<i>N</i>-Hydroxy-<i>N</i>-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases
Alzheimer’s disease (AD) is a complex disorder characterized by impaired neurotransmission in cholinergic and monoaminergic neurons, which, in combination with the accumulation of misfolded proteins and increased oxidative stress, leads to the typical features of the disease at the biomolecular leve...
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/21/7437 |
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| author | Óscar M. Bautista-Aguilera José M. Alonso Marco Catto Isabel Iriepa Damijan Knez Stanislav Gobec José Marco-Contelles |
| author_facet | Óscar M. Bautista-Aguilera José M. Alonso Marco Catto Isabel Iriepa Damijan Knez Stanislav Gobec José Marco-Contelles |
| author_sort | Óscar M. Bautista-Aguilera |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is a complex disorder characterized by impaired neurotransmission in cholinergic and monoaminergic neurons, which, in combination with the accumulation of misfolded proteins and increased oxidative stress, leads to the typical features of the disease at the biomolecular level. Given the limited therapeutic success of approved drugs, it is imperative to explore rationally supported therapeutic approaches to combat this disease. The search for novel scaffolds that bind to different receptors and inhibit AD disease-related enzymes could lead to new therapeutic solutions. Here, we describe <i>N</i>-hydroxy-<i>N</i>-propargylamide hybrids <b>1</b>–<b>6</b>, which were designed by combining the structures of Contilisant—a multifunctional anti-AD ligand—and ferulic acid, a natural antioxidant with various other biological activities. Among the synthesized compounds, we identified compound <b>4</b> as a micromolar inhibitor of hAChE with a potent radical-scavenging capacity comparable to resveratrol and Trolox. In addition, compound <b>4</b> chelated copper(II) ions associated with amyloid <i>β</i> pathology, mitochondrial dysfunction, and oxidative stress. The promising in vitro activity combined with favorable drug-like properties and predicted blood-brain barrier permeability make compound <b>4</b> a multifunctional ligand that merits further studies at the biochemical and cellular levels. |
| first_indexed | 2024-03-09T18:48:03Z |
| format | Article |
| id | doaj.art-8078d56a965e4cc89b09a239954326f4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T18:48:03Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-8078d56a965e4cc89b09a239954326f42023-11-24T06:04:11ZengMDPI AGMolecules1420-30492022-11-012721743710.3390/molecules27217437<i>N</i>-Hydroxy-<i>N</i>-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine OxidasesÓscar M. Bautista-Aguilera0José M. Alonso1Marco Catto2Isabel Iriepa3Damijan Knez4Stanislav Gobec5José Marco-Contelles6Universidad de Alcalá, Departamento de Química Orgánica y Química Inorgánica, Ctra, Madrid-Barcelona Km 33.6, 28871 Alcalá de Henares, Madrid, SpainUniversidad de Alcalá, Departamento de Química Orgánica y Química Inorgánica, Ctra, Madrid-Barcelona Km 33.6, 28871 Alcalá de Henares, Madrid, SpainDepartment of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, ItalyUniversidad de Alcalá, Departamento de Química Orgánica y Química Inorgánica, Ctra, Madrid-Barcelona Km 33.6, 28871 Alcalá de Henares, Madrid, SpainUniversity of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, SloveniaUniversity of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, SloveniaLaboratory of Medicinal Chemistry (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, SpainAlzheimer’s disease (AD) is a complex disorder characterized by impaired neurotransmission in cholinergic and monoaminergic neurons, which, in combination with the accumulation of misfolded proteins and increased oxidative stress, leads to the typical features of the disease at the biomolecular level. Given the limited therapeutic success of approved drugs, it is imperative to explore rationally supported therapeutic approaches to combat this disease. The search for novel scaffolds that bind to different receptors and inhibit AD disease-related enzymes could lead to new therapeutic solutions. Here, we describe <i>N</i>-hydroxy-<i>N</i>-propargylamide hybrids <b>1</b>–<b>6</b>, which were designed by combining the structures of Contilisant—a multifunctional anti-AD ligand—and ferulic acid, a natural antioxidant with various other biological activities. Among the synthesized compounds, we identified compound <b>4</b> as a micromolar inhibitor of hAChE with a potent radical-scavenging capacity comparable to resveratrol and Trolox. In addition, compound <b>4</b> chelated copper(II) ions associated with amyloid <i>β</i> pathology, mitochondrial dysfunction, and oxidative stress. The promising in vitro activity combined with favorable drug-like properties and predicted blood-brain barrier permeability make compound <b>4</b> a multifunctional ligand that merits further studies at the biochemical and cellular levels.https://www.mdpi.com/1420-3049/27/21/7437cholinesterasesferulic acidmolecular modellingmonoamine oxidaseradical-scavengerantioxidant |
| spellingShingle | Óscar M. Bautista-Aguilera José M. Alonso Marco Catto Isabel Iriepa Damijan Knez Stanislav Gobec José Marco-Contelles <i>N</i>-Hydroxy-<i>N</i>-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases Molecules cholinesterases ferulic acid molecular modelling monoamine oxidase radical-scavenger antioxidant |
| title | <i>N</i>-Hydroxy-<i>N</i>-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases |
| title_full | <i>N</i>-Hydroxy-<i>N</i>-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases |
| title_fullStr | <i>N</i>-Hydroxy-<i>N</i>-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases |
| title_full_unstemmed | <i>N</i>-Hydroxy-<i>N</i>-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases |
| title_short | <i>N</i>-Hydroxy-<i>N</i>-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases |
| title_sort | i n i hydroxy i n i propargylamide derivatives of ferulic acid inhibitors of cholinesterases and monoamine oxidases |
| topic | cholinesterases ferulic acid molecular modelling monoamine oxidase radical-scavenger antioxidant |
| url | https://www.mdpi.com/1420-3049/27/21/7437 |
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