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.
Rossi M, F.M. (2021). Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease. JOURNAL OF MEDICINAL CHEMISTRY, 64(8), 4972-4990 [10.1021/acs.jmedchem.1c00048].
Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease
Rossi MPrimo
Investigation
;Freschi MSecondo
Investigation
;Salerno AInvestigation
;Malaguti MInvestigation
;Bergamini CInvestigation
;Bartolini MInvestigation
;Angeloni CWriting – Original Draft Preparation
;Hrelia SWriting – Review & Editing
;Bolognesi ML.
Ultimo
Writing – Original Draft Preparation
2021
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.File | Dimensione | Formato | |
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JMedChem 2021 pdf editoriale.pdf
Open Access dal 09/04/2022
Descrizione: Rossi M et al 2021
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