Design, Synthesis and Pharmacological Evaluation ofN‐Benzyl Linoleamide Analogues fromTropaeolum tuberosumas NF‐κB Inhibitors and Nrf2 Activators

Abstract

Nineteen N-benzyl linoleamide analogues (macamide from Tropaeolum tuberosum) were synthesised, modifying the molecular structure (benzyl position, aromatic ring and carbonyl group). The structures were confirmed using nuclear magnetic resonance and mass spectrometry techniques. Cell viability and anti-inflammatory activity of these compounds were evaluated in three brain cell lines (C8-D1 A, Neuro-2a, and EOC 13.31). Regarding the effect on NF-kB, several analogues had better inhibition potential than their natural precursor (N-benzyl linoleamide), being the N-(1-(3,5-dimethyl-α-methylbenzyl)-linolethiamide the most active, with IC 50 values of 0.01 � 0.01, 0.01 � 0.01 and 0.02 � 0.01 μM, respectively. Finally, all analogues activated Nrf2, with the same compound being the most active, presenting EC 50 values of 0.03 � 0.01, 0.07 � 0.01 and 0.11 � 0.02 nM, respectively. Analysing the link between chemical structure and pharmacological activity, our study shows that the changes made to N-benzyl linoleamide lead us to obtaining an analogue with greater anti-inflammatory activity than its precursor and with potential for the treatment of migraine.