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

Publication date: 30 August 2017
Source:European Journal of Pharmaceutical Sciences, Volume 106
Author(s): 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
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.

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