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  • In our ongoing investigation of the structure activity relat

    2019-07-18

    In our ongoing investigation of the structure activity relationship of benzenesulfonamide anti-inflammatory activity, we designed and synthesized a novel set of benzenesulfonamide derivatives starting from commercially available sodium saccharin. The pivotal features of our approach aimed to do some structural variations on celecoxib skeleton to explore the shifting effect of pyrazole ring located at para-position of the benzensulfonamide moiety as seen in celecoxib to ortho-position, as in our targets 19 and 20 on not only COX-2 selectivity but also to explore the new possible receptor interactions. Moreover, the effect of replacement of the ortho pyrazole ring with its bioisosteres, such as, 1,3,4-oxadiazole i.e. 12 and 13 and triazole, i.e. 15 and 16 was also considered. Another focus of our investigation was rigidification of the benzenesulfonamide moiety, by ring closure towards the dipyrazole derivative 23, to adopt a preferred binding conformation to COX-2 and reduce the entropic loss, which might enhance the potency and efficacy as well.
    Discussion
    Conclusion Two new series, namely, benzenesulfonamide and 1,2-benzisothiazol-3(2H)-one-1,1-dioxide derivatives were synthesized using sodium saccharin as cheapest starting synthon. In vitro COX-2 inhibitory activity study revealed that benzenesulfonamides bearing pyrazole ring 19 and 20 showed high activity against COX-2 with IC50: 0.09 (SI = 135.9) and 0.06 μM (SI = 154), respectively, meanwhile the cyclized benzenesulfonamide bearing dipyrazole rings 23 (IC50: 0.05 μM, SI = 236) was the most potent, with a comparable activity to celecoxib (IC50: 0.05 μM, SI = 296.0). Moreover, anti-inflammatory activity and ulcer liability evaluation demonstrated compounds 19, 20 and 23 possessed significant anti-inflammatory activity with low gastric ulceration which was comparable to celecoxib. Docking study showed that compounds 19 and 20 can occupy the binding site of the enzyme with binding interaction Torcetrapib where ranging from −10.6 kcal/mol to −11.3 kcal/mol compared to celecoxib −13.8 kcal/mol. Compound 23 binds to an exposed pocket of COX-2 with binding energy −6.3 kcal/mol. The obtained results from the in silico pharmacokinetic properties calculation, for compounds 19, 20 and 23, suggested that these compounds could be promising leads for further investigation to explore more about the structure inhibitor relationship and develop novel selective COX-2 inhibitors agent.
    Experimental
    Acknowledgment
    Meningioma is the most common primary brain tumor in cats. Feline meningiomas show less aggressive behaviour than human and canine meningiomas, thus their classification is not adaptable to the human 2007 WHO classification (, ). Several studies have reported an association between cyclooxygenase-2 (COX-2) expression in human meningiomas with cell proliferation or tumor grade (). In one canine study, significant correlation between COX-2 immunoreactivity patterns and morphologic features of meningioma malignancy were not detected ().
    Introduction We consider normal algebraic varieties X defined over the field of complex numbers. If X has finitely generated divisor class group K and only constant invertible global regular functions, then one defines the K-graded Cox ring of X as follows, see [2] for details: If the Cox ring is a finitely generated -algebra, then one has the total coordinate space . We say that X admits iteration of Cox rings if there is a chain dominated by a factorial variety where in each step, is the total coordinate space of and the characteristic quasitorus of , having the divisor class group of as its character group. Note that if the divisor class group K of X is torsion free, then is a unique factorization domain and iteration of Cox rings is trivially possible. As soon as K has torsion, it may happen that during the iteration process a total coordinate space with non-finitely generated divisor class group pops up and thus there is no chain of total coordinate spaces as above, see [1, Rem. 5.12].