Synthesis, in vitro and in vivo biological evaluation,COX-1/2 inhibition and molecular docking study of indole-N-acylhydrazone derivatives |
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Authors: | Ana Daura Travassos de Oliveira Moraes Mirelly Dianne Santos de Miranda Íris Trindade Tenório Jacob Cézar Augusto da Cruz Amorim Ricardo Olímpio de Moura Simone Ângela Soares da Silva Milena Botelho Pereira Soares Sinara Mônica Vitalino de Almeida Túlio Ricardo Couto de Lima Souza Jamerson Ferreira de Oliveira Teresinha Gonçalves da Silva Cristiane Moutinho Lagos de Melo Diogo Rodrigo Magalhães Moreira Maria do Carmo Alves de Lima |
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Institution: | 1. Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos (DANTI), 50670-901 Recife, PE, Brazil;2. Universidade Estadual da Paraíba (UEPB), Departamento de Farmácia, 58429-500 Campina Grande, PB, Brazil;3. Fundação Oswaldo Cruz, Centro de Pesquisa Gonçalo Moniz/Laboratório de Engenharia Tecidual e Imunofarmacologia, 40296-710 Salvador, BA, Brazil;4. Universidade de Pernambuco (UPE), Faculdade de Ciências, Educação e Tecnologia de Garanhuns (FACETEG), 55290-000 Garanhuns, PE, Brazil;5. Universidade Federal Rural de Pernambuco (UFRPE), Unidade Acadêmica de Serra Talhada (UAST), 56909-535 Serra Talhada, PE, Brazil |
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Abstract: | The objective of this work was to obtain and evaluate anti-inflammatory in vitro, in vivo and in silico potential of novel indole-N-acylhydrazone derivatives. In total, 10 new compounds (3a–j) were synthesized in satisfactory yields, through a condensation reaction in a single synthesis step. In the lymphoproliferation assay, using mice splenocytes, 3a and 3b showed inhibition of lymphocyte proliferation of 62.7% (±3.5) and 50.7% (±2), respectively, while dexamethasone presented an inhibition of 74.6% (±2.4). Moreover, compound 3b induced higher Th2 cytokines production in mice splenocytes cultures. The results for COX inhibition assays showed that compound 3b is a selective COX-2 inhibitor, but with less potency when compared to celecoxib, and compound 3a not presented selectivity towards COX-2. The molecular docking results suggest compounds 3a and 3b interact with the active site of COX-2 in similar conformations, but not with the active site of COX-1, and this may be the main reason to the COX-2 selectivity of compound 3b. In vivo carrageenan-induced paw edema assays were adopted for the confirmation of the anti-inflammatory activity. Compound 3b showed better results in suppressing edema at all tested concentrations and was able to induce an edema inhibition of 100% after 5?h of carrageenan injection at the 30?mg?kg?1 dosage, corroborating with the COX inhibition and lymphoproliferation results. I addition to our experimental results, in silico analysis suggest that compounds 3a and 3b present a well-balanced profile between pharmacodynamics and pharmacokinetics. Thus, our preliminary results revealed the potentiality of a new COX-2 selective derivative in the modulation of the inflammatory process. |
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Keywords: | Inflammation Indoles COX Docking |
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