Pharmacological evaluation and molecular docking of new di-tert-butylphenol compound, LQFM-091, a new dual 5-LOX/COX inhibitor.

Abstract

Dual 5-LOX/COX inhibitors are potential new dual drugs to treat inflammatory conditions. This research aimed to design, synthesis and to evaluate the anti-inflammatory and antinociceptive effects of the new compound, which is derived from nimesulide and darbufelone lead compounds. The new dual inhibitor 5-LOX/COX has the possible advantage of gastrointestinal safety. A voltammetric experiment was conducted to observe the drug's antioxidative effect. A formalin test, a hot plate test and carrageenan-induced mechanical hyperalgesia were employed to evaluate the analgesic nature of LQFM-091. To evaluate anti-inflammatory activity, we measured edema, leukocyte count, myeloperoxidase activity and cytokines levels in carrageenan-induced inflammation tests. We elucidated the underlying mechanisms by assessing the interaction the with COXs and LOX enzymes by colorimetric screening assay and molecular docking. The lethal dose (LD50) was estimated using 3T3 Neutral Red Uptake assay. Our results indicate that the LQFM-091 prototype is a powerful antioxidant, as well as able to inhibit COX-1, COX-2 and LOX activities. LQFM091 was classified in GHS category 4 (300<LD50<2000mg/Kg). This prototype showed analgesic activity in the formalin test and decreased carrageenan-induced mechanical hyperalgesia. Furthermore, LQFM-091 reduced the paw edema induced by carrageenan and reduced the leukocyte count, myeloperoxidase activity, TNF-α and IL-1β levels in the pleural exudate. Another interesting finding was the absence of gastrointestinal lesions. These data indicate that LQFM-091 produced antinociceptive and anti-inflammatory effects while maintaining gastrointestinal safety. Furthermore, this compound presented a safe toxicological profile. Blocked COXs and LOX enzymes are important targets for manipulating the mechanism of this compound.

• Authors: Roberta Campos Lino, Daiany Priscila Bueno da Silva, Iziara Ferreira Florentino, Dayane Moreira da Silva, José Luís Rodrigues Martins, Daniel da Costa Batista, Karla Carneiro de Siqueira Leite, Bianca Villavicencio, Géssica A Vasconcelos, Andreia Luiza Pereira Silva, Renato Ivan de Ávila, Hugo Verli, Marize Campos Valadares, Eric de Souza Gil, Boniek G Vaz, Luciano M Lião, Ricardo Menegatti, Elson Alves Costa
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 106 Pg. 231-243 (Aug 30 2017) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 28599988 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• Cyclooxygenase Inhibitors
• Cytokines
• LQFM-091
• Lipoxygenase Inhibitors
• Phenols
• Sulfonamides
• Carrageenan
• Peroxidase
• Lipoxygenase
• Prostaglandin-Endoperoxide Synthases
• nimesulide

Topics

• 3T3 Cells
• Animals
• Carrageenan
• Cell Survival (drug effects)
• Cyclooxygenase Inhibitors (pharmacology, therapeutic use)
• Cytokines (immunology)
• Edema (chemically induced, drug therapy)
• Female
• Hot Temperature
• Hyperalgesia (chemically induced, drug therapy)
• Leukocyte Count
• Lipoxygenase (metabolism)
• Lipoxygenase Inhibitors (pharmacology, therapeutic use)
• Mice
• Molecular Docking Simulation
• Pain Measurement
• Peroxidase (immunology)
• Phenols (pharmacology, therapeutic use)
• Physical Stimulation
• Pleurisy (chemically induced, drug therapy, immunology)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Stomach Ulcer (chemically induced, drug therapy)
• Sulfonamides