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  • Furthermore positioning the naphthalene nucleus in d within


    Furthermore, positioning the naphthalene nucleus in 3d within the main active site and forming one hydrogen bond with Tyr385 in addition to many hydrophobic interactions with Val349, Leu352, Gly526, Ala527 and Leu531 residues, correlates well with the position and hydrophobic interactions of the trifluoromethyl pyrazole fragment of S-58 with the same residues (Fig. 5). Overall, these interactions and binding pattern of 3d into COX-2 active site may reflect the high COX-2 inhibitory activity and selectivity of this compound.
    Conclusion In summary, 12 new final naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) were synthesized, characterized and evaluated in vitro as dual COXs/LOX inhibitors. Among the tested compounds, the aryl carboximidamide derivatives with 4-Cl, 4-OMe, 3,4-di-OMe and phenyl groups were the most potent as dual COX-2/15-LOX inhibitors than reference celecoxib and that compounds 3b, 3c, 3d and 3g could be considered as promising candidates for the future development as anti-inflammatory agents. Compound 3g (aryl 67 8 carboximidamide derivative) is promising lead compounds that had strong potential to be further developed as novel selective COX-2/15-LOX inhibitors. Further structural optimization of these promising anti-inflammatory agents especially is ongoing for more precise SAR information and agents that are more potent.
    Acknowledgment This research was partially supported by the Korea Institute of Science and Technology (2018 KIST School Partnership Research Grant).
    Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed and cost-effective drugs for pain relief. They represent approximately 5–10% of all medications prescribed each year [1]. These medications inhibit the cyclooxygenase enzymes (COX-1 and COX-2), which are responsible for arachidonic 67 8 metabolism to prostaglandin H2 (PGH2), the precursor for prostacyclin (PGI2), prostaglandin-E2 (PGE2) and thromboxane-A2 (TXA2) synthesis [2]. Chronic use of NSAIDs has been implicated in sever gastric ulcers and renal disorders [3] due to inhibition of COX-1. These side effects of the traditional NSAIDs are the main reason for drug intolerability and discontinuation [4]. Previous studies succeeded in the synthesis of new NSAIDs as selective COX-2 inhibitors, namely “coxibs” to minimise the danger of gastric ulcers [5], however the cardiovascular adverse effects were significant [[6], [7], [8]]. Within the coxibs class of drugs, Celecoxib has the advantage of lowering cardiovascular toxicity compared to other coxibs [9]. Various attempts for safer NSAIDs have been made in the last few years, through optimization of benzenesulfonamide-based derivatives, considering celecoxib 1, bearing a pyrazole ring linked to benzenesulfonamide ring at N-1 and p-tolyl group at C-5, as a lead compound (Fig. 1) [10]. Saccharin 2 has played a crucial role in the development of several biologically active agents such as repinotan, supidimide and ipsapirone [11]. Meanwhile, piroxicam 3, the lead compound of oxicams NSAIDs family (Fig. 1), was discovered as a saccharin derivative through utilizing the Gabriel–Colman rearrangement under basic conditions [12]. The varied functionality associated with sodium saccharin, as a useful chiron, has promoted many attempts for synthesis of a wide range of benzenesulfonamides. Several studies have investigated the analgesic and anti-inflammatory activities of the benzenesulfonamides scaffold attached to a pyrazole moiety [13]. For instance, compounds 4 and 5 possessed higher analgesic and anti-inflammatory activities than celecoxib [13,14]. In addition, it was reported that 1,5-diphenyl pyrazoles exhibited anti-inflammatory activities less than diclofenac against COX-1 but they showed a reasonable in vitro COX-2 inhibitory activity with IC50 value of 0.45 μM [15]. Likewise, compounds 6 displayed high COX-2 selectivity and high anti-inflammatory activity compared to celecoxib [16]. Celecoxib derivative 7 was found to have higher anti-inflammatory activity and COX-2 selectivity with reasonable ulcer index [17]. The pyrazolyl benzenesulfonamides linked to thiazolidinone 8 and pyrazole 9 displayed higher COX-2 selectivity with minimal potential for gastric injury (Fig. 2) [18].