Molecular docking and pharmacological/toxicological assessment of a new compound designed from celecoxib and paracetamol by molecular hybridization.

Nonsteroidal anti-inflammatory drugs are commonly used worldwide; however, they have several adverse effects, evidencing the need for the development of new, more effective and safe anti-inflammatory and analgesic drugs. This research aimed to design, synthesize and carry out a pharmacological/toxicological investigation of LQFM-102, which was designed from celecoxib and paracetamol by molecular hybridization. To evaluate the analgesic effect of this compound, we performed formalin-induced pain, hot plate and tail flick tests. The anti-inflammatory effect of LQFM-102 was evaluated in carrageenan-induced paw oedema and pleurisy tests. The biochemical markers indicative of toxicity-AST, ALT, GSH, urea and creatinine-as well as the index of gastric lesion after prolonged administration of LQFM-102 were also analyzed. In addition, the interaction of LQFM-102 with COX enzymes was evaluated by molecular docking. In all experimental protocols, celecoxib or paracetamol was used as a positive control at equimolar doses to LQFM-102. LQFM-102 reduced the pain induced by formalin in both phases of the test. However, this compound did not increase the latency to thermal stimuli in the hot plate and tail flick tests, suggesting an involvement of peripheral mechanisms in this effect. Furthermore, LQFM-102 reduced paw oedema, the number of polymorphonuclear cells, myeloperoxidase activity and TNF-α and IL-1ß levels. Another interesting finding was the absence of alterations in the markers of hepatic and renal toxicity or lesions of gastric mucosa. In molecular docking simulations, LQFM-102 interacted with the key residues for activity and potency of cyclooxygenase enzymes, suggesting an inhibition of the activity of these enzymes.

Mechanism involved in the anti-inflammatory effect of Spiranthera odoratissima (Manacá)

Acetic acid-induced writhing, hot-plate, carrageenan-induced pleurisy, formalin-induced pain, croton oil-induced ear edema, vascular permeability tests and phospholipase A2 activity assay were used to study the analgesic and/or anti-inflammatory activity of the hydromethanolic fraction of ethanolic extract from Spiranthera odoratissima A. St.-Hil., Rutaceae, leaves (HMF) and its subfraction (sub-Fr10-28). HMF and sub-Fr10-28 reduced the leukocyte migration on the carrageenan-induced pleurisy test; sub-Fr10-28 reduced the pain reaction time in the second phase of formalin-induced pain, as well as the ear edema and vascular permeability. Both HMF and sub-Fr10-28 inhibited the phospholipase A2 activity. These results suggest that the analgesic effect of this plant could be, in part, due to an anti-inflammatory action produced by the inhibition of phospholipase A2 activity.