The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 μM), confirming the design rationale.

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

Département de Toxicologie et Risques Chimiques Institut de Recherche Biomédicale des Armées 91220 Brétigny sur Orge France

Department for Life Quality Studies Alma Mater Studiorum University of Bologna Corso d'Augusto 237 47921 Rimini Italy

Department of Pharmacy and Biotechnology Alma Mater Studiorum 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

School of Pharmacy University of Camerino Via Madonna delle Carceri 9 62032 Camerino MC Italy

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