, based on structural motifs previously identified by our team, was employed to generate ligands that simultaneously target COX-2, 15-LOX, and PPARγ in the context of metabolic dysfunction-associated fatty liver disease (MAFLD). Notable COX-2 inhibitory activities (IC50 =...
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| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , , , , , , , , , , |
| التنسيق: | article |
| منشور في: |
2025
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| الموضوعات: | |
| الوصول للمادة أونلاين: | http://dx.doi.org/10.1016/j.ejmech.2025.117415 https://www.sciencedirect.com/science/article/pii/S0223523425001801 http://hdl.handle.net/10576/64011 |
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| _version_ | 1857415084446318592 |
|---|---|
| author | Mai S., El-Shoukrofy |
| author2 | Ismail, Azza Elhamammy, Reem H. Abdelhady, Sherien A. Nassra, Rasha Makkar, Monica S. Agami, Mahmoud A. Wahid, Ahmed Nematalla, Hisham A. Sai, Minh Merk, Daniel El-Yazbi, Ahmed F. Belal, Ahmed S.F. Eid, Ali H. Elzahhar, Perihan A. |
| author2_role | author author author author author author author author author author author author author author |
| author_facet | Mai S., El-Shoukrofy Ismail, Azza Elhamammy, Reem H. Abdelhady, Sherien A. Nassra, Rasha Makkar, Monica S. Agami, Mahmoud A. Wahid, Ahmed Nematalla, Hisham A. Sai, Minh Merk, Daniel El-Yazbi, Ahmed F. Belal, Ahmed S.F. Eid, Ali H. Elzahhar, Perihan A. |
| author_role | author |
| dc.creator.none.fl_str_mv | Mai S., El-Shoukrofy Ismail, Azza Elhamammy, Reem H. Abdelhady, Sherien A. Nassra, Rasha Makkar, Monica S. Agami, Mahmoud A. Wahid, Ahmed Nematalla, Hisham A. Sai, Minh Merk, Daniel El-Yazbi, Ahmed F. Belal, Ahmed S.F. Eid, Ali H. Elzahhar, Perihan A. |
| dc.date.none.fl_str_mv | 2025-03-27T08:19:34Z 2025-05-05 |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://dx.doi.org/10.1016/j.ejmech.2025.117415 02235234 https://www.sciencedirect.com/science/article/pii/S0223523425001801 http://hdl.handle.net/10576/64011 289 1768-3254 |
| dc.language.none.fl_str_mv | en |
| dc.rights.none.fl_str_mv | http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Thiazolones PPARγ COX-2 15-LOX Multi-targeting Liver inflammation Metabolic diseases |
| dc.title.none.fl_str_mv | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | A hybrid pharmacophore model, based on structural motifs previously identified by our team, was employed to generate ligands that simultaneously target COX-2, 15-LOX, and PPARγ in the context of metabolic dysfunction-associated fatty liver disease (MAFLD). Notable COX-2 inhibitory activities (IC50 = 0.065–0.24 μM) were observed relative to celecoxib (IC50 = 0.049 μM). The two most effective 15-LOX inhibitors, 2a and 2b, exhibited 69 % and 57 % of quercetin's action, respectively. Utilizing the rat hemi-diaphragm model to assess in vitro glucose uptake capacity, compounds 2a and 2b demonstrated significant glucose uptake potential in the absence of insulin, surpassing that of pioglitazone. Compound 2a activated PPARγ with an EC50 value of 3.4 μM in a Gal4-hybrid reporter gene assay, indicating partial agonistic action. Interesting binding interactions with targets of interest were identified by molecular docking studies. As well, the expression levels of 20-HETE, Il-1β and TNF-α were decreased in LPS-challenged RAW264.7 macrophages upon treatment with compound 2a. The pharmacokinetic analysis of 2a and assessment of its in vivo efficacy in addressing hepatic impairment in rat models of diabetes and pre-diabetes were carried out. Together, these findings may offer preliminary insights into the potential of these compounds for further refinement in the existing therapeutic arsenals for metabolic diseases. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | qu_feb79d3e4a8c5aa07c9526f94dbb71e1 |
| identifier_str_mv | 02235234 289 1768-3254 |
| language_invalid_str_mv | en |
| network_acronym_str | qu |
| network_name_str | Qatar University repository |
| oai_identifier_str | oai:qspace.qu.edu.qa:10576/64011 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | http://creativecommons.org/licenses/by/4.0/ |
| spelling | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammationMai S., El-ShoukrofyIsmail, AzzaElhamammy, Reem H.Abdelhady, Sherien A.Nassra, RashaMakkar, Monica S.Agami, Mahmoud A.Wahid, AhmedNematalla, Hisham A.Sai, MinhMerk, DanielEl-Yazbi, Ahmed F.Belal, Ahmed S.F.Eid, Ali H.Elzahhar, Perihan A.ThiazolonesPPARγCOX-215-LOXMulti-targetingLiver inflammationMetabolic diseasesA hybrid pharmacophore model, based on structural motifs previously identified by our team, was employed to generate ligands that simultaneously target COX-2, 15-LOX, and PPARγ in the context of metabolic dysfunction-associated fatty liver disease (MAFLD). Notable COX-2 inhibitory activities (IC50 = 0.065–0.24 μM) were observed relative to celecoxib (IC50 = 0.049 μM). The two most effective 15-LOX inhibitors, 2a and 2b, exhibited 69 % and 57 % of quercetin's action, respectively. Utilizing the rat hemi-diaphragm model to assess in vitro glucose uptake capacity, compounds 2a and 2b demonstrated significant glucose uptake potential in the absence of insulin, surpassing that of pioglitazone. Compound 2a activated PPARγ with an EC50 value of 3.4 μM in a Gal4-hybrid reporter gene assay, indicating partial agonistic action. Interesting binding interactions with targets of interest were identified by molecular docking studies. As well, the expression levels of 20-HETE, Il-1β and TNF-α were decreased in LPS-challenged RAW264.7 macrophages upon treatment with compound 2a. The pharmacokinetic analysis of 2a and assessment of its in vivo efficacy in addressing hepatic impairment in rat models of diabetes and pre-diabetes were carried out. Together, these findings may offer preliminary insights into the potential of these compounds for further refinement in the existing therapeutic arsenals for metabolic diseases.A significant portion of this work was supported by the Alexandria University Research Support Initiative “Alex-RSI” CALL -1, Egypt. Open access funding provided by Qatar National Library.2025-03-27T08:19:34Z2025-05-05Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://dx.doi.org/10.1016/j.ejmech.2025.11741502235234https://www.sciencedirect.com/science/article/pii/S0223523425001801http://hdl.handle.net/10576/640112891768-3254enhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:qspace.qu.edu.qa:10576/640112025-03-27T19:07:21Z |
| spellingShingle | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation Mai S., El-Shoukrofy Thiazolones PPARγ COX-2 15-LOX Multi-targeting Liver inflammation Metabolic diseases |
| status_str | publishedVersion |
| title | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation |
| title_full | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation |
| title_fullStr | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation |
| title_full_unstemmed | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation |
| title_short | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation |
| title_sort | Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation |
| topic | Thiazolones PPARγ COX-2 15-LOX Multi-targeting Liver inflammation Metabolic diseases |
| url | http://dx.doi.org/10.1016/j.ejmech.2025.117415 https://www.sciencedirect.com/science/article/pii/S0223523425001801 http://hdl.handle.net/10576/64011 |