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A competent synthesis and efficient anti-inflammatory responses of isatinimino acridinedione moiety via suppression of in vivo NF-κB, COX-2 and iNOS signaling.
- Source :
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Bioorganic chemistry [Bioorg Chem] 2019 Sep; Vol. 90, pp. 103047. Date of Electronic Publication: 2019 Jun 11. - Publication Year :
- 2019
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Abstract
- A potent Nonsterodial Anti-inflammatory Drug (NSAID) candidates has been conceived and built by an assembly of a hydrophilic, fluorescent and COX-2 inhibiting units in the same molecule. The isatinimino-acridinedione core (TM-7) was achieved in a simple three step synthetic procedure viz (i) a multicomponent reaction between dimedone, aldehyde and amine to furnish the nitroacridinedione (4), (ii) reduction step and (iii) schiff's-base condensation with isatin. The excellent anti-inflammatory pharmacological efficiency of the drug was established by in vivo biological experiments. Accordingly, it was found that the treatment with the synthesized isatinimino analogues (dosage: 30 mg/kg) inhibited protein expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB) as well as production of prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) levels induced by carrageenan. Further, a comparative molecular modeling analysis of TM-7 carried out with the crystal structure of aspirin acetylated human COX-2 suggested effectively binding and efficient accommodation inside the active site's gorge.<br /> (Copyright © 2019. Published by Elsevier Inc.)
- Subjects :
- Acridones chemical synthesis
Acridones metabolism
Animals
Anti-Inflammatory Agents, Non-Steroidal chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal metabolism
Catalytic Domain
Cyclooxygenase 2 chemistry
Cyclooxygenase 2 metabolism
Cyclooxygenase 2 Inhibitors chemical synthesis
Cyclooxygenase 2 Inhibitors metabolism
Cytokines metabolism
Edema drug therapy
Humans
Indomethacin therapeutic use
Isatin metabolism
Male
Molecular Docking Simulation
NF-kappa B metabolism
Nitric Oxide Synthase Type II metabolism
Protein Binding
Rats, Wistar
Signal Transduction drug effects
Acridones therapeutic use
Anti-Inflammatory Agents, Non-Steroidal therapeutic use
Cyclooxygenase 2 Inhibitors therapeutic use
Inflammation drug therapy
Isatin analogs & derivatives
Isatin therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 90
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31234130
- Full Text :
- https://doi.org/10.1016/j.bioorg.2019.103047