Abstract
The five-membered heterocyclic group of pyrazoles/pyrazolines plays important role in drug discovery. Pyrazoles and pyrazolines present a wide range of biological activities. The synthesis of the pyrazolines and pyrazole derivatives was accomplished via the condensation of the appropriate substituted aldehydes and acetophenones, suitable chalcones and hydrazine hydrate in absolute ethanol in the presence of drops of glacial acetic acid. The compounds are obtained in good yields 68–99% and their structure was confirmed using IR, 1H-NMR, 13C-NMR and elemental analysis. The novel derivatives were studied in vitro for their antioxidant, anti-lipid peroxidation (AAPH) activities and inhibitory activity of lipoxygenase. Both classes strongly inhibit lipid peroxidation. Compound 2g was the most potent lipoxygenase inhibitor (IC50 = 80 µM). The inhibition of the carrageenin-induced paw edema (CPE) and nociception was also determined, with compounds 2d and 2e being the most potent. Compound 2e inhibited nociception higher than 2d. Pyrazoline 2d was found to be active in a preliminary test, for the investigation of anti-adjuvant-induced disease (AID) activity. Pyrazoline derivatives were found to be more potent than pyrazoles. Docking studies of the most potent LOX inhibitor 2g highlight hydrophobic interactions with VAL126, PHE143, VAL520 and LYS526 and a halogen bond between the chlorine atom and ARG182.
Highlights
Pyrazoles constitute a principal heterocyclic family containing two nitrogen atoms in their five-membered heterocyclic ring [1] exhibiting a wide range of chemical, biological, agrochemical and pharmacological properties [2]
Several researchers [29,30,31,32,33] have reported the implication of reactive oxygen species (ROS), e.g., hydroxyl radical, superoxide anion and hydrogen peroxide, in disorders associated with oxidative stress. Based on these observations and in continuation with our work related to the synthesis of anti-inflammatory agents, we describe the synthesis and the in vitro evaluation of a number of novel pyrazole and pyrazoline derivatives as antioxidants, lipoxygenase inhibitors and in vivo as anti-inflammatory and analgesic agents influencing adjuvantinduced arthritis
The synthesis of the pyrazolines and pyrazole derivatives was accomplished via the condensation of the appropriate substituted aldehydes, suitable chalcones and hydrazine hydrate in absolute ethanol in the presence of drops of glacial acetic acid, as presented in Scheme 1 [34]
Summary
Pyrazoles constitute a principal heterocyclic family containing two nitrogen atoms in their five-membered heterocyclic ring [1] exhibiting a wide range of chemical, biological, agrochemical and pharmacological properties [2]. Gave the generic name “pyrazole” to the above class of compounds synthesizing the first pyrazolin-5-one (3-methyl-1-phenyl-2-pyrazolin-5-one), many papers have reported the antipyretic, anti-inflammatory and analgesic activity of several pyrazoles, pyrazolin-3-ones and pyrazolidine-3,5-diones [5,6,7,8,9]. Many of these derivatives have been clinically applied as non- steroidal anti-inflammatory agents, such as anti-pyrine (2,3-dimethyl-1-phenyl3-pyrazolin-5-one) or phenazone (analgesic and antipyretic), metamizole or dipyrone (analgesic and antipyretic), phenylbutazone (anti-inflammatory and antipyretic), aminopyrine or aminophenazone (anti-inflammatory, antipyretic and analgesic), sulfinpyrazone (chronic gout) and oxyphenbutazone (antipyretic, analgesic, anti-inflammatory, mild uricosuric) [10]. Used NSAIDs exert their activity via the inhibition of both isoforms including major side effects at the gastrointestinal and renal level [14] due to their inhibition of COX-1-mediated physiological prostaglandins
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