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  • Rambabu et al reported A


    Rambabu et al. reported A series of novel N-substituted 2-(2-oxo-2H-chromen-4-yloxy)propanamide derivatives synthesized from readily available 4-hydroxy coumarin to the corresponding ethyl 2-(2-oxo-2H-chromen-4-yloxy)propanoate followed by hydrolysis and further reacted with different substituted amines. Amongst the compounds synthesized, The quinolone analogue showed balanced selectivity toward COX-2 over COX-1 inhibition and good docking scores when docked into the COX-2 protein [108]. Lu et al. have designed novel series of coumarin sulfonamides derivatives to improve biological activities of COX-2 inhibition Among them, compound 71 showed most powerful selective inhibitory and antiproliferative activity (IC50=0.09μM for COX-2, IC50=48.20μM for COX-1, IC50=0.36μM against HeLa cells), comparable to the control positive compound Celecoxib (0.31μM, 43.37μM, 7.79μM). Cancer cell apoptosis assay were performed and results indicated that compound 71 effectively fuels HeLa Oxytocin apoptosis in a dose and time-dependent manner. Further, 71 could significantly suppress cancer cell adhesion, migration and invasion which were essential process of cancer metastasis. Docking simulations results was further indicated that compound 71 could bind well to the COX-2 active site [109]. Conclusion: Although the study of natural and synthetic coumarins used as effective COX-inhibitors is still in its nascent stage, however over the past two decades there has been a foray into searching better drugs with minimal side effects. There is scope for more development as new research into study of COX and its related pathway emerges, as is observed by the report of biological evaluation and molecular docking studies reported in recent past. Here, we make a comprehensive record of the study of coumarins used as COX-inhibitors and also hope that it will help the workers to further their work as a point of reference.
    Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) comprise a heterogeneous group of medications, with analgesic, antipyretic and anti-inflammatory activity [1]. They act as inhibitors of prostaglandin synthesis through non-selective inhibition of COX enzymes but as a side effect they cause mucosal damage, ulceration and ulcer complication [2]. There are two cyclooxygenase enzymes, one predominating at sites of inflammation (COX-2) and one constitutively expressed in the gastrointestinal tract (COX-1), this led to the important therapeutic development of COX-2 inhibitors [3]. COX-2 inhibitors were found to exert anti-inflammatory and analgesic effects without the complications associated with existing non-selective inhibitors [4]. Several selective COX-2 inhibitors have been reported and many of them have reached market as parecoxib sodium, valdecoxib, rofecoxib, and celecoxib as shown in Fig. 1 [5]. Pyrazole ring plays an important role in medicinal chemistry, the use of pyrazole cores in biologically active molecules have stimulated the need for efficient ways to make these heterocyclic lead [6]. Several pyrazole compounds have been reported to be potential therapeutic agents for the treatment of inflammation and not associated with adverse effects including the marketed selective COX-2 inhibitor drug like celecoxib [7]. Moreover, several pyrazole derivatives were reported as anti-inflammatory [8], [9] in addition to pyrazolo [3,4-b] pyridine derivatives were synthesized and investigated for their anti-inflammatory agents and were recognized as promising multi-potent anti-inflammatory agents [10] Fig. 2. Encouraged with the above survey, the present study aimed to develop and synthesize novel compounds bearing pyrazole and pyrazolo [3,4-b] pyridine rings and test their biological activity as anti-inflammatory agents by inhibition of COX-2 enzyme. In addition, to test their safety on the gastrointestinal tract.
    Conclusion The synthesis of the new pyrazoles and pyrazolo[3,4-b] pyridines was achieved with the aim of finding new derivatives with anti-inflammatory activity by inhibition of COX-2 enzyme overcoming the side effects of non-selective anti-inflammatory drugs which was revealed by in-vivo determination of ulcerogenic effect. The most potent derivatives were found to be of the pyrazole ring derivatives, while the pyrazolo[3,4-b] pyridines were found to be of moderate activity in comparison to celecoxib and indomethacin as reference drugs.