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https://www.arca.fiocruz.br/handle/icict/25933
STRUCTURAL DESIGN, SYNTHESIS AND SUBSTITUENT EFFECT OF HYDRAZONE-N-ACYLHYDRAZONES REVEAL POTENT IMMUNOMODULATORY AGENTS
Hidrazonas
Metilação
Peritonite
Efeitos Substituintes
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Universidade Federal de Pernambuco. Centro de Tecnologia e Geociências. Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed., Recife, PE, Brazil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Universidade Federal de Pernambuco. Centro de Tecnologia e Geociências. Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed., Recife, PE, Brazil
Instituto Federal Goiano. Ceres, GO, Brasil
University of Geneva, University of Lausanne. School of Pharmaceutical Sciences. Geneva, Switzerland
University of Geneva, University of Lausanne. School of Pharmaceutical Sciences. Geneva, Switzerland
University of Geneva, University of Lausanne. School of Pharmaceutical Sciences. Geneva, Switzerland
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Universidade Federal de Pernambuco. Centro de Tecnologia e Geociências. Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed., Recife, PE, Brazil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Universidade Federal de Pernambuco. Centro de Tecnologia e Geociências. Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed., Recife, PE, Brazil
Instituto Federal Goiano. Ceres, GO, Brasil
University of Geneva, University of Lausanne. School of Pharmaceutical Sciences. Geneva, Switzerland
University of Geneva, University of Lausanne. School of Pharmaceutical Sciences. Geneva, Switzerland
University of Geneva, University of Lausanne. School of Pharmaceutical Sciences. Geneva, Switzerland
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Abstract
4-(Nitrophenyl)hydrazone derivatives of N-acylhydrazone were synthesized and screened for suppress lymphocyte proliferation and nitrite inhibition in macrophages. Compared to an unsubstituted N-acylhydrazone, active compounds were identified within initial series when hydroxyl, chloride and nitro substituents were employed. Structure-activity relationship was further developed by varying the position of these substituents as well as attaching structurally-related substituents. Changing substituent position revealed a more promising compound series of anti-inflammatory agents. In contrast, an N-methyl group appended to the 4-(nitrophenyl)hydrazone moiety reduced activity. Anti-inflammatory activity of compounds is achieved by modulating IL-1β secretion and prostaglandin E2 synthesis in macrophages and by inhibiting calcineurin phosphatase activity in lymphocytes. Compound SintMed65 was advanced into an acute model of peritonitis in mice, where it inhibited the neutrophil infiltration after being orally administered. In summary, we demonstrated in great details the structural requirements and the underlying mechanism for anti-inflammatory activity of a new family of hydrazone-N-acylhydrazone, which may represent a valuable medicinal chemistry direction for the anti-inflammatory drug development in general.
Keywords in Portuguese
Agentes anti-inflamatóriosHidrazonas
Metilação
Peritonite
Efeitos Substituintes
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