Synthesis, Cyclooxygenase Inhibition, Anti‐Inflammatory Evaluation, and Ulcerogenic Liability of New 1,3,5‐Triarylpyrazoline Derivatives Possessing a Methanesulfonyl Pharmacophore

Non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of rheumatic arthritis, pain, and many different types of inflammatory disorders, cause serious gastrointestinal (GI) side effects. The free carboxylic acid group existing on their chemical structure is correlated with GI toxicity related with all routine NSAIDs. Replacing this functional group with the 1,3,4-oxadiazole bioisostere is a generally used strategy to obtain an anti-inflammatory agent devoid of GI side effects. In the present work, a novel group of 5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one Mannich bases were synthesized and characterized on the basis of IR, H NMR, and elemental analysis results. The target compounds were first tested for cytotoxicity to determine a non-toxic concentration for anti-inflammatory screening. Anti-inflammatory effects of the compounds were evaluated by in vitro lipopolysaccharide (LPS)-induced NO production and in vivo carrageenan footpad edema with ulcerogenic profile. In LPS-induced RAW 264.7 macrophages, most of the compounds showed inhibitory activity on nitrite production while compounds 5a, 5h, and 5j exhibited the best profiles by suppressing the NO production. To evaluate the in vivo anti-inflammatory potency of the compounds, the inflammatory response was quantified by increment in paw size in the carrageenan footpad edema assay. The anti-inflammatory data scoring showed that compounds 5a-d, 5g, and 5j, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5g was comparable to that of the reference drug indomethacin with 53.9% and 55.5% inhibition in 60 and 120 min, respectively.

Section: Introductionmentioning

confidence: 99%

Some Novel Mannich Bases of 5‐(3,4‐Dichlorophenyl)‐1,3,4‐oxadiazole‐2(3H)‐one and Their Anti‐Inflammatory Activity

Koksal

Ozkan-Dagliyan

Ozyazici

et al. 2017

“…Chalcones have been receiving increasing attention due to their wide range of biological activities along with the COX inhibitory activity. [ 16–19 ] A literature survey revealed that they show their anti‐inflammatory activity through suppression of NO, COX‐2, TNF‐α, IL‐1β, inducible nitric oxide synthase (iNOS), and other essential cytokines. [ 20–23 ] Zarghi et al [ 24–26 ] reported a novel class of compounds possessing an acyclic 1,3‐diarylprop‐2‐en‐1‐one structural template as COX inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, biological evaluation, and docking studies of some novel chalcones as selective COX‐2 inhibitors

Çavuşoğlu

Sağlık

Çevik

et al. 2020

A new series of chalcones (1−9) possessing an SO2CH3 COX‐2 pharmacophore at the para position of the C‐1 phenyl ring was synthesized via the Claisen–Schmidt condensation reaction and examined for their inhibition potential against cyclooxygenase (COX) enzymes. Their structures were elucidated by infrared, 1H NMR (nuclear magnetic resonance), 13C NMR, and high‐resolution mass spectroscopic methods. Enzyme inhibition studies revealed that most of the compounds showed a moderate‐to‐strong inhibitory activity (IC50 = 0.18−0.34 μM) against the COX‐2 enzyme as compared with celecoxib (IC50 = 0.12 μM), ibuprofen (IC50 = 5.33 μM), and nimesulide (IC50 = 1.68 μM). Among these compounds, 1‐[4‐(methylsulfonyl)phenyl]‐3‐(2,3‐dichlorophenyl)prop‐2‐en‐1‐one (5), 1‐[4‐(methylsulfonyl)phenyl]‐3‐(2,4‐dichlorophenyl)prop‐2‐en‐1‐one (6), and 1‐[4‐(methylsulfonyl)phenyl]‐3‐(2‐chloro‐6‐fluorophenyl)prop‐2‐en‐1‐one (8) became prominent with IC50 values of 0.21, 0.19, and 0.18 μM, respectively. According to molecular docking studies of the most effective compounds, it was found that the compounds interact with amino acids that are important in COX‐2 selectivity, such as Arg499 and Phe504.

“…Among the family of biologically active heterocycles, special interest has been given to pyrazole‐containing compounds as potential anti‐inflammatory, antinociceptive, and antipyretic agents especially after the discovery of antipyrine at 1884 as the first anti‐inflammatory pyrazole analog. As a consequence, a tremendous number of pyrazoles has been prepared, biologically investigated, and some of them have been introduced clinically.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Anti‐Inflammatory Activity, and COX‐1/2 Inhibition Profile of Some Novel Non‐Acidic Polysubstituted Pyrazoles and Pyrano[2,3‐c]pyrazoles

Faidallah

Rostom

2017

The synthesis and evaluation of the anti-inflammatory activity of some structure hybrids comprising basically the 5-hydroxy-3-methyl-1-phenyl-4-substituted-1H-pyrazole scaffold directly linked to a variety of heterocycles and functionalities, or annulated as pyrano[2,3-c]pyrazoles, is described. According to the in vivo results and a comprehensive structure-activity relationship study, five analogs (5, 10, 17, 19, and 27) displayed remarkable anti-inflammatory profiles showing distinctive % protection and ED values, especially 10 and 27 (ED 35.7 and 38.7 μmol/kg, respectively) which were nearly equiactive to celecoxib (ED 32.1 μmol/kg). Compounds 10, 17, and 27 exhibited distinctive COX-2 inhibition with a noticeable COX-2 selectivity (SI values 7.83, 6.87, and 7.16, respectively), close to that of celecoxib (SI 8.68). Additionally, 5, 10, 17, 19, and 27 proved to be gastrointestinal tract safe (0-20% ulceration) and non-toxic, being well tolerated by the experimental animals up to 250 mg/kg orally and 80 mg/kg parenterally. Collectively, the in vivo ED values for the most potent five derivatives agree with their in vitro COX-2 selectivity indices, suggesting their usefulness as selective anti-inflammatory COX-2 inhibitors. The bipyrazole 10 and the pyranopyrazole 27 could be considered as the most active members in this study, being nearly equiactive to celecoxib, besides their obvious selective COX-2 inhibition, high safety margin, and predicted pharmacokinetic (ADME-T) suitability for oral use.