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Antioxidants
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Multitarget Directed Antioxidants for Stroke
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Multitarget Directed Antioxidants for Stroke

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 8642

Special Issue Editor

Prof. Dr. José Luis Marco-Contelles

E-Mail Website
Guest Editor
Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain
Interests: Alzheimer’s disease; biological evaluation; drug discovery; medicinal chemistry; molecular design; neurodegenerative diseases; stroke; synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oxidative stress is a common event that occurs in neurovascular diseases, such as stroke. At present, there is no efficient and effective cure for stroke; consequently, therapies based on the development of novel natural or synthetic antioxidant agents, able to scavenge toxic-free radicals, are extremely appealing therapeutic approaches. The complex nature of cerebral ischemia has prompted the therapeutic shift towards multitarget, single molecular entities that are able to inhibit/modulate a number of relevant biological targets involved in the progress and development of stroke. The Special Issue “Multitarget Directed Antioxidants for Stroke” will provide updated information regarding the multifaceted research progress in stroke therapy. Original papers, communications and reviews that cover topics such as rational design, the discovery of antioxidants, neuroprotectants, the development of multitarget compounds,  and repositioning approaches are all welcome.

Prof. Dr. José Luis Marco-Contelles
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antioxidants
  • biological activity
  • chemical synthesis
  • drug discovery
  • molecular modeling
  • multitarget small molecules
  • neuroprotection
  • polypharmacology
  • repositioning drugs
  • stroke

Published Papers (4 papers)

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Research

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13 pages, 2143 KiB  
Article
Synthesis and Antioxidant Properties of Novel 1,2,3-Triazole-Containing Nitrones
by Dimitra Hadjipavlou-Litina, Iwona E. Głowacka, José Marco-Contelles and Dorota G. Piotrowska
Antioxidants 2023, 12(1), 36; https://doi.org/10.3390/antiox12010036 - 24 Dec 2022
Cited by 4 | Viewed by 1599
Abstract
Herein, we report the synthesis and antioxidant capacity of twelve novel 1,2,3-triazole-containing nitrones such as N-(2-(4-aryl-1H-1,2,3-triazol-1-yl)ethylidene)methanamine oxides 8a–f and N-(2-(4-aryl)-1H-1,2,3-triazol-1-yl)ethylidene)-2-methylpropan-2-amine oxides 9a–f, bearing an N-methyl, and an N-t-butyl substituent, respectively, [...] Read more.
Herein, we report the synthesis and antioxidant capacity of twelve novel 1,2,3-triazole-containing nitrones such as N-(2-(4-aryl-1H-1,2,3-triazol-1-yl)ethylidene)methanamine oxides 8a–f and N-(2-(4-aryl)-1H-1,2,3-triazol-1-yl)ethylidene)-2-methylpropan-2-amine oxides 9a–f, bearing an N-methyl, and an N-t-butyl substituent, respectively, at the nitrogen of the nitrone motif. Nitrones 8 and 9 were studied with regard to their antioxidant ability, as well as their ability to inhibit soybean lypoxygenase (LOX), and their in vitro antioxidant activity. For this, we used three different antioxidant assays, such as that featuring the interaction with the water-soluble azo compound AAPH for the inhibition of lipid peroxidation (LP), the competition with the DMSO for scavenging hydroxyl radicals, and the ABTS•+–decolorization assay. t-Butyl nitrone 9e, bearing the 2,4-difluorophenyl motif, showed a strong LP inhibitory effect (100%), close to the reference compound Trolox (93%), being the most potent LP inhibitor (LPi) of the whole series of tested nitrones. Nitrones 9d, 9e and 9f, bearing the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, were almost equipotent, and the most potent hydroxyl radical scavengers (~100%), more potent than Trolox (88%), were used as a reference compound. Regarding the LOX inhibition, the most potent inhibitor was the t-butyl substituted nitrone 9f (27 μM), bearing the 4-fluoro-3-methylphenyl motif, being 60-fold less potent than NDGA (0.45 μM), which was used as the standard in this test. The results from the antioxidant determination in the ABTS radical cation (ABTS•+) decolorization assay were not significant. N-Methyl nitrone 8f, bearing the 4-fluoro-3-methylphenyl motif, was the only promising representative, with a value of 34.3%, followed by nitrone 9f (16%). From the antioxidant analyses, we have identified N-(2-(4-(4-fluoro-3-methylphenyl)-1H-1,2,3-triazol-1-yl)ethylidene)-2-methylpropan-2-amine oxide (9f), bearing t-butyl and 4-fluoro-3-methylphenyl motifs in its structure, as the most balanced and potent antioxidant agent among the tested nitrones, as it was the most potent LOX inhibitor (27 μM), an extremely efficient and potent hydroxyl radical scavenger (99.9%), as well as one of the most potent LPi (87%) and ABTS•+ scavengers (16%). Full article
(This article belongs to the Special Issue Multitarget Directed Antioxidants for Stroke)
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20 pages, 2162 KiB  
Article
Polyfunctionalized α-Phenyl-tert-butyl(benzyl)nitrones: Multifunctional Antioxidants for Stroke Treatment
by Daniel Diez-Iriepa, Damijan Knez, Stanislav Gobec, Isabel Iriepa, Cristóbal de los Ríos, Isaac Bravo, Francisco López-Muñoz, José Marco-Contelles and Dimitra Hadjipavlou-Litina
Antioxidants 2022, 11(9), 1735; https://doi.org/10.3390/antiox11091735 - 31 Aug 2022
Cited by 3 | Viewed by 1637
Abstract
Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on stroke, a more tolerable and efficient therapy for [...] Read more.
Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on stroke, a more tolerable and efficient therapy for stroke is being sought that focuses on the control and scavenging of highly toxic reactive oxygen species by appropriate small molecules, such as nitrones with antioxidant properties. In this context, herein we report here the synthesis, antioxidant, and neuroprotective properties of twelve novel polyfunctionalized α-phenyl-tert-butyl(benzyl)nitrones. The antioxidant capacity of these nitrones was investigated by various assays, including the inhibition of lipid peroxidation induced by AAPH, hydroxyl radical scavenging assay, ABTS+-decoloration assay, DPPH scavenging assay, and inhibition of soybean lipoxygenase. The inhibitory effect on monoamine oxidases and cholinesterases and inhibition of β-amyloid aggregation were also investigated. As a result, (Z)-N-benzyl-1-(2-(3-(piperidin-1-yl)propoxy)phenyl)methanimine oxide (5) was found to be one of the most potent antioxidants, with high ABTS+ scavenging activity (19%), and potent lipoxygenase inhibitory capacity (IC50 = 10 µM), selectively inhibiting butyrylcholinesterase (IC50 = 3.46 ± 0.27 µM), and exhibited neuroprotective profile against the neurotoxicant okadaic acid in a neuronal damage model. Overall, these results pave the way for the further in-depth analysis of the neuroprotection of nitrone 5 in in vitro and in vivo models of stroke and possibly other neurodegenerative diseases in which oxidative stress is identified as a critical player. Full article
(This article belongs to the Special Issue Multitarget Directed Antioxidants for Stroke)
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9 pages, 729 KiB  
Article
Synthesis and Antioxidant Properties of HeteroBisNitrones Derived from Benzene Dicarbaldehydes
by Daniel Diez-Iriepa, Isabel Iriepa, Francisco López-Muñoz, José Marco-Contelles and Dimitra Hadjipavlou-Litina
Antioxidants 2022, 11(8), 1575; https://doi.org/10.3390/antiox11081575 - 15 Aug 2022
Cited by 2 | Viewed by 1367
Abstract
We report herein the synthesis and antioxidant profile of nine novel heterobisnitrones (hBNs) as new α-phenyl-tert-butylnitrone (PBN) analogues. The synthesized hBNs 1–9 were evaluated for their antioxidant activity using different in vitro techniques, while they were also tested as inhibitors [...] Read more.
We report herein the synthesis and antioxidant profile of nine novel heterobisnitrones (hBNs) as new α-phenyl-tert-butylnitrone (PBN) analogues. The synthesized hBNs 1–9 were evaluated for their antioxidant activity using different in vitro techniques, while they were also tested as inhibitors of soybean LOX, as an indication of their anti-inflammatory effect. Nitrone hBN9 is the most potent antioxidant presenting higher anti-lipid peroxidation and hydroxyl radicals scavenging activities as well as higher lipoxygenase inhibition. In silico calculations reveal that hBN9 follows Lipinski’s rule of five and that the molecule is able to penetrate theoretically the brain. All these results led us to propose hBN9 as a new potent antioxidant nitrone. Full article
(This article belongs to the Special Issue Multitarget Directed Antioxidants for Stroke)
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Review

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21 pages, 1115 KiB  
Review
Targeting Oxidative Stress in Intracerebral Hemorrhage: Prospects of the Natural Products Approach
by Yingyi Zheng, Ruoqi Li and Xiang Fan
Antioxidants 2022, 11(9), 1811; https://doi.org/10.3390/antiox11091811 - 14 Sep 2022
Cited by 9 | Viewed by 3563
Abstract
Intracerebral hemorrhage (ICH), the second most common subtype of stroke, remains a significant cause of morbidity and mortality worldwide. The pathological mechanism of ICH is very complex, and it has been demonstrated that oxidative stress (OS) plays an important role in the pathogenesis [...] Read more.
Intracerebral hemorrhage (ICH), the second most common subtype of stroke, remains a significant cause of morbidity and mortality worldwide. The pathological mechanism of ICH is very complex, and it has been demonstrated that oxidative stress (OS) plays an important role in the pathogenesis of ICH. Previous studies have shown that OS is a therapeutic target after ICH, and antioxidants have also achieved some benefits in the treatment of ICH. This review aimed to explore the promise of natural products therapy to target OS in ICH. We searched PubMed using the keywords “oxidative stress in intracerebral hemorrhage” and “natural products in intracerebral hemorrhage”. Numerous animal and cell studies on ICH have demonstrated the potent antioxidant properties of natural products, including polyphenols and phenolic compounds, terpenoids, alkaloids, etc. In summary, natural products such as antioxidants offer the possibility of treatment of OS after ICH. However, researchers still have a long way to go to apply these natural products for the treatment of ICH more widely in the clinic. Full article
(This article belongs to the Special Issue Multitarget Directed Antioxidants for Stroke)
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