Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 μM, and a similar inhibition profile of the human isoform (IC50 = 5.7 μM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 μM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.

Biomedical Research Centre University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic; National Institute of Mental Health Topolová 748 250 67 Klecany Czech Republic

Biomedical Sciences Institute Federal University of Rio de Janeiro 21941 902 Rio de Janeiro RJ Brazil

CENAUREMN Department of Organic and Inorganic Chemistry Federal University of Ceará 60021 970 Fortaleza CE Brazil

Chemistry Institute University of Brasília Campus Universitário Darcy Ribeiro 70910 900 Brasília DF Brazil

Department for Life Quality Studies University of Bologna Corso D'Augusto 237 47921 Rimini Italy

Department of Pharmacy and Biotechnology University of Bologna Via Belmeloro 6 40126 Bologna Italy

Department of Pharmacy Health Sciences Faculty University of Brasília Campus Universitário Darcy Ribeiro 70910 900 Brasília DF Brazil; LADETER Catholic University of Brasília QS 07 Lote 01 EPCT Águas Claras 71966 700 Brasília DF Brazil

LICC Laboratório Integrado de Computação Científica NUPEM Federal University of Rio de Janeiro 27901 000 Macaé RJ Brazil

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