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  3. New phenolic cinnamic acid derivatives as selective COX-2 inhibitors. Design, synthesis, biological activity and structure-activity relationships

New phenolic cinnamic acid derivatives as selective COX-2 inhibitors. Design, synthesis, biological activity and structure-activity relationships

  • Bioorg Chem. 2019 Oct:91:103179. doi: 10.1016/j.bioorg.2019.103179.
Daniela Ribeiro 1,  Carina Proença 1,  Carla Varela 2,  João Janela 3,  Elisiário J Tavares da Silva 2,  Eduarda Fernandes 4,  Fernanda M F Roleira 5
Affiliations

Affiliations

  • 1 LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
  • 2 Pharmaceutical Chemistry Laboratory, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CIEPQPF Centre for Chemical Processes Engineering and Forest Products, University of Coimbra, 3030-790 Coimbra, Portugal.
  • 3 Pharmaceutical Chemistry Laboratory, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
  • 4 LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal. Electronic address: egracas@ff.up.pt.
  • 5 Pharmaceutical Chemistry Laboratory, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CIEPQPF Centre for Chemical Processes Engineering and Forest Products, University of Coimbra, 3030-790 Coimbra, Portugal. Electronic address: froleira@ff.uc.pt.
PMID: 31404794 DOI: 10.1016/j.bioorg.2019.103179
Abstract

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 μM), 10 (IC50 = 2.4 ± 0.6 μM) and 23 (IC50 = 1.09 ± 0.09 μM). Those can be considered starting point hit compounds for further optimization as potential non-steroidal anti-inflammatory drugs.

Keywords

COX-1 inhibition; Phenolic cinnamic acids; Phenolic cinnamic amides; Selective COX-2 inhibition; Structure-activity relationships; Synthesis.

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