As part of our efforts to develop sustainable drugs for Alzheimer's disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liquid (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compounds with concomitant anti-amyloid and antioxidant activities. Ten new derivatives, carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). 5 and 11 were found to inhibit human BChE at a single-digit micromolar concentration. Transmission electron microscopy revealed the potential of five derivatives to modulate Aβ aggregation, including 5 and 11. In HORAC assays, 5 and 11 performed similarly to standard antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in in vitro studies in neuronal cell cultures, 5 and 11 were found to effectively inhibit reactive oxygen species production at a 10 μM concentration. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD.

Biomedical Research Centre University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic

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 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

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence Trebesska 1575 500 01 Hradec Kralove Czech Republic

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

Tanz Centre for Research in Neurodegenerative Diseases and Dept of Medical Biophysics University of Toronto Krembil Discovery Tower 60 Leonard Avenue 6KD 402 M5T 2S8 Toronto ON Canada

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