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

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

  • Meira CS FIOCRUZ, Instituto Gonçalo Moniz, 40296-710 Salvador, BA, Brazil.
  • Dos Santos Filho JM UFPE, Centro de Tecnologia e Geociências, Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed(®), CEP 50740-521 Recife, PE, Brazil.
  • Sousa CC FIOCRUZ, Instituto Gonçalo Moniz, 40296-710 Salvador, BA, Brazil.
  • Anjos PS FIOCRUZ, Instituto Gonçalo Moniz, 40296-710 Salvador, BA, Brazil.
  • Cerqueira JV FIOCRUZ, Instituto Gonçalo Moniz, 40296-710 Salvador, BA, Brazil.
  • Dias Neto HA UFPE, Centro de Tecnologia e Geociências, Laboratory of Design and Synthesis Applied to Medicinal Chemistry-SintMed(®), CEP 50740-521 Recife, PE, Brazil.
  • da Silveira RG IFG, Campus Ceres, CEP 76300-000 Ceres, GO, Brazil.
  • Russo HM School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, CMU - Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland.
  • Wolfender JL School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, CMU - Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland.
  • Queiroz EF School of Pharmaceutical Sciences, EPGL, University of Geneva, University of Lausanne, CMU - Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland.
  • Moreira DRM FIOCRUZ, Instituto Gonçalo Moniz, 40296-710 Salvador, BA, Brazil.
  • Soares MBP FIOCRUZ, Instituto Gonçalo Moniz, 40296-710 Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, 41253-190 Salvador, BA, Brazil. Electronic address: milena@bahia.fiocruz.br.
Show more…
  • 2018-03-11
Published in:
  • Bioorganic & medicinal chemistry. - 2018
Anti-inflammatory agents
Hydrazones
Methylation
Peritonitis
Substituent effects
Animals
Anti-Inflammatory Agents
Cell Survival
Crystallography, X-Ray
Dinoprostone
Disease Models, Animal
Drug Design
G1 Phase Cell Cycle Checkpoints
Hydrazones
Immunologic Factors
Interleukin-1beta
Lipopolysaccharides
Macrophages, Peritoneal
Male
Mice
Mice, Inbred BALB C
Molecular Conformation
Nitric Oxide
Peritonitis
Structure-Activity Relationship
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/76539
Statistics
Document views: 11 File downloads: