Pyrazoles and Pyrazolines as Anti-Inflammatory Agents

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.

Structural Insights into Pyrazoles as Agents against Anti‐inflammatory and Related Disorders

“…[151] Pyrazolines bearing phenyl and benxyloxy substitutions at C3 and C5 exerts greater anti-inflammatory effect than the standard indomethacin, and this can be considered for developing newer leads. [152] From the above findings it is concluded that the phenyl ring with electron donating group substitution attached to the pyrazole moiety is essential for excellent COX-2 inhibitory activity.…”

“…Compound bearing 3‐phenoxy and 3,5‐dimethyl benzyloxy benzaldehyde at acetohydrazide on pyrazole nucleus was found to exhibit excellent anti‐inflammatory activity with IC50<0.78 μM each compared to 5.6 μM of diclofenac indicating that the electron withdrawing groups on the phenyl ring of pyrazole possess excellent anti‐inflammatory activity [151] . Pyrazolines bearing phenyl and benxyloxy substitutions at C3 and C5 exerts greater anti‐ inflammatory effect than the standard indomethacin, and this can be considered for developing newer leads [152] …”

Molecular Docking Studies on Some 4,5-Dihydro-1h-Pyrazole Derivatives as Cyclooxygenase Inhibitors

“…Simultaneously, circulation of leukocytes and endothelial cells are provided to the injured/infected tissue. Nonsteroidal antiinflammatory drugs target the phase of the inflammation by inhibiting cyclooxygenase (COX) enzymes [1,2].…”

“…NSAIDs display their activities on both of the COX isozymes. Since the inhibition of the COX-1 enzyme is responsible for the gastrointestinal and renal adverse effects of NSAIDs, it was thought that these side effects could be eliminated only by inhibiting the COX-2 enzyme [2]. When selective inhibition of the COX-2 enzyme appeared to cause serious cardiovascular problems, a balanced inhibition of both isozymes became important [7,8].…”

“…The pyrazole ring, a 5-membered ring system containing two nitrogen atoms, and its monounsaturated derivative, the 4,5-dihydro-1H-pyrazole ring, are in the structure of many nonsteroidal antiinflammatory drugs (NSAIDs) such as antipyrine, phenazone, metamizole and phenylbutazone [2]. These ring systems inhibit cyclooxygenase enzymes, particularly the COX-2 enzyme [10][11][12][13][14][15][16].…”