Design, synthesis and pharmacological assessment of new pyrazole compounds
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Inflammopharmacology
ORIGINAL ARTICLE
Design, synthesis and pharmacological assessment of new pyrazole compounds Jordana C. Oliveria1 · Daiany P. B. Silva6 · Iziara F. Florentino6 · Lidya C. da Silva2 · Germán Sanz2 · Boniek G. Vaz2 · Francine Pazini3 · Flávio S. de Carvalho1 · Luciano M. Lião4 · Thaís Rosa Marques dos Santos5 · Marize C. Valadares5 · Elson A. Costa6 · Fernanda Cristina Alcantara dos Santos7 · Bianca Villavicencio8 · Hugo Verli8 · Ricardo Menegatti1 Received: 5 March 2020 / Accepted: 29 May 2020 © Springer Nature Switzerland AG 2020
Abstract Aims This study investigated the antinociceptive and anti-inflammatory effects of new pyrazole compounds LQFM011(5), LQFM043(6) and LQFM044(7) as well as the mechanisms of action and acute in vitro toxicity. Main methods The antinociceptive activity was evaluated using the acetic acid-induced abdominal writhing test, formalininduced pain test and the Randall–Selitto test. The anti-inflammatory activity was evaluated using models of paw oedema and pleurisy induced by carrageenan; cell migration, the levels of tumour necrosis factor α (TNF-α) and myeloperoxidase (MPO) enzyme activity were evaluated. In addition, the ability to inhibit phospholipase A2 (PLA2) in vitro and docking in PLA2 were used. Acute oral systemic toxicity in mice was evaluated through the neutral red uptake assay. Key findings The synthesised compounds (5–7), delivered via gavage (p.o.) at 70, 140 or 280 µmol/kg, decreased the number of writhings induced by acetic acid; the three compounds (280 µmol/kg p.o.) reduced the paw licking time in the first and second phase of the formalin test and decreased the nociceptive threshold variation in the Randall–Selitto test. Furthermore, this dose reduced oedema formation, leucocyte migration (specifically through reduction in polymorphonuclear cell movement) and increased mononuclear cells. MPO activity and the levels of pro-inflammatory cytokines TNF-α were decreased. Evaluation of PLA2 inhibition via the docking simulation revealed more interactions of LQFM043R(6) and LQFM044(7), data that corroborated the half-maximal inhibitory concentration ( IC50) of PLA2 inhibition in vitro. Therefore, LQFM011(5), LQFM043(6) and LQFM044(7) were classified with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) as category 4. Keywords Anti-inflammatory · Pyrazole · TNF-α · PLA2
* Ricardo Menegatti [email protected] 1
Laboratory of Medicinal Pharmaceutical Chemistry, College of Pharmacy, Federal University of Goiás, Goiâniam, GO, Brazil
Laboratory of Chromatography and Mass Spectrometry (LaCEM), Chemistry Institute, Federal University of Goiás, Goiânia, GO, Brazil
2
3
Institute of Health Sciences, Federal University of Mato Grosso, Sinop, MT, Brazil
4
Laboratory of Nuclear Magnetic Resonance, Chemistry Institute, Federal University of Goiás, Goiânia, GO, Brazil
5
Laboratory of Pharmacology and Cell Toxicology, Faculty of Pharmacy, Federal University of Goiás, Goiânia, GO, Brazil
6
Laboratory of Pharm
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