Journal
BIOORGANIC CHEMISTRY
Volume 91, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.103179
Keywords
Phenolic cinnamic acids; Phenolic cinnamic amides; Synthesis; COX-1 inhibition; Selective COX-2 inhibition; Structure-activity relationships
Funding
- Fundacao para a Ciencia e Tecnologia (FCT) [UID/QUI/50006/2019]
- Ministerio da Ciencia, Tecnologia e Ensino Superior (MCTES)
- Ministerio da Ciencia, Tecnologia e Ensino Superior (MCTES) through Programa Operacional Competitividade e Internacionalizacao (COMPETE) [POCI-01-0145-FEDER-029253]
- FCT [SFRH/BD/116005/2016]
- Fundo Social Europeu (FSE)
- FEDER -European Regional Development Fund through the COMPETE Programme (Operational Programme for Competitiveness)
- FCT - Fundacao para a Ciencia e a Tecnologia (Portuguese Foundation for Science and Technology) [REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07-CT62-FEDER-002012]
- FCT - Fundacao para a Ciencia e a Tecnologia (Portuguese Foundation for Science and Technology) through Rede Nacional de Ressonancia Magnetica Nuclear (RNRMN)
- Fundação para a Ciência e a Tecnologia [SFRH/BD/116005/2016] Funding Source: FCT
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Selective inhibition of cyclooxygenase (COX)-2 enzyme is an important achievement when looking for potent anti-inflammatory agents, with fewer gastrointestinal side effects. In this work, a new series of cinnamic acid derivatives, namely hexylamides, have been designed, synthesized and evaluated in human blood for their inhibitory activity of COX-1 and COX-2 enzymes. From this, new structure-activity relationships were built, showing that phenolic hydroxyl groups are essential for both COX-1 and COX-2 inhibition. Furthermore, the presence of bulky hydrophobic di-tert-butyl groups in the phenyl ring strongly contributes for selective COX-2 inhibition. In addition, a correlation with the theoretical log P has been carried out, showing that lipophilicity is particularly important for COX-2 inhibition. Further, a plasma protein binding (PPB) prediction has been performed revealing that PPB seems to have no influence in the activity of the studied compounds. From the whole study, effective selective inhibitors of COX-2 were found, namely compound 9 (IC50 = 3.0 +/- 0.3 mu M), 10 (IC50 = 2.4 +/- 0.6 mu M) and 23 (IC50 = 1.09 +/- 0.09 mu M). Those can be considered starting point hit compounds for further optimization as potential non-steroidal anti-inflammatory drugs.
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