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  • Leukotrienes themselves are implicated in the development of


    Leukotrienes themselves are implicated in the development of gastrointestinal ulcers, asthmas, and different inflammatory processes [18], [19]. It is noteworthy that COX isozymes and LOX share the same substrate arachidonic acid; therefore, inhibition of prostaglandins production by cyclooxygenase pathway can lead to increased substrate availability and increased production of leukotrienes by lipoxygenase pathway [20], [21], [22]. Although, R. Mashima and T. Okuyama reported that 15-LOX performs multiple functions and that down regulation or general inhibition of 15-LOX delays the resolving of NSC 74859 [23]. It is now clear that PGs and LTs have complementary effects regarding development and persistent inflammatory processes [24]. In view of these perceptions, it has been proposed that limiting the production of both leukotrienes and prostaglandins might have synergistic and wide spectrum anti-inflammatory effects, as well as, production of new entities with safe gastrointestinal and cardiovascular profiles [25]. Recently, enormous trials have been applied to develop dual COX and LOX inhibitors with moderate selectivity towards COX-2 at micromole level [26]. Amidoxime and 1,2,4-oxadiazole containing compounds showed significant pharmacological effects as antihyperglycemic activity, anti-inflammatory activity, antimycobacterial activity, muscarinic agonist activity and serotonergic inhibitory activity, peptide inhibitory activity [27], [28], [29], [30]. Both moieties have been incorporated as carboxylic and ester group bioisosteres, respectively, with the aim of designing prodrugs with an improved PK and PD properties [30]. Moreover, for the purposes of synthesizing nitric oxide-releasing non-steroidal anti-inflammatory prodrugs, NO-NSAIDs, amidoxime moiety has shown its ability to release NO in vivo [31]. Naproxen is one of NSAIDs that has important medical applications in case of arthritis, ankylosing spondylitis, gout, menstrual cramps and others. However, its chronic use can adversely produce gastric ulceration and bleeding [32], [33]. Therefore, synthetic approaches have being intensively applied to design naproxen derivatives with improved safety profile via derivatization of the carboxylate function of naproxen [34], [35], [36]. Encouraged by all these facts, we hereby report the synthesis of non-carboxylic analogues of naproxen by O-acylation of aryl amidoximes (2b-g) to the corresponding aryl carboximidamides (3b-g) and their cyclization to the corresponding 3-aryl-1,2,4-oxadiazoles (4b-g). The rationally designed compounds have a typical molecular pattern to fulfill the pharmacophoric necessities for better COX binding recognition represented by naproxen moiety and an additional bulk volume represented by terminal phenyl ring to bind exclusively to COX-2 binding site. The current study has investigated the possibility of masking the naproxen carboxylic group to disguise its direct adverse reactions with potential in vitro selective COX-2 inhibitory activity (Fig. 1).
    Results and discussion
    Molecular docking study In order to elucidate the biological activity and the difference in selectivity profile of the newly synthesized naproxen derivatives toward COX subtypes based on their orientation and binding patterns, the most potent compound 3d was selected for molecular docking studies into the active site of COX-2 using CDOCKER embedded in Discovery Studio software [40]. To validate our docking protocol settings, we have re-docked the co-crystallized ligand S-58 after being extracted from the used 3D protein structure of COX-2 (pdb code: 1CX2) using the same protocol settings utilized for docking simulation of our compound 3d. It was clear that the used docking protocol closely reproduced the bound structure with RMSD value of1.03 Å confirming the confidence in our docking study. The 3D crystal structures of COX-2 enzymes complexes with its co-crystallized ligand (PDB codes: 1CX2) was used for this study. The presence of an additional side pocket is one of the well-known features of COX-2 binding site. This side pocket was formed because of the replacement of the amino acid residue Ile523 in COX-1 with the less bulky Val523 in COX-2, which increases the volume of the COX-2 active site [41]. Moreover, it makes the COX-2 protein accommodate bulkier structures and allows other interactions with amino acid residues such as Arg513, substituted by a His513 in COX-1 [30]. It was reported that the traditional COX-2 inhibitors adopt binding with Arg513 in the COX-2 additional pocket, often via sulfonamide or sulfone groups, to attain their activity and selectivity over COX-1. Interestingly, analysis of the docking results of compound 3d revealed that 3d exhibited not only similar binding pattern and interactions to that of the co-crystallized bromocelecoxib, S-58 ligand, but also compound 3d was engaged in hydrogen bond interaction with Arg513 (Fig. 4) which is essential for activity and selectivity toward COX-2 over COX-1. It was clear from (Fig. 4) that the orientation of the dimethoxy phenyl moiety in compound 3d within the additional side pocket of COX-2 was similar to fitting of sulfonamide moiety of S-58 into the same side pocket. In addition, compound 3d formed hydrophobic interactions with Leu352, Ser353, Ala516, Phe518 and Val523 residues. Therefore and because of the larger volume of COX-2 active site, it could accommodate the dimethoxy phenyl moiety in compound 3d with almost the same binding pattern within the entire COX-2 active site.