Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2

[Display omitted] In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-(...

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Published in:Bioorganic & medicinal chemistry letters 2015-08, Vol.25 (15), p.2931-2936
Main Authors: Srinivas, V., Mohan, Chakrabhavi Dhananjaya, Baburajeev, C.P., Rangappa, Shobith, Jagadish, Swamy, Fuchs, Julian E., Sukhorukov, Alexey Yu, Chandra, Mason, Daniel J., Sharath Kumar, Kothanahally Shivaramu, Madegowda, Mahendra, Bender, Andreas, Basappa, Rangappa, Kanchugarakoppal Subbegowda
Format: Article
Language:English
Subjects:
Anti-Inflammatory Agents - chemical synthesis
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacology
COX2
Cyclooxygenase 2 - chemistry
Cyclooxygenase 2 - immunology
Cyclooxygenase 2 Inhibitors - chemical synthesis
Cyclooxygenase 2 Inhibitors - chemistry
Cyclooxygenase 2 Inhibitors - pharmacology
Humans
Inflammation - drug therapy
Inflammation - enzymology
Inflammation - immunology
Molecular Docking Simulation
Oxazines
Oxazines - chemical synthesis
Oxazines - chemistry
Oxazines - pharmacology
Proinflammatory disease
SCS-Bi2O3
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Summary:[Display omitted] In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7μM) over COX1 (40.4μM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.05.047