title: New Coumarin Derivatives as Potent Selective COX-2 Inhibitors: Synthesis, Anti-Inflammatory, QSAR, and Molecular Modeling Studies.
abstract: 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 IC50 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.
authors.affiliation: Chemistry of Natural and Microbial Products Department, National Research Center, Dokki, Cairo, Egypt.
authors.forename: Dina H
authors.initials: DH
authors.lastname: Dawood
authors.affiliation: Chemistry of Natural Compounds Department, National Research Center, Dokki, Cairo, Egypt.
authors.forename: Rasha Z
authors.initials: RZ
authors.lastname: Batran
authors.affiliation: Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.|Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah, Saudi Arabia.
authors.forename: Thoraya A
authors.initials: TA
authors.lastname: Farghaly
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, Egypt.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Khedr
authors.affiliation: Research Unit, Saco Pharm. Co., 6th October City, Egypt.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Abdulla
mesh_terms: D000818:Animals; D002351:Carrageenan; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced
chemical_list: D003374:Coumarins; D052246:Cyclooxygenase 2 Inhibitors; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D007213:Indomethacin
keywords: Anti-inflammatory; COX-2 inhibitors; Molecular docking; QSAR; Thiazolylcoumarin