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.

• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   patologie   MeSH
• Anacardium chemie   metabolismus   MeSH
• buněčné linie MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• katalytická doména MeSH
• lidé MeSH
• ligandy * MeSH
• lipopolysacharidy farmakologie   MeSH
• mikroglie cytologie   účinky léků   metabolismus   MeSH
• neuroprotektivní látky chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• ořechy chemie   metabolismus   MeSH
• racionální návrh léčiv MeSH
• rostlinné extrakty chemie   MeSH
• simulace molekulární dynamiky MeSH
• takrin chemie   metabolismus   MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cytokiny MeSH
• ligandy * MeSH
• lipopolysacharidy MeSH
• neuroprotektivní látky MeSH
• rostlinné extrakty MeSH
• takrin MeSH