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  • Haggar et al reported the

    2019-07-11

    Haggar et al. reported the synthesis of two new series of 8-(2-imino/oxo/thioxo pyrimidin-4-yl)-4-methyl-6-nitro-2-oxo-2H-chromen-7-yl benzoates 56 (X=O, S, NH) and 8-(pyrazol-3-yl)-4-methyl-6-nitro-2-oxo-2H-chromen-7-yl benzoates 57 [Y=C(O)CH3, 2,4-(NO2)2C6H3]. The 8-acetyl-4-methyl-6-nitro-2-oxo-2H-chromen-7-yl benzoate exhibited the most potent activity with 24.12% inhibition 2h post Purvalanol B injection and 16.38% inhibition 3h post carrageenan injection. In silico comparative COX-1 and COX-2 docking study was performed in order to explain the possible interactions and the docking scores of all the compounds with cyclooxygenases (Cox1 and Cox2) enzymes using autodock 4.2 program. The results revealed more selective COX-2 binding affinities of all the compds. over COX-1, whereas, compound (Ar=4-OHC6H4) exhibited non-selective COX-1 and COX-2 fitting [94]. The authors further reported synthesis of a series of 6-(substituted benzylamino)-7-hydroxy-4-methyl-2H-chromen-2-ones 58. Compounds (R=NO2, N(CH3)2,NH-CO-CH3, 3-NO2) showed significant (p<0.001) reduction of rat paw edema volume after 1h from the administration of the carrageenan compared to the reference drug, indomethacin. While, compounds (R=NH-CO-CH3, 3-OH 4-OCH3) showed the highest anti-inflammatory activity, surpassing indomethacin after 3h with 44.05% and 38.10% inhibition, respectively. Further a molecular docking study was performed against the COX enzyme using the MOE 10.2010 software [95]. Saha et al. reported in silico binding affinity prediction of benzylpyrazolyl coumarin 59 scaffolds to cyclooxygenase-II (COX-II) enzyme and a green synthetic route to access these scaffolds using a neutral ionic liquid, [pmIm]Br as the reusable catalyst and reaction media under metal-free conditions. The integrated scaffolds, benzylpyrazolyl coumarins exhibited stronger binding affinity to COX-II inhibitor than their individual moieties, 3-benzyl coumarins and pyrazolones. Further, 4-((4-hydroxy-2-oxo-2H-chromen-3-yl)(4-nitrophenyl)methyl)- 5-methyl-2-phenyl-1H-pyrazol-3(2H)-one was even better binding affinity than the marketed anti-inflammatory drug, celecoxib [96]. Timonen et al. reported a synthesis of a series of 7-(2-oxoalkoxy)coumarins 60 by conjugating substituted 7-hydroxycoumarins with chloroketones. The anti-inflammatory properties of 7-(2-oxoalkoxy)coumarins 60 were studied in LPS-induced inflammatory response in J774 macrophages. 17 compounds inhibited NO and IL-6 production over 50% at 100μM concns. IC50 values of the best inhibitors were 21μM/24μM (NO/IL-6) and 30μM/10μM (NO/IL-6). The main result was that substitution with 7-(2-oxoalkoxy) group improved the anti-inflammatory properties of most of the investigated 7-hydroxycoumarins [97]. Further 7-hydroxycoumarins have been synthesized by Pechmann cyclisation using differently substituted resorcinols employing perchloric acid as the condensing agent were studied by the same group. Fifteen of the tested 7-hydroxycoumarins also inhibited IL-6 production but none of them had any major inhibitory effect on COX-2 expression [98]. Stefani et al. reported synthesis of a series of 3-(triazolyl)coumarins tested them for their anti-inflammatory properties, the compounds have profound effect on nitric oxide synthase but not on COX-2 enzymes [99]. Sandhya et al. reported various aromatic and heterocyclic amines analogues of coumarins 62 and tested for its analgesic, anti-inflammatory, antimicrobial activities. Three compounds, such as N-(benzothiazolyl)glycine 4-methyl-2-oxo-2H-1-benzopyran-7-yl esters, showed significant anti-inflammatory, analgesic and antimicrobial activities. Further docking studies on COX-2 predict the binding affinity and orientation at the active site of the receptor. It was found that the three active compounds interacted with Arg 44 amino acid, which may be involved in COX-2 inhibition. The authors ascertain that, this could be due to the formation of more effective hydrogen bond with the receptor (Fig. 9a, Fig. 9b) [100].