Synthesis and Identification of Small Compounds Active in Neurodegeneration

A special issue of Chemistry (ISSN 2624-8549). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 12088

Special Issue Editors


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Guest Editor
Department of Pharmacy, University “G. D’Annunzio”, Chieti, Italy
Interests: antioxidants; bioactive compounds; small molecules; polyphenols; antibacterial activity; anticancer activity; medicinal chemistry; synthesis
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Guest Editor
Justus Liebig University Giessen, Giessen, Germany
Interests: brain aging; neurodegenerative diseases; food-based prevention; pharmacological intervention; mitochondrial function
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s Disease, affect millions of people worldwide and are increasingly recognized as one of the most prevalent disorders with high burden to the patients, their families, and society. Despite substantial effort to advance the understanding of the etiology and potential treatment of neurodegeneration, information is still incomplete because many potential mechanisms are implicated in neurodegenerative pathology such as neuroinflammation, mitochondrial dysfunction and disequilibrium in protein homeostasis, aging, genetic variants, traumatic injury, oxidative stress, inflammation, toxic exposure and stress. However, very few drugs have been successful for the treatment of CNS diseases, and the therapeutic efficacy is greatly limited by many factors such as ineffective transport of drugs across the Blood-Brain Barrier (BBB). Different molecular properties (molecular size, hydrophilicity, dissociation degree, etc.) are fundamental to cross the BBB, and optimization of these parameters still remains a significant challenge in the development of neurological therapeutics. Natural sources and chemical synthesis are two options for developing novel neuroprotective drug candidates. The aim of this Special Issue is to spot recent advances in “Synthesis and Identification of Small Compounds Active in Neurodegeneration”, including original research papers or up-to-date, comprehensive reviews, highlighting recent identification of synthetic as well as small, natural-based molecules regarding the use of nanomaterials as versatile drug transport systems across BBB. We believe this Special Issue is a relevant and timely one, and we look forward to receiving your contributions.

You may choose our Joint Special Issue in Molecules.

Dr. Barbara De Filippis
Prof. Dr. Gunter P. Eckert
Guest Editors

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Keywords

  • small active compounds
  • food chemistry
  • neurodegenerative diseases
  • medicinal and pharmaceutical chemistry
  • BBB
  • synthesis
  • nanoformulations

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Published Papers (4 papers)

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Research

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19 pages, 14791 KiB  
Article
Homotaurine and Curcumin Analogues as Potential Anti-Amyloidogenic Agents
by Jose Paredes Quiroz, Andi Zeng, Michelle Young, Patrick Gordon, Aadya Jaipuria, Kristi J. Reed, Greg M. Landry, Suhui Yang, Shreya Asher, Sabrina Ruoyao Chen Zhang and Ronny Priefer
Chemistry 2023, 5(1), 223-241; https://doi.org/10.3390/chemistry5010018 - 07 Feb 2023
Viewed by 1515
Abstract
Currently, there is neither a cure for Alzheimer’s disease (AD) nor a way to stop the progressive death of neuronal cells associated with this devastating aliment. To date, there are only medications that temporarily slow its progression, and do not interfere with its [...] Read more.
Currently, there is neither a cure for Alzheimer’s disease (AD) nor a way to stop the progressive death of neuronal cells associated with this devastating aliment. To date, there are only medications that temporarily slow its progression, and do not interfere with its pathogenesis. One of the hallmarks of AD is the presence of amyloid-beta plaques derived from the metabolism of the amyloid precursor protein, via the cleavage by beta followed by gamma secretase. Homotaurine, a naturally occurring small molecule found in some seaweeds, and curcumin, a phenolic antioxidant found in Curcuma longa, have been extensively studied as potential compounds to prevent/reverse plaque formation. In this study, libraries of chalcones and extended chalcones based on curcumin, as well as aminopropylsulfonamides inspired by homotaurine, were synthesized. Using fluorescence spectroscopic analysis with Thioflavin T, the anti-aggregation effect on Aβ42 was determined. A select number of newly synthesized chalcones and extended chalcone analogs were revealed to be potential anti-amyloidogenic agents. These were further evaluated with regard to their neurotoxicity/neuroprotection. The extended chalcone analogs that displayed the most anti-aggregation effect on Aβ42 were further analyzed in an MTT assay. Although none of the compounds alone displayed any neurotoxicity, none were able to provide neuroprotection against Aβ42. Full article
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14 pages, 4032 KiB  
Article
Piperine Derivatives Enhance Fusion and Axonal Transport of Mitochondria by Activating Mitofusins
by Lihong Zhang, Xiawei Dang, Antonietta Franco, Haiyang Zhao and Gerald W. Dorn II
Chemistry 2022, 4(3), 655-668; https://doi.org/10.3390/chemistry4030047 - 23 Jun 2022
Cited by 6 | Viewed by 2990
Abstract
Piperine (1-piperoylpiperidine) is the major pungent component of black pepper (Piper nigrum) and exhibits a spectrum of pharmacological activities. The molecular bases for many of piperine’s biological effects are incompletely defined. We noted that the chemical structure of piperine generally conforms [...] Read more.
Piperine (1-piperoylpiperidine) is the major pungent component of black pepper (Piper nigrum) and exhibits a spectrum of pharmacological activities. The molecular bases for many of piperine’s biological effects are incompletely defined. We noted that the chemical structure of piperine generally conforms to a pharmacophore model for small bioactive molecules that activate mitofusin (MFN)-mediated mitochondrial fusion. Piperine, but not its isomer chavicine, stimulated mitochondrial fusion in MFN-deficient cells with EC50 of ~8 nM. We synthesized piperine analogs having structural features predicted to optimize mitofusin activation and defined structure-activity relationships (SAR) in live-cell mitochondrial elongation assays. When optimal spacing was maintained between amide and aromatic groups the derivatives were potent mitofusin activators. Compared to the prototype phenylhexanamide mitofusin activator, 2, novel molecules containing the piperidine structure of piperine exhibited markedly enhanced passive membrane permeability with no loss of fusogenic potency. Lead compounds 5 and 8 enhanced mitochondrial motility in cultured murine Charcot-Marie-Tooth disease type 2A (CMT2A) neurons, but only 8 improved mitochondrial transport in sciatic nerve axons of CMT2A mice. Piperine analogs represent a new chemical class of mitofusin activators with potential pharmaceutical advantages. Full article
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Review

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20 pages, 2618 KiB  
Review
Questions in the Chemical Enzymology of MAO
by Rona R. Ramsay and Alen Albreht
Chemistry 2021, 3(3), 959-978; https://doi.org/10.3390/chemistry3030069 - 31 Aug 2021
Cited by 5 | Viewed by 3108
Abstract
We have structure, a wealth of kinetic data, thousands of chemical ligands and clinical information for the effects of a range of drugs on monoamine oxidase activity in vivo. We have comparative information from various species and mutations on kinetics and effects of [...] Read more.
We have structure, a wealth of kinetic data, thousands of chemical ligands and clinical information for the effects of a range of drugs on monoamine oxidase activity in vivo. We have comparative information from various species and mutations on kinetics and effects of inhibition. Nevertheless, there are what seem like simple questions still to be answered. This article presents a brief summary of existing experimental evidence the background and poses questions that remain intriguing for chemists and biochemists researching the chemical enzymology of and drug design for monoamine oxidases (FAD-containing EC 4.1.3.4). Full article
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18 pages, 1891 KiB  
Review
Carbon Monoxide Therapy Using Hybrid Carbon Monoxide-Releasing/Nrf2-Inducing Molecules through a Neuroprotective Lens
by Flavia Cavicchioli, Izzy M. Cesarotti, Madison Fangman, Josh Lua, Raymond Hautamaki and Sylvain Doré
Chemistry 2021, 3(3), 800-817; https://doi.org/10.3390/chemistry3030057 - 23 Jul 2021
Cited by 2 | Viewed by 3169
Abstract
Carbon monoxide (CO) has long been known for its toxicity. However, in recent decades, new applications for CO as a therapeutic compound have been proposed, and multiple forms of CO therapy have since been developed and studied. Previous research has found that CO [...] Read more.
Carbon monoxide (CO) has long been known for its toxicity. However, in recent decades, new applications for CO as a therapeutic compound have been proposed, and multiple forms of CO therapy have since been developed and studied. Previous research has found that CO has a role as a gasotransmitter and promotes anti-inflammatory and antioxidant effects, making it an avenue of interest for medicine. Such effects are possible because of the Nrf2/HO1 pathway, which has become a target for therapy development because its activation also leads to CO release. Currently, different forms of treatment involving CO include inhaled CO (iCO), carbon monoxide-releasing molecules (CORMs), and hybrid carbon monoxide-releasing molecules (HYCOs). In this article, we review the progression of CO studies to develop possible therapies, the possible mechanisms involved in the effects of CO, and the current forms of therapy using CO. Full article
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