دورية أكاديمية
أعرض في EDS

Design, synthesis and molecular modeling of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives as anti-inflammatory agents by inhibition of COX-2/iNOS production and down-regulation of NF-κB/MAPKs in LPS-induced RAW264.7 macrophage cells.

التفاصيل البيبلوغرافية
العنوان: Design, synthesis and molecular modeling of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives as anti-inflammatory agents by inhibition of COX-2/iNOS production and down-regulation of NF-κB/MAPKs in LPS-induced RAW264.7 macrophage cells.
المؤلفون: Cai X; Department of Pharmacy, The Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China., Cai J; Department of Interventional Therapy, The Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China., Fang L; Department of Pharmacy, The Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China., Xu S; Department of Pharmacy, The Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China., Zhu H; Department of Pharmacy, The Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China., Wu S; Department of Pharmacy, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China., Chen Y; Department of Pharmacology, Shantou University Medical College, Shantou 515041, Guangdong, China. Electronic address: chenyicun2018@163.com., Fang S; Department of Pharmacy, The Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China. Electronic address: fangshuopo1993@163.com.
المصدر: European journal of medicinal chemistry [Eur J Med Chem] 2024 Jun 05; Vol. 272, pp. 116460. Date of Electronic Publication: 2024 Apr 27.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
مواضيع طبية MeSH: Lipopolysaccharides*/pharmacology , Lipopolysaccharides*/antagonists & inhibitors , Cyclooxygenase 2*/metabolism , NF-kappa B*/metabolism , NF-kappa B*/antagonists & inhibitors , Drug Design* , Nitric Oxide Synthase Type II*/metabolism , Nitric Oxide Synthase Type II*/antagonists & inhibitors , Pyrazoles*/pharmacology , Pyrazoles*/chemistry , Pyrazoles*/chemical synthesis , Macrophages*/drug effects , Macrophages*/metabolism , Down-Regulation*/drug effects, Animals ; Mice ; RAW 264.7 Cells ; Structure-Activity Relationship ; Molecular Structure ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal/chemistry ; Models, Molecular ; Dose-Response Relationship, Drug ; Cyclooxygenase 2 Inhibitors/pharmacology ; Cyclooxygenase 2 Inhibitors/chemical synthesis ; Cyclooxygenase 2 Inhibitors/chemistry ; Mitogen-Activated Protein Kinases/metabolism ; Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Thiazoles/pharmacology ; Thiazoles/chemistry ; Thiazoles/chemical synthesis ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/chemical synthesis ; Anti-Inflammatory Agents/chemistry ; Steroids/pharmacology ; Steroids/chemistry ; Steroids/chemical synthesis ; Molecular Docking Simulation
مستخلص: It has been reported that 4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazolinone and dihydropyrazole moiety into steroid skeleton to design and synthesize a novel series of D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives, and assessed their in vitro anti-inflammatory profiles against Lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. The anti-inflammatory activities assay demonstrated that compound 12e was considered as the most effective anti-inflammatory drug, which suppressed the expression of pro-inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), it also dose-dependently inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 macrophage cells. Furthermore, the results of the Western blot analysis showed a correlation between the inhibition of the Nuclear factor-kappa B (NF-κB) and Mitogen-activated protein kinases (MAPKs) signaling pathways and the suppressive effects of compound 12e on pro-inflammatory cytokines. Molecular docking studies of compound 12e into the COX-2 protein receptor (PDB ID: 5IKQ) active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of dexamethasone (DXM), explaining their remarkable COX-2 inhibitory activity. The findings revealed that these candidates could be identified as potent anti-inflammatory agents, compound 12e could be a promising drug for the treatment of inflammatory diseases.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
فهرسة مساهمة: Keywords: Anti-inflammatory; Cytotoxicity; Dihydropyrazole; Pregnenolone; RAW 264.7 cells; Steroid; Thiazolinone
المشرفين على المادة: 0 (Lipopolysaccharides)
EC 1.14.99.1 (Cyclooxygenase 2)
0 (NF-kappa B)
EC 1.14.13.39 (Nitric Oxide Synthase Type II)
0 (Pyrazoles)
0 (Anti-Inflammatory Agents, Non-Steroidal)
0 (Cyclooxygenase 2 Inhibitors)
EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
0 (Thiazoles)
0 (Anti-Inflammatory Agents)
0 (Steroids)
تواريخ الأحداث: Date Created: 20240505 Date Completed: 20240525 Latest Revision: 20240531
رمز التحديث: 20240531
DOI: 10.1016/j.ejmech.2024.116460
PMID: 38704943
قاعدة البيانات: MEDLINE
الوصف
تدمد:1768-3254
DOI:10.1016/j.ejmech.2024.116460