-quinazolinones containing various substituents on diaryl rings have been synthesized and evaluated for their cyclooxygenase-2 inhibitory activity by the colorimetric COX (ovine) inhibitor screening assay and anti-inflammatory activity by the carrageenan-induced rat paw edema assay. 2-(4-Nitrophenyl)-3-(4-tolyl)-4(3H)-quinazolinone showed a maximum COX-2 inhibition of 27.72% at 22 µM concentration in the present series and exhibited a mild anti-inflammatory activity at a dose of 50 mg/kg in carrageenan-induced rat paw edema assay.Keywords: 4(3H)-quinazolinones, COX-2 inhibitors.One of the aims of medicinal chemists is to develop drugs that would hit single targets. Selective drug action is intended to minimize undesired side effects. By optimizing binding to a selected target protein, safe and efficacious drug molecules could be developed for the treatment of a disease. The discovery of isoforms of cyclooxygenase enzyme as COX-1 and COX-2 showed that the side effects of NSAIDs were due to their unwanted inhibition of COX-1 along with the desired blockade of COX-2 enzyme. This discovery led to the development of selective COX-2 inhibitors, which are almost free of gastric side effects and possess potent antiinflammatory activity [1]. The COX-2 inhibitors have been successful in treating such inflammatory diseases as acute pain, rheumatoid arthritis, and osteoarthritis; a few of them are also being studied for treating different types of cancers and Alzheimer's disease [2]. Despite a few latest cautionary reports, COXIB treatment has a high degree of benefit over risk, and the strategies for the use of NSAIDs have been described [3].Unlike classic NSAIDs, which have a diverse class of chemical structures, the selective COX-2 inhibitors can be classified into two classes as (i) acidic methane sulfonamides containing diphenyl ethers, e.g., nimesulide 1 [4] and NS-398 2 [5], and (ii) vicinal diaryl heterocycles with sulfamoyl or methylsulfonyl substitution, e.g., etoricoxib [6], celecoxib [7], refocoxib [8], and valdecoxib [9]. A central carbo/heterocyclic ring system bearing two vicinal aryl moieties is a prerequisite for selective COX-2 inhibitors. A wide variety of heterocycles can serve as a template for COX-2 inhibitors, i.e., pyrazole (celecoxib), isoxazole (valdecoxib, paracoxib sodium), furan (rofecoxib), oxazole (JTE-522), thiophene (DuP-697), pyridine 3 (etoricoxib), pyrazine 4 [10], and quinoxaline 5 [10].
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. COX-2 inhibitors have been successful in treating inflammatory diseases like acute pain, rheumatoid arthritis and osteoarthritis; a few of them are also being studied for treating different types of cancer and Alzheimer's disease (1). Despite a few recent cautionary reports, the coxib treatment has a high degree of benefit over risk, and strategies for using NSAIDs have been described by Antman et al. (2). A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl--1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for anti--inflammatory activity by the rat paw edema method. p--Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4--methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 µmol L -1 and COX-1 enzyme inhibition of 44% at 88 mmol L -1 concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 µmol L -1 ) and higher COX-1 enzyme inhibition (53% at 88 µmol L -1 ) but, marked in vivo anti-inflammatory activity (71% at 25 mg kg -1 ) vs. celecoxib (48% at 12.5 mg kg -1 ). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.
Fused pyrimidine derivatives R 0515Synthesis and Antiinflammatory Activity of 2,3-Diaryl-4(3H)-quinazolinones. -Eighteen title compounds of type (VI) or (VIII) are prepared and evaluated for their cyclooxygenase-2 inhibitory activities by the colorimetric COX (ovine) inhibitor and for their antiinflammatory activities. Compound (VIc) is found to be the most potent COX-2 inhibitor and exhibits mild antiinflammatory effects. -(YADAV, M. R.; SHIRUDE, S. T.; PARMAR, A.; BALARAMAN, R.; GIRIDHAR, R.; Chem.
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