Synthesis and Characterization of Novel IMIDAZO[1,2- A]Pyridine Derivatives as Potential CYCLOOXYGENASE-2 (COX-2) Inhibitors (original) (raw)
Related papers
Molecules
Cyclooxygenase-2 (COX-2) is implicated in the development of chronic inflammatory diseases. Recently, pyridazine derivatives have emerged as a novel prototype to develop COX-2 inhibitors. Accordingly, some pyridazine-based COX-2 inhibitors are reported herein. The reaction of aldehyde 3 and different hydrazines yielded the corresponding hydrazones. The hydrazones were further derivatized to the title compounds, which were assessed for COX-1 and COX-2 inhibitory action, gastric ulcerogenic effects, and lipid peroxidation properties. Molecular docking studies and determination of the physicochemical parameters were also carried out. The allocated structures of the reported compounds were coherent with their spectroscopic data. The compounds 9a (IC50 = 15.50 nM, 114.77%), 9b (IC50 = 17.50 nM, 101.65%), 12 (IC50 = 17.10 nM, 104.03%), 16b (IC50 = 16.90 nM, 105.26%), and 17 (IC50 = 17.70 nM, 100.5%) displayed better COX-2 inhibition than celecoxib (IC50 = 17.79 nM, 100%). These outcomes w...
Iranian Journal of Basic Medical Sciences, 2010
Objective(s) In recent years highly selective COX-2inhibitors were withdrawn from the market because of an increased risk of cardiovascular complications. In this study we were looking for potent compounds with moderate selectivity for cox-2. So, four analogues of 4, 5-diaryl-2-(2-alkylthio-5-imidazolyl) imidazole derivatives were synthesized and their anti-inflammatory and anti-nociceptive activities were evaluated on male BALB/c mice (25-30 g). Molecular modeling and in vitro COX-1 and COX-2 isozyme inhibition studies were also performed. Materials and Methods 2-(2-Alkylthio-5-imidazolyl)-4,5-diphenylimidazole compounds were obtained by the reaction of benzyl with 2-alkylthio-1-benzylimidazole-5-carbaldehyde, in the presence of ammonium acetate. Spectroscopic data and elemental analysis of compounds were obtained and their structures elucidated. Anti-nociception effects were examined using writhing test in mice. The effect of the analogues (7.5, 30, 52.5 and 75 mg/kg) against acut...
Oriental journal of chemistry, 2015
A new series of thiadiazole linked pyrazole benzenesulfonamide derivatives were synthesized by the condensation of aldehydic pyrazole with aryl substituted thiadiazole amine followed by Schiff base reaction. The synthesized compounds (6a-o) were characterized by IR, NMR, and Mass spectral data, further evaluated their in-vivo anti-inflammatory, analgesic and invitro COX-II inhibition assay. The compounds 6b and 6m showed most significant in-vivo antiinflammatory with 72.33 &71.17% inhibition along analgesic activity having 67.89% and 71.37 % respectively. Their selectivity against COX-II enzyme with selectivity index 67.81 and 66.38 was established for 6b and 6m, which is compared with Celecoxib. During the gastric ulceration study, selected compounds couldn’t observed any ulcerogenic effect on gastric mucosa.The in-silico pharmacokinetic profile and molecular docking study exposed very good binding affinity towards the Cyclooxygenase (COX-II) enzyme (PDB Id: 3PGH), therefore the co...
2010
A new series of 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4ones, possessing a methylsulfonyl pharmacophore, were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition studies were performed to acquire structureactivity relationship data with respect to the point that molecular modeling studies showed that designed compounds bind in the primary binding site such that the C-2 para-SO 2 Me substituent inserts into the 2°pocket present in COX-2 enzyme. COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC 50 values in the highly potent 0.21 to 0.34 lM range, and COX-2 selectivity indexes in the 222.3 to [476 range. 3-Benzyl-2-(4-methylsulfonylphenyl)-1,3-oxazolidine-4(5H)-one was identified as the most potent (IC 50 = 0.21 lM) and selective (S.I. [ 476) COX-2 inhibitor among the synthesized compounds. It also was a more selective COX-2 inhibitor than the parent reference compound celecoxib (S.I. [ 403).
A new series of triarylpyrazoline derivatives 8a–p containing the most important COX-2 pharmacophore (SO 2 CH 3 or/and SO 2 NH 2) were synthesized by reaction of propen-1-one derivatives 6a–h with different phenyl hydrazine hydrochloride derivatives 7a–b in aqueous ethanol. All prepared compounds were evaluated for their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and showed good in vivo anti-inflammatory activity. Compounds 8g, 8j and 8o showed the highest anti-inflammatory activity and were less ulcerogenic (Ulcer Index = 6.85, 7.7, 5.92, respectively) than indomethacin (Ulcer Index = 12.3) and comparable to celecoxib (Ulcer Index = 4.85).
Bioorganic Medicinal Chemistry Letters, 2009
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
Journal of Heterocyclic Chemistry, 2002
A group of 1,2-diphenyl-3,5-dioxopyrazolidines possessing a methylsulfonyl (11) or sulfonamide (15) substituent at the para position of the N 1-phenyl ring, in conjunction with a hydrogen, methyl or fluoro substituent at the para position of the N 2-phenyl ring, and a C-4 n-butyl, methyl or spiro-cyclopropyl substituent were synthesized for evaluation as potential cyclooxygenase-2 (COX-2) selective inhibitor antiinflammatory agents. The title compounds 11 and 15 were synthesized using a four-step and a three-step reaction sequence, respectively. Thus, the acetic acid promoted condensation of a nitrosobenzene 5 with an aniline derivative (6, 12) gave the corresponding azobenzene product (8, 13) which was reduced with zinc dust in the presence of ammonium chloride to yield the corresponding hydrazobenzene (9, 14). Base-catalyzed condensation of 9 and 14 with a malonyl dichloride (10) afforded the target 3,5-dioxopyrazolidine product (11, 15). 4-n-Butyl-1-(4-methylsulfonylphenyl)-2-phenyl-3,5-dioxopyrazolidine (11a) was a selective COX-1 inhibitor (COX-1 IC 50 = 8.48 µM). In contrast, 4-n-butyl-1-(4-methylsulfonylphenyl)-2-(4-tolyl)-3,5-dioxopyrazolidine (11b, COX-2 IC 50 = 11.45 µM) and 4-n-butyl-1-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)-3,5-dioxopyrazolidine (11c, COX-2 IC 50 = 9.86 µM) were about 46-fold and 20-fold less selective COX-2 inhibitors respectively, relative to the reference drug celecoxib.
Bioorganic & Medicinal Chemistry Letters, 1998
A series of novel 2-pyridinyl-3-(4-methylsulfonyl)phenylpyridines has been synthesized and evaluated with respect to their ability to inhibit the isozymes of cyclooxygenase, COX-l, and COX-2. Optimum COX-2 activity is observed by introduction of a substituent at C5 of the central pyridine. 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine 33 was identified as the optimum compound in this series.