Synthesis of 2,3-diaryl-1,3-thiazolidine-4-one derivatives as selective cyclooxygenase (COX2) inhibitors (original) (raw)
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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).
Bioorganic & Medicinal Chemistry Letters, 1999
A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors.
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, 1999
A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.A series of novel sulfone substituted 4,5-diarylthiazoles were synthesized and shown to display exceptionally selective COX-2 inhibition.
Bioorganic & Medicinal Chemistry, 2009
A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3benzthiazinan-4-one (7b) as a potent (IC 50 = 0.05 lM) and selective (selectivity index = 259) COX-2 inhibitor.
Nowadays, COX-2 inhibitors such as valdecoxib are removed from the market because of their cardiovascular toxicity and their potential to increase the risk of strokes. In response to this, medicinal chemists have attempted to synthesize new classes of COX-2 Inhibitors. Materials and Methods: In this study, three novel analogues of thiazolidin-4-ones derivatives 2a-c were synthesized. The ability of these compounds to inhibit ovine COX-1 and COX-2 (0.2-0.8 µM) was determined using a colorimetric method. The cytotoxic effect of the synthesized compounds (25-100 M) was also investigated by measuring their cytotoxicity against Caco-2 and MCF-7 cell lines using MTT assay. Cell apoptosis was determined by flow cytometry. Writhing test (7.5-75 mg/kg) was used to examine the antinociceptive effects in mice. The effect of the analogues against acute inflammation (7.5-75 mg/kg) was also studied using xylene-induced ear edema test in mice. Results: The synthesized compounds showed a weak capacity to inhibit the proliferation of Caco-2 and MCF-7 cell lines. The COX-2 inhibition potency and selectivity index for test compounds 2a-b were as follows; celecoxib > 2b > 2a. On the other hand, all three analogues exhibited strong antinociceptive activity against acetic acid-induced writhing. The anti-inflammatory and antinociceptive effects of the analogues were markedly more than positive control, celecoxib. Conclusion: This study demonstrates that the antinociceptive and anti-inflammatory activity profiles exhibited by the novel synthesized compounds are independent from their COX-2 inhibitory potencies. The found antinociceptive and anti-inflammatory effects can be caused by interaction with other target; independent from COX-2. Accordingly, the compounds 2a-c could serve as lead compounds to develop novel anti-inflammation and antinociceptive drugs.
ChemInform, 2005
First synthesis of novel 1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl substituted 1,5-diarylpyrazoles has been accomplished via oxidative cyclization of 4-nuoro-2-methyl benzenesulfonamide followed by the treatment with hydrazine and then with 1,3dicarbonyl compounds. A number of 1,5-diarylpyrazoles were synthesized in good yields and some of them were of potential biological interest. Cyclooxygenase-2 (COX-2) inhibitors are the topic of re'"cent research due to their antiinflammatory activity with reduced side effects of traditional NSAIDs at the gastrointestinal level (mucosal damage, bleeding) and less frequently, at the renal level. Most of the COX-2 inhibitors belong to the vicinal diary! heterocyclic class of compounds having an aminosulfonyl (S0 2 NH 2) or a methanesulfone (S0 2 Me) moiety attached to the p-position of one of the aryl ring. After the discovery of inducible isozyme (COX-2) in 1991, the methanesulfonanilide (NS398) and the diarylheterocycle (DUP-697) were first identified as non-ulcerogenic antiinflammatory agents (Fig. I) 1 • 2 • Subsequent research and rational drug design resulted in a number of potent and selective COX-2 inhibitors which validated the initial concept that a selective COX-2 inhibitor would illicit effective anti-inflammatory activity without the adverse ulcerogenic effect associated with the use of NSAIDs that inhibit both COX-I and COX-2. Accordingly celecoxib 3 and rofecoxib 4 followed by valdecoxib 5 and etoricoxib 6 became the first and second-generation selective COX-2 inhibitors (Fig. l) to enter the market. Celecoxib, a selective COX-2 inhibitor, belongs to a diary I heterocyclic class where two aryl moieties are attached to the adjacent positions of the central pyrazole ring. The 4benzenesulfonamide group attached to the nitrogen atom of the pyrazole ring is thought to be responsible for its efficacy and COX-2 selectivity in different models of inflammation. Recent study revealed that this class of compounds could be useful as dual COX-2/5-LO (5-lipooxygenase) inhibi-"'DRF Publication No. 340. toedicated to ProfessorS. M. Mukherji.
Egyptian Journal of Chemistry, 2021
Thiazolidinone, a saturated form of thiazole with a carbonyl group on fourth carbon, has been considered as a magic moiety (wonder nucleus) that possesses almost all types of biological activities. A new series of 4-thiazolidinones bearing ketoprofen moiety had been designed, then synthesized by reacting Schiff-base with chloroacetic acid and sodium acetate in ethanol according to Baldwin rules for ring closure and finally evaluated as a potent cyclooxygenase-2 (COX-2) inhibitors. Characterization and identification of the synthesized compounds were established by the determination of 1H-NMR spectra,13C-NMR, FT-IR spectroscopy, and physical properties. These newly synthesized compounds have been evaluated in vivo for their anti-inflammatory efficiency and In silico selectivity toward COX-2 through molecular docking by using GOLD suite v.5.6.2. All the tested compounds via molecular docking showed anti-inflammatory activity and some of them have significant activity when compared wit...
Thiazole derivatives as inhibitors of cyclooxygenases in vitro and in vivo
European Journal of Pharmacology, 2015
Cyclooxygenases (COXs) are important membrane-bound heme containing enzymes important in platelet activation and inflammation. COX-1 is constitutively expressed in most cells whereas COX-2 is an inducible isoform highly expressed in inflammatory conditions. Studies have been carried out to evaluate thiazole derivatives as anti-inflammatory molecules. In this study, we investigated the in vitro and in vivo effects of two novel thiazole derivatives compound 1 (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol-2-yl] acetamide) and compound 2 (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol) on prostaglandin E 2 (PGE 2 ) production and COX activity in inflammatory settings. Our results reveal a potent inhibition of both compound 1 (IC50 9.01 70.01 mM) and 2 (IC50 11.65 76.20 mM) (Mean 7S.E. M.) on COX-2-dependent PGE 2 production. We also determined whether COX-1 activity was inhibited. Using cells stably over-expressing COX-1 and human blood platelets, we showed that compound 1 is a specific inhibitor of COX-1 with IC50 (5.56 Â 10 À 8 7 2.26 Â 10 À 8 mM), whereas compound 2 did not affect COX-1. Both compounds exhibit anti-inflammatory effect in the dorsal air pouch model of inflammation as shows by inhibition of PGE 2 secretion. Modeling analysis of docking in the catalytic site of COX-1 or COX-2 further confirmed the difference in the effect of these two compounds. In conclusion, this study contributes to the design of new anti-inflammatory agents and to the understanding of cyclooxygenase inhibition by thiazole.