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Antioxidants
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Multi-Target Profile of Antioxidant Compounds, Including Repurposing and Combination Strategies—2nd...
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Multi-Target Profile of Antioxidant Compounds, Including Repurposing and Combination Strategies—2nd Edition

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: 30 June 2025 | Viewed by 3472

Special Issue Editor

Dr. Roberta Rocca

E-Mail Website
Guest Editor
Dipartimento di Scienze della Salute, Università “Magna Graecia” di Catanzaro, Campus “Salvatore Venuta”, Viale Europa, 88100 Catanzaro, Italy
Interests: docking; nucleic acids; drug design; molecular modeling; molecular dynamics; virtual screening; drug repurposing; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Our previous edition garnered an exceptional response, with a substantial number of high-quality submissions, resulting in a successful compilation of cutting-edge research and review articles. Building on this success, I am delighted to announce the second edition of our Special Issue, titled “Multi-Target Profile of Antioxidant Compounds, Including Repurposing and Combination Strategies—2nd Edition”.

The second edition of our Special Issue centers on the pivotal role of oxidative stress in multifactorial diseases, including cancer, neurodegenerative disorders, and stroke, underscoring the urgent need for more effective treatments. This edition emphasizes the development of multi-targeting antioxidant and anti-inflammatory compounds as promising therapeutic agents, focusing on leveraging in silico techniques to enhance drug design. We invite contributions that explore innovative approaches in polypharmacology, particularly in designing and synthesizing novel antioxidant molecules, drug repurposing strategies, and discovering off-target effects for antioxidant therapies.

Dr. Roberta Rocca
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

  • polypharmacology
  • multi-target ligands
  • rational drug
  • design repurposing
  • off-target effects
  • computational techniques

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Published Papers (3 papers)

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Research

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33 pages, 7247 KiB  
Article
Exploratory Data Analysis of the In Vitro Effects of Novel Hydrazide-Hydrazone Antioxidants in the Context of In Silico Predictors
by Yordan Yordanov, Virginia Tzankova, Denitsa Stefanova, Maya Georgieva and Diana Tzankova
Antioxidants 2025, 14(5), 566; https://doi.org/10.3390/antiox14050566 - 8 May 2025
Viewed by 389
Abstract
Substantial in vitro experimental data have been produced about the safety, antioxidant, neuro- and hepatoprotective effects of a series of recently synthesized N-pyrrolyl hydrazide-hydrazones (compounds 5, 5a–5g). However, compound activity across multiple assays varies and it is challenging to [...] Read more.
Substantial in vitro experimental data have been produced about the safety, antioxidant, neuro- and hepatoprotective effects of a series of recently synthesized N-pyrrolyl hydrazide-hydrazones (compounds 5, 5a–5g). However, compound activity across multiple assays varies and it is challenging to elucidate the favorable physicochemical characteristics of the studied compounds and guide further lead optimization. The aim of the current study is to apply exploratory data analysis in order to profile the biological effects of the novel hydrazide-hydrazones, gain insights related to their mechanisms of action in the context of in silico predictions and identify key predictor–outcome relationships. We collected a dataset from available in vitro studies of compounds 5, 5a–5g. It included cytotoxicity values, protection against hydrogen peroxide-induced damage in HepG2 and SH-SY5Y cells, two radical scavenging assays and a hemolysis assay across a range of treatment concentrations. SwissADME-based predictions of chemometric and ADME parameters and pro-oxidant enzyme docking data were generated to provide context for the interpretation of in vitro outcome patterns and identify causal relationships. Multiple factor analysis (MFA), followed by hierarchical clustering on principal components (HCPC), was applied to profile compounds’ biological behavior. This revealed that differences in the number of H-bond donors, in the permeability coefficient and in the docking scores to two pro-oxidant enzymes could aid in explaining the effects of compounds with similar in vitro profiles. HCPC differentiated 5a as mostly neuroprotective, 5 and 5d as hepatoprotective radical scavengers, 5g with higher docking affinity to 5-lipoxygenase (5-LOX) and myeloperoxidase (MPO) and 5b, 5c and 5f as having less H-bond donors and variable in vitro activity. The consensus application of three variable selection approaches based on standard lasso regression, robust penalized regression and random forest confirmed the relationships between some in vitro outcomes and LogP, pan-assay interference (PAINS) alerts, 5-LOX allosteric site docking and H-bond donor numbers. The exploratory analysis of the combined in vitro and in silico dataset provides useful insights which could help explain the major drivers behind the experimental results. It can be informative in the design of new, improved members of the series of novel N-pyrrolyl hydrazide-hydrazones with better neuroprotective potential and less side effects. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, Including Repurposing and Combination Strategies—2nd Edition)
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16 pages, 1895 KiB  
Article
Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD+ Depletion with Salvage Pathway Impairment
by Sho Nishida, Tamaki Ishima, Daiki Iwami, Ryozo Nagai and Kenichi Aizawa
Antioxidants 2025, 14(1), 62; https://doi.org/10.3390/antiox14010062 - 7 Jan 2025
Viewed by 1325
Abstract
Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) is a serious issue for long-term graft survival in kidney transplantation. However, the pathophysiology of TAC nephrotoxicity remains unclear. In this study, we analyzed whole blood samples from mice that developed TAC nephrotoxicity in order to discover [...] Read more.
Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) is a serious issue for long-term graft survival in kidney transplantation. However, the pathophysiology of TAC nephrotoxicity remains unclear. In this study, we analyzed whole blood samples from mice that developed TAC nephrotoxicity in order to discover its mechanism. Mice were divided into a TAC group and a control group (n = 5 per group). The TAC group received TAC subcutaneously (1 mg/kg/day for 28 days), while the control group received normal saline instead. After the administration period, whole blood was collected and metabolomic analysis was performed, revealing significant changes in 56 metabolites. The major metabolic changes were related to uremic toxins, vascular damage, and NAD+. NAD+ levels were significantly lower in the TAC group, and ADP-ribose, nicotinamide, and nicotinamide N-oxide, which are degradation products of NAD+, were significantly higher, suggesting impairment of the NAD+ salvage pathway. NAD+ deficiency suggests cellular aging and mitochondrial dysfunction, which may induce vascular damage and chronic kidney disease. Our study demonstrated a correlation between low NAD+ levels and the pathophysiology of TAC nephrotoxicity. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, Including Repurposing and Combination Strategies—2nd Edition)
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Review

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33 pages, 2595 KiB  
Review
New Insights into Aspirin’s Anticancer Activity: The Predominant Role of Its Iron-Chelating Antioxidant Metabolites
by George J. Kontoghiorghes
Antioxidants 2025, 14(1), 29; https://doi.org/10.3390/antiox14010029 - 29 Dec 2024
Cited by 1 | Viewed by 1344
Abstract
Epidemiological studies have suggested that following long-term, low-dose daily aspirin (LTLDA) administration for more than 5 years at 75–100 mg/day, 20–30% of patients (50–80 years old) had a lower risk of developing colorectal cancer (CRC) and about the same proportion in developing iron [...] Read more.
Epidemiological studies have suggested that following long-term, low-dose daily aspirin (LTLDA) administration for more than 5 years at 75–100 mg/day, 20–30% of patients (50–80 years old) had a lower risk of developing colorectal cancer (CRC) and about the same proportion in developing iron deficiency anemia (IDA). In cases of IDA, an increase in iron excretion is suspected, which is caused by aspirin chelating metabolites (ACMs): salicylic acid, salicyluric acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. The ACMs constitute 70% of the administered aspirin dose and have much longer half-lives than aspirin in blood and tissues. The mechanisms of cancer risk reduction in LTLDA users is likely due to the ACM’s targeting of iron involved in free radical damage, iron-containing toxins, iron proteins, and associated metabolic pathways such as ferroptosis. The ACMs from non-absorbed aspirin (about 30%) may also mitigate the toxicity of heme and nitroso-heme and other iron toxins from food, which are responsible for the cause of colorectal cancer. The mode of action of aspirin as a chelating antioxidant pro-drug of the ACMs, with continuous presence in LTLDA users, increases the prospect for prophylaxis in cancer and other diseases. It is suggested that the anticancer effects of aspirin depend primarily on the iron-chelating antioxidant activity of the ACMs. The role of aspirin in cancer and other diseases is incomplete without considering its rapid biotransformation and the longer half-life of the ACMs. Full article
(This article belongs to the Special Issue Multi-Target Profile of Antioxidant Compounds, Including Repurposing and Combination Strategies—2nd Edition)
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