Amide derivatives of [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids as potential analgesic and anti-inflammatory compounds.
In this study, we have explored the prevention of gastric side effects such as gastric lesions and bleeding while maintaining the high analgesic and anti-inflammatory activities by the derivatization of the carboxylate moiety into amides in [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids. We have tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Compounds 3a, 3d, 3e, 3j and 3k potent analgesic and anti-inflammatory activities without gastric lesions in the tested animals. Therefore, conversion of the carboxylate moiety into certain amide derivatives generated potent analgesic and anti-inflammatory compounds while eliminating the gastrointestinal side effects. Cyclooxygenase (COX)-selectivity of the active compounds was also investigated by using in vitro human whole blood assay. Compounds 3a, 3e, 3h and 3k selective inhibition of COX-2 to some extent although the inhibitory activity was not very potent.
Banoglu
Erden
E
Department of Pharmaceutical Chemistry, Division of Pharmaceutical Sciences, Faculty of Pharmacy, Gazi University, 06330 Etiler-Ankara, Turkey. banoglu@gazi.edu.tr
Okçelik
Berna
B
Kupeli
Esra
E
Unlü
Serdar
S
Yeşilada
Erdem
E
Amat
Mercé
M
Caturla
Joan F
JF
Sahin
M Fethi
MF
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000097:blood; D007928:Lethal Dose 50; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010147:Pain Measurement; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship
C477538:(5-chloro-6-(2-chlorobenzoyl)-2-benzoxazolinone-3-yl)acetic acid; C477539:(5-chloro-6-(2-fluorobenzoyl)-2-benzoxazolinone-3-yl)acetic acid; D000085:Acetates; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D010080:Oxazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse