Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents

Article Article scientifique Article Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents eng 2018 author Meira Cássio S author Dos Santos Filho José Maurício author Sousa Caroline C author Anjos Pâmela S author Cerqueira Jéssica V author Dias Neto Humberto A author da Silveira Rafael G author Russo Blanco Helena 55020 author Wolfender Jean-Luc 135649 author Queiroz Emerson F author Moreira Diogo R M author Soares Milena B P 1971-1985 10.1016/j.bmc.2018.02.047 29523468 0968-0896 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. Dewey 615 31 Section des sciences pharmaceutiques 17 false 882 Phytochimie et produits naturels bioactifs Bioorganic & Medicinal Chemistry 26 8 c7248892-5e04-41bf-bfb2-5ddf3cab5e94 Article (Published version) Restricted Meira-2018-Structuraldesignsynthesis.pdf 2403248 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques

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Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents	Bioorganic & Medicinal Chemistry			2018	474	0

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