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

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Abstract

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-1β 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.

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Acknowledgments

The authors are grateful to CNPq (132596/2013-0) and CAPES (2017OB826336) for their financial support.

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  1. Laboratory of Pharmacology of Natural and Synthetic Products, Department of Pharmacology, Institute of Biological Sciences, Federal University of Goiás, Campus Samambaia - ICB 2 - Sala 216, CP 131, Goiânia, GO, CEP 74001-970, Brazil

    Daiany P. B. da Silva, Iziara F. Florentino, Dayane M. da Silva, Roberta C. Lino, Carina S. Cardoso, Lorrane K. S. Moreira & Elson A. Costa

  2. Chemistry Institute, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil

    Géssica A. Vasconcelos, Boniek G. Vaz & Luciano M. Lião

  3. Nucleus of Studies and Research Toxicopharmacological, Federal University of Goiás, Goiânia, GO, Brazil

    Daniela C. Vinhal & Luiz C. da Cunha

  4. Laboratory of Medicinal Pharmaceutical Chemistry, Faculty of Pharmacy, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil

    Anna C. D. Cardoso & Ricardo Menegatti

  5. Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Bianca Villavicencio & Hugo Verli

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  1. Daiany P. B. da Silva
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da Silva, D.P.B., Florentino, I.F., da Silva, D.M. et al. Molecular docking and pharmacological/toxicological assessment of a new compound designed from celecoxib and paracetamol by molecular hybridization. Inflammopharmacol 26, 1189–1206 (2018). https://doi.org/10.1007/s10787-018-0516-7

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