1. Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer’s Disease
- Author
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Florian Nachon, Ondrej Soukup, Luciana de Camargo Nascente, Fabien Chantegreil, Michele Rossi, Marco Malaguti, Maria Laura Bolognesi, Sarah de Melo Viana Teixeira, Michela Freschi, Silvana Hrelia, Manuela Bartolini, Alessandra Salerno, Luiz Antonio Soares Romeiro, Christian Bergamini, Cristina Angeloni, Lukas Prchal, and Rossi M, Freschi M, de Camargo Nascente L, Salerno A, de Melo Viana Teixeira S, Nachon F, Chantegreil F, Soukup O, Prchal L, Malaguti M, Bergamini C, Bartolini M, Angeloni C, Hrelia S, Soares Romeiro LA, Bolognesi ML.
- Subjects
Lipopolysaccharides ,Cell Survival ,Molecular Dynamics Simulation ,Pharmacology ,Ligands ,01 natural sciences ,Neuroprotection ,Article ,Cell Line ,ACETYLCHOLINESTERASE ,NEUROINFLAMMATION ,BUTYRYLCHOLINESTERASE ,MICROGLIA ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Multi target ,Alzheimer Disease ,Catalytic Domain ,Drug Discovery ,medicine ,Humans ,Nuts ,Anacardium ,CRYSTAL-STRUCTURE ,Neuroinflammation ,Butyrylcholinesterase ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Binding Sites ,Plant Extracts ,Chemistry ,Drug discovery ,Acetylcholinesterase ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Neuroprotective Agents ,SUSTAINABLE DRUG DISCOVERY ,Enzyme ,ALZHEIMER'S DISEASE ,Drug Design ,Tacrine ,Cytokines ,Molecular Medicine ,TACRINE HYBRIDS ,medicine.drug - Abstract
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 mu M), confirming the design rationale.
- Published
- 2021