pyrazolone and Edema

New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX) and their selectivity indices were calculated. The results showed that compounds 3f, 3h, 3l, and 3p have an excellent COX-2 selectivity index. Moreover, they showed potent 5-LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti-inflammatory activity using the carrageenan-induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX-2 and 5-LOX active sites was performed to rationalize their anti-inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual-acting COX-2/5-LOX inhibitors to be used as potent and safe anti-inflammatory agents.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Carrageenan; Celecoxib; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Edema; Indomethacin; Lipoxygenase Inhibitors; Molecular Structure; Prostaglandin-Endoperoxide Synthases; Pyrazolones; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Ulcer

A new series of pyrazolone-pyridazine conjugates 3 and 4a-l were synthesized and characterized by spectroscopic means and elemental analyses. All compounds were tested in vivo for their anti-inflammatory and analgesic properties against diclofenac, as reference compound. The synthesized compounds were also evaluated for their ability to inhibit the production of certain inflammatory cytokines such as TNF-α and IL-6 in serum samples. The ulcerogenic potential of the synthesized compounds was also determined. IC50 values for inhibition of COX-1 and COX-2 enzymes were investigated in vitro for the most active candidates. Molecular docking was performed on the active site of COX-2 to predict their mode of binding to the amino acids. Among the synthesized derivatives, compounds 4c and 4e showed good analgesic and anti-inflammatory activities with lower ulcer index than the reference drug.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Cytokines; Dose-Response Relationship, Drug; Edema; Humans; Mice; Models, Molecular; Molecular Structure; Pyrazolones; Pyridazines; Structure-Activity Relationship

The anti-inflammatory activity of a new class of phenyl-pyrazolone derivatives, structurally related to phenidone, has been evaluated using the Croton oil ear test in mice as model of acute inflammation. Derivative 5h reduces the percentage of oedema similarly to indomethacin and more efficiently than phenylbutazone. The anti-inflammatory activity of these two reference drugs depends on their COX inhibition, but for the synthesized derivatives it has not been demonstrated a significant COX or LOX inhibition, as previously reported. While the anti-inflammatory activity of phenidone is correlated to its anti-oxidant properties, the redox potential of these compounds appears not decisive in the inflammatory process inhibition. In order to investigate the mechanism of action for these compounds, we quantified their anti-oxidant activity and the lipophilicity, and a relationship between the calculated logP and the percentage of oedema reduction was found. We hypothesize that the anti-inflammatory activity, recorded in vivo, could be related to lipophilic parameter of these compounds.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Dose-Response Relationship, Drug; Edema; Male; Mice; Pyrazolones

The synthesis of a group of thiazolidine derivatives with pyrazolone-5 substituent is described. The structure of the new compounds is supported by 1H- and 13C-NMR spectra. Group of compounds was tested in vivo for their antiinflammatory activity. The obtained results gave the opportunity to separate the perspective groups of potential NSAIDs, which have got greater antiinflammatory activity than the best standard drugs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Edema; Pyrazoles; Pyrazolones; Rats; Structure-Activity Relationship; Thiazoles