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Renata Barbosa de Oliveirahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4797723H8&tokenCaptchar=03AFcWeA4x2qRVdEzboCWwnHqhpwn2lx81mK4sRgKWv5EHB1i7rBSWhsc1lzqQN9zMtOCAJhYgPMejWEgGdFFlJ2UkjWbDJ3RIiI3XShqC_p2vbsYMKuqqADo3a_SJx87beqpp1y5UJAd7xGGoDDzQnoSmqwd72lJqBND_mSc6JTkW55pC-vhZCGynw0fzoVImjDCUr1m2xQ8yiW2LiFI5NuiMRkxmqX0jx_n37y1wS4t2xBs-JIHdR2D8g0C2JJkbvMU5qito1mbi4qxrqBXfPLm_1Hu-2pJh-H4baAGiOMxSxDZb6Py9QYBv0Q1PeBwB2yscvzV2319i7fOP7koDuB-NYbgarL8s0xVKbdSioWlrvaLtxxvwW8VWztrL5qRrS6Uh92f0kN1uI4dZb3rA-0fYIlxwIjLF92rWsapHVsznPjsXw4NHUt2YWmx4Y2GKWkfTNoREuWF1ZDlTL6UHajHO3hMKf-UzG-M3rOWzUcOSnvs2hk25nK3XJWgFo5DA9DKRiO8d4NufzwNa_F6rdlnteG4m9dNo2ttlEj93wDpUjEjRvdwmvVLNV3cDrLBSKBdetBL_MMGSQrDtD4P_7_kbI4SjD8qCZkF-QqkWsWj0dGhUHCcNRsEThiago Belarmino de SouzaGustavo Henrique Ribeiro VianaÂngela Cristina Leal Badaró TrintadeRodrigo Maia de Páduahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4639230A7&tokenCaptchar=03AFcWeA61mjpUjuCfLl3TOICmnUzEJl8KowiXaY_-zTKJRrhAA9VVWmdeYDhg6fnqkkX34euXo7na9EwzjG-BUGPd4iXONcpJ0Huy91-qk8B4RJCvQeDcV9eVNOt0vAU4tAApbEYkHDWFzwnK9qpGoLtZJTi_ELCS6x6KTwCWeuZjH09EROJ5BpgajY3qnLlMVjKGc8YqZO8brQGA4T5Up2W0TvgenIIKn0a5vGfCnMdsT36IWB1U3xwRWFJPLE21LF5ETBQQ-1l-E96On9B3cr-2lRctbO67PedQQAib_0PnQNHDjOPBI8ixcMSv2p03p-nGo4ZWNYfGVSfeiPq70n1bbHdE9S93ZEpncHEA5M_QNJQWpgvD0Tt69d8YG7TNLdZvjj2q9icxct_j3CGcc-CIosTSfnGUyx_PEKQxfrkp-tGhFak7gz0eSCLkl7nRnNyFRCHntalIoQZ3i-wwISFu9s_Rv-IkxqHJbB6Ih9SQLkM9YxdG5C5fEyd6dGmSoZUuDl8YKxSsa1SG4NaWYuikm1S3drj6X2SLanOwtNH-P_sKC0ALMDmylk6PCGqKWHvjYo1jbccn_q1i_91qpDjnMP-SKFsd_SAUKzFgHpA9cAhHopyOVLwClêudiomar Inácio Lino2023-11-07T16:30:24Z2023-11-07T16:30:24Z2023-02-28http://hdl.handle.net/1843/60568A dor é considerada como uma experiência desagradável e envolve vários aspectos sensoriais e emocionais do indivíduo. O tratamento farmacológico da dor inclui os AINES como paracetamol, naproxeno e os derivados da morfina como codeína e fentanil. Ambas as classes apresentam vários efeitos adversos, os ANES são associados a sangramento gastrointestinal e úlceras e os derivados da morfina causam sedação, depressão respiratória e dependência. Novas alternativas para o manejo da dor são necessárias. Estudos de reposicionamento de fármacos permitiram a identificação do antibiótico clindamicina como potencial anti-inflamatório. Modificações moleculares na estrutura da clindamicina assim como síntese de análogos mais simples foram propostos com o intuído de estabelecer uma relação estrutura atividade antimicrobiana X anti-inflamatória. Neste contexto, foram sintetizados, no presente trabalho, derivados e análogos da clindamicina utilizando materiais de partida de fácil acesso (L-prolina, α-D-glicopiranosídeo de metila, N-metil-2-pirrolcarboxaldeído e clindamicina) e reações clássicas de síntese orgânica, tais como, alquilação, acetilação, redução, oxidação, aminação redutiva, amidação, reação de substituição nucleofílica e cicloadição 1,3-dipolar. Foram sintetizados no total 30 compostos sendo cinco inéditos (1a, 1b, 2, 10 e 11). Os compostos sintetizados foram submetidos a ensaios in vitro para avaliação da atividade antibacteriana. Após otimização das reações, os produtos foram obtidos, de forma geral, com bons rendimentos. A atividade anti-inflamatória do derivado peracetilado da clindamicina (2) foi avaliada em modelo murino com resultados comparáveis aos obtidos para a clindamicina. A principal vantagem deste derivado é que não apresentou atividade antimicrobiana in vitro. Nenhuma das substâncias sintetizadas apresentou atividade antimicrobiana, o que indica potencial seletividade em relação à atividade anti-inflamatória. Para confirmação desta premissa, a atividade anti-inflamatória dos demais compostos sintetizados será posteriormente avaliada. Os resultados obtidos nesse trabalho se mostraram promissores, abrindo novas perspectivas para síntese de outros análogos com possibilidade de otimização da atividade biológica.The pain is considered an unpleasant experience and involves several sensory and emotional aspects of the individual. The pharmacological one mainly includes NSAIDs such as paracetamol, naproxen, e morphine derivatives, such as codeine and fentanyl. It is well known that both NSAID classes and opioid derivatives have several adverse effects. The NSAID are associated with gastrointestinal bleeding and ulcers and the morphine derivatives are susceptible to sedation, respiratory depression and dependence. New alternatives for pain management are necessary. Drug repositioning studies allowed the identification of the antibiotic clindamycin as a potential anti-inflammatory drug. Molecular modifications in the structure of clindamycin, as well as the synthesis of analogues with a simpler chemical structure, were proposed with the aim of establishing a structure relationship between antimicrobial and anti-inflammatory activity. In this context, in the present work, derivatives and analogues of clindamycin were synthesized using easily accessible starting materials (L-proline, methyl α-D-glucopyranoside, N-methyl-2-pyrrolecarboxaldehyde and clindamycin) and classic reactions in organic synthesis, such as alkylation, acetylation, reduction, oxidation, reductive amination, amidation, nucleophilic substitution reaction and 1,3-dipolar cycloaddition A total of 30 compounds were synthesized, five of which were new (1a, 2, 10 and 11). The synthesized compounds were subjected to in vitro tests to evaluate their antibacterial activity. After optimizing the reactions, the products were generally obtained in good yields. The anti-inflammatory activity of the peracetylated clindamycin derivative (2) was evaluated in a murine model with results comparable to those obtained for clindamycin. The main advantage of this derivative is that it did not show antimicrobial activity in vitro. None of the synthesized substances showed antimicrobial activity, which indicates a potential selectivity in relation to anti-inflammatory activity. To confirm this premise, the anti-inflammatory activity of the synthesized substances will be further evaluated. The results obtained in this work were promising, opening new perspectives for the synthesis of other analogues with the possibility of optimizing the biological activity.porUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em Ciências FarmacêuticasUFMGBrasilFARMACIA - FACULDADE DE FARMACIAInflamaçãoClindamicinaAnti-inflamatórioDerivados e análogos da clindamicinaL-prolinaSíntese e avaliação da atividade anti-inflamatória e antibacteriana de derivados e análogos da clindamicina.Synthesis and evaluation of the anti-inflammatory and antibacterial activity of clindamycin derivatives and analogues.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALTESE FINAL Geral_Final 23.10..pdfTESE FINAL Geral_Final 23.10..pdfSíntese e avaliação da atividade anti-inflamatória e antibacteriana de derivados e análogos da clindamicinaapplication/pdf14271145https://repositorio.ufmg.br/bitstream/1843/60568/1/TESE%20FINAL%20%20Geral_Final%2023.10..pdf50c5d20c5e017b7b734b5f6a40b47854MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/60568/2/license.txtcda590c95a0b51b4d15f60c9642ca272MD521843/605682023-11-07 13:30:25.23oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-11-07T16:30:25Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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