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Synthesis, evaluation and docking of novel pyrazolo pyrimidines as potent p38α MAP kinase inhibitors with improved anti-inflammatory, ulcerogenic and TNF-α inhibitory properties.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2019 Jun; Vol. 87, pp. 550-559. Date of Electronic Publication: 2019 Mar 15. - Publication Year :
- 2019
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Abstract
- A series of nine new N-substituted-4-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzamides (6a-i) derivatives was synthesized. All the compounds were screened in-vitro for BSA anti-denaturation property, antioxidant assay and p38α MAP kinase inhibition. The in vitro anti-inflammatory assay results revealed that the compounds (6f-i) showed better activity than the compounds 6a-e. Compound 6f bearing the 4-chlorophenyl group showed in vitro anti-inflammatory activity (82.35 ± 4.04) comparable to standard drug diclofenac sodium (84.13 ± 1.63) and better p38α MAP kinase inhibitory activity (IC <subscript>50</subscript> = 0.032 ± 1.63 µM) than the prototypic inhibitor SB203580 (IC <subscript>50</subscript> = 0.041 ± 1.75 µM). The selected active compounds (6f-i) were further studied in animal models for anti-inflammatory activity, ulcerogenic liability, lipid peroxidation and TNF-α inhibition potential. Compound 6f showed promising anti-inflammatory potential with a percentage inhibition of 83.73% when compared to the standard, diclofenac sodium (78.05%). Compound 6f was also found to show reduced ulcerogenic liability and lipid peroxidation in comparison to the standard. This compound also potently inhibited the lipopolysaccharide (LPS)-induced TNF-α production in mice model (ID <subscript>50</subscript> = 8.23 mg/kg) in comparison to SB 203580 (ID <subscript>50</subscript> = 26.38 mg/kg). The molecular docking of compounds 6a-i against p38α MAP kinase receptor was also performed to understand ligand receptor interaction. Amongst all synthesized molecules compound 6f displayed highest docking score of -9.824. It showed hydrogen bonding interactions with Asn115 and pi-cation interaction with Lys53.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Anti-Inflammatory Agents, Non-Steroidal chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal chemistry
Anti-Ulcer Agents chemical synthesis
Anti-Ulcer Agents chemistry
Dose-Response Relationship, Drug
Edema drug therapy
Edema metabolism
Female
Lipopolysaccharides antagonists & inhibitors
Lipopolysaccharides pharmacology
Male
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Pyrazoles chemical synthesis
Pyrazoles chemistry
Pyrimidines chemical synthesis
Pyrimidines chemistry
Rats
Rats, Wistar
Structure-Activity Relationship
Tumor Necrosis Factor-alpha antagonists & inhibitors
Tumor Necrosis Factor-alpha biosynthesis
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases metabolism
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Anti-Ulcer Agents pharmacology
Protein Kinase Inhibitors pharmacology
Pyrazoles pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 87
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30928877
- Full Text :
- https://doi.org/10.1016/j.bioorg.2019.03.037