| 4,5-Diarylisoxazoles (32a--p), 3,4-diaryl-5-trifluoromethylisoxazoles (36, 42), 4,5-diphenyl-3-methylsulfonamidoisoxazole (44), 4,5-diaryl-3-methylisoxazoles (48a--b) and 4,5-diaryl-4-isoxazolines (50a--k) possessing H, F, MeS, McSO, and/or MeSO2 substituents at the para-position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX-2 inhibitory and anti inflammatory (AI) agents.; 4,5-Diarylisoxazoles 32a--p exhibited potent analgesic and AI activities, but those compounds evaluated (32a, 32b, and 32m) were non-selective inhibitors of COX-2. In contrast, 3-(4-methylsulphonyl phenyl)-4-phenyl-5-trifluoro methyl isoxazole (36), which retained good analgesic and AI activities, was a highly potent and selective COX-2 inhibitor (COX-1 IC50 > 500 muM; COX-2 IC50 < 0.001 muM; SI of > 500,000) relative to celecoxib (COX-1 IC50 = 22.9 muM; COX-2 IC50 = 0.0567 muM; SI = 404). 4,5-Diphenyl-3-methylsulfonamidoisoxazole (44) exhibited potent and selective COX-2 inhibition (COX-1 IC50 > 200 muM; COX-2 IC50 = 0.226 muM; SI = 752).; 4,5-Diaryl-4-isoxazolines (50a--i), having two C-3 hydrogen atoms, exhibited potent analgesic and AI activities, but those compounds evaluated (50a, 50b, 50h, and 50i) were non-selective inhibitors of COX-2. However, 2,3-dimethyl-5-(4-methylsulphonylphenyl)-4-phenyl-4-isoxazoline (50k) exhibited excellent analgesic and AI activities, and selective COX-2 inhibition (COX-1 IC50 = 258 muM; COX-2 IC50 = 0.004 muM; SI = 61,454).; Docking isoxazoles 32e, 32m, 36, 44, and 48a--b, and isoxazolines 50h, and 50k in the binding site of the COX-1 and COX-2 isozymes and comparative molecular volume analysis for compounds 32m and 50h showed that the size and nature of the central ring substituents are crucial to selective inhibition of COX-2. The intermolecular energy between the docked ligands and both COX-1 and COX-2 was a determinant of enzyme inhibition in quantitative structure activity relationship (QSAR) regression equations.; Finally, celecoxib (54, 57) and rofecoxib ( 61) analogues, in which the respective SO2NH2 and SO2Me pharamacophores were replaced by an azido substituent, were synthesized. Docking compounds 54, 57 and 61 analogues in COX-2 showed that the azido substituent was inserted into the secondary pocket of the COX-2 binding site where it underwent electrostatic interaction with Arg513. The 1,5-diarylisoxazole (57 ) was a more selective COX-2 inhibitor than the 1,3-regioisomer ( 54). The rofecoxib analogue 61, the most potent and selective inhibitor of COX-2 in this group (COX-1 IC50 = 159.7 muM; COX-2 IC50 = 0.196 muM; SI = 812), exhibited good AI and analgesic activities. |
