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New Coumarin Derivatives as Potent Selective COX‐2 Inhibitors: Synthesis, Anti‐Inflammatory, QSAR, and Molecular Modeling Studies
Author(s) -
Dawood Dina H.,
Batran Rasha Z.,
Farghaly Thoraya A.,
Khedr Mohammed A.,
Abdulla Mohamed M.
Publication year - 2015
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500274
Subject(s) - chemistry , in vivo , coumarin , thiazoline , cyclooxygenase , in vitro , celecoxib , anti inflammatory , quantitative structure–activity relationship , docking (animal) , carrageenan , pharmacology , stereochemistry , selectivity , structure–activity relationship , biochemistry , enzyme , organic chemistry , biology , medicine , microbiology and biotechnology , nursing , catalysis
Two new series of coumarin derivatives incorporating thiazoline and thiazolidinone moieties were designed, synthesized, and investigated in vivo for their anti‐inflammatory activities using the carrageenan‐induced rat paw edema model and in vitro for their inhibitory activities against the human cyclooxygenase (COX)‐1 and COX‐2 isoforms. Most of the synthesized compounds demonstrated exceptionally high in vivo anti‐inflammatory activity and displayed superior GI safety profiles (0–7% ulceration) as compared to indomethacin. All the bioactive compounds showed in vitro high affinity and selectivity toward the COX‐2 isoenzyme, compared to the reference celecoxib with IC 50 values ranging from 0.31 to 0.78 μM. The ethyl thiosemicarbazone 2b , thiazoline derivatives 3a , 3b , 5b , 6a , and 7f , and the thiazolidinone compounds 8b and 9a showed the highest in vivo and in vitro anti‐inflammatory activities with remarkable COX‐2 selectivity. Quantitative structure–activity relationship study (QSAR) was done and resulted in a highly predictive power R 2 (0.908). A molecular docking study revealed a relationship between the docking affinity and the biological results.