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

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Ribeiro, D (Author) Other; Poenca, C (Author) Other; Varela, C (Author) Other; Janela, J (Author) Other; da Silva, EJT (Author) Other; Eduarda Fernandes (Author) FFUP; Roleira, FMF (Author) Other

Journal

Title: Bioorganic Chemistry

Vol. 91

ISSN: 0045-2068

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 8 Citations

Other information

Authenticus ID: P-00Q-Y5K

DOI: 10.1016/j.bioorg.2019.103179

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10