Cinnamoyl- N -Acylhydrazone-Donepezil Hybrids: Synthesis and Evaluation of Novel Multifunctional Ligands Against Neurode
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ORIGINAL PAPER
Cinnamoyl‑N‑Acylhydrazone‑Donepezil Hybrids: Synthesis and Evaluation of Novel Multifunctional Ligands Against Neurodegenerative Diseases Cindy Juliet Cristancho Ortiz1 · Caio Miranda Damasio1 · Letizia Pruccoli2 · Nathália Fonseca Nadur3 · Luciana Luiza de Azevedo3 · Isabella Alvim Guedes4 · Laurent Emmanuel Dardenne4 · Arthur Eugen Kümmerle3 · Andrea Tarozzi2 · Claudio Viegas Jr.1 Received: 23 July 2020 / Revised: 25 September 2020 / Accepted: 7 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract A new series of ten multifunctional Cinnamoyl-N-acylhydrazone-donepezil hybrids was synthesized and evaluated as multifunctional ligands against neurodegenerative diseases. The molecular hybridization approach was based on the combination of 1-benzyl-4-piperidine fragment from the anti-Alzheimer AChE inhibitor donepezil (1) and the cinnamoyl subunit from curcumin (2), a natural product with remarkable antioxidant, neuroprotective and anti-inflammatory properties, using a N-acylhydrazone fragment as a spacer subunit. Compounds 4a and 4d showed moderate inhibitory activity towards AChE with IC50 values of 13.04 and 9.1 µM, respectively. In addition, compound 4a and 4d showed a similar predicted binding mode to that observed for donepezil in the molecular docking studies. On the other hand, compounds 4a and 4c exhibited significant radical scavenging activity, showing the best effects on the DPPH test and also exhibited a significant protective neuronal cell viability exposed to t-BuOOH and against 6-OHDA insult to prevent the oxidative stress in Parkinson’s disease. Similarly, compound 4c was capable to prevent the ROS formation, with indirect antioxidant activity increasing intracellular GSH levels and the ability to counteract the neurotoxicity induced by both OAβ1-42 and 3-NP. In addition, ADMET in silico prediction indicated that both compounds 4a and 4c did not show relevant toxic effects. Due to their above-mentioned biological properties, compounds 4a and 4c could be explored as lead compounds in search of more effective and low toxic small molecules with multiple neuroprotective effects for neurodegenerative diseases. Graphic Abstract
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11064-020-03148-2) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article
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Vol.:(0123456789)
Neurochemical Research
Keywords Cinnamoyl-N-acylhydrazone-donepezil hybrids MTDLs · Multifunctional ligands · Neurodegenerative diseases · Molecular hybridization
Introduction Neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis, are a heterogeneous group of neurological disorders caused by the progressive death of neurons in different regions of the nervous system, leading to locomotion and behavior impairments, cognitive decline and deme
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