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

Publication date: Available online 25 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Cássio S. Meira, José Maurício dos Santos Filho, Caroline C. Sousa, Pâmela S. Anjos, Jéssica V. Cerqueira, Humberto A. Dias Neto, Rafael G. da Silveira, Helena M. Russo, Jean-Luc Wolfender, Emerson F. Queiroz, Diogo R.M. Moreira, Milena B.P. Soares
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 antiinflammatory agents. In contrast, an N-methyl group appended to the 4-(nitrophenyl)hydrazone moiety reduced activity. Antiinflammatory 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 antiinflammatory activity of a new family of hydrazone-N-acylhydrazone, which may represent a valuable medicinal chemistry direction for the antiinflammatory drug development in general.

Graphical abstract

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