Revisiting capsaicin and nonivamide: Their analogs exert strong inhibitory activity against cholinesterases

The scientific community has long been interested in capsaicin, and the extensive hunt for AChE and BChE enzyme inhibitors is still ongoing. In this investigation analogs of capsaicin, such as the pharmaceutical nonivamide, which is preferred in clinical settings for the topical treatment of pain, were explored in the search for appropriate inhibitors. Thus, to test their inhibitory effect on AChE and BChE, we synthesized a short series of derivatives derived from vanillylamide. Consequently, it was discovered that compounds 12 , 34 , and 35 , which have K i values in the sub-micromolar concentration range, are especially effective inhibitors. Compound 12 demonstrated dual mixed-type (competitive/uncompetitive) inhibitory activity for both enzymes; compound 34 showed selective mixed-type inhibitory activity for AChE, and compound 35 was found to have selective uncompetitive activity for AChE. • Capsaicin is the bioactive constituent in red hot chili peppers. • Capsaicin is no inhibitor of acetylcholinesterases (AChE or BChE). • Analogs derived from (di)-vanillylamine were strong inhibitors of these enzymes. • Inhibition >99 % and sub-micromolar K i values were achieved. • Analogs acted either as mixed-type or uncompetitive inhibitor.