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Phenolic Compounds: Chemistry and Health Benefits

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: 30 November 2026 | Viewed by 3740

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Editors

Prof. Dr. Mirela Kopjar

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Guest Editor

Department of Food Technologies, Faculty of Food Technology Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
Interests: phenolics; anthocyanins; antioxidants; flavor compounds of fruits and fruit products
Special Issues, Collections and Topics in MDPI journals

Dr. Josipa Krezić

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Guest Editor Assistant

Faculty of Agriculture and Food Technology, University of Mostar, Mostar, Bosnia and Herzegovina
Interests: advanced encapsulation technologies; molecular mechanisms of phenolic compound encapsulation; stabilization of bioactive compounds and aromas; phytochemical characterization and antioxidant potential of food matrices

Special Issue Information

Dear Colleagues,

Phenolic compounds are a structurally diverse class of plant secondary metabolites, ranging from simple phenolic acids to complex polymers such as tannins and lignans. In recent years, they have attracted growing scientific interest due to their significant health-promoting properties, including antioxidant activity and the ability to modulate inflammatory pathways, microbial growth, and carcinogenic processes. These characteristics make phenolic compounds highly promising for applications in functional foods, nutraceuticals, and therapeutic products.

However, their effective application is often hindered by chemical instability and susceptibility to degradation during extraction, processing, and storage. Factors such as temperature, light, oxygen, and pH can markedly affect their stability, bioavailability, and biological efficacy, underscoring the need for innovative analytical methods, advanced extraction technologies, and effective stabilization and delivery strategies.

This Special Issue of Molecules aims to bring together high-quality original research articles and comprehensive reviews addressing recent advances in the chemical characterization, isolation, stability, and bioactivity of natural phenolic compounds.

Prof. Dr. Mirela Kopjar
Guest Editor

Dr. Josipa Krezić
Guest Editor Assistant

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Keywords

phenolic compounds
polyphenols
antioxidant activity
bioactivity
extraction techniques
chemical characterization
stability
bioavailability
functional foods

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Published Papers (8 papers)

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Research

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21 pages, 3286 KB

Open AccessArticle

Preparation of Quercetin-Loaded Lipid Nanoparticle-Embedded Hydrogels and Stability Studies

by Chatchapong Tangjidapichai, Sarin Tadtong, Chuda Chittasupho and Weerasak Samee

Molecules 2026, 31(14), 2539; https://doi.org/10.3390/molecules31142539 - 22 Jul 2026

Viewed by 286

Abstract

Quercetin, a plant-derived flavonoid with potent antioxidant and anti-inflammatory properties, is limited for topical use by its poor aqueous solubility, low bioavailability, and chemical instability. This research developed and validated a formulation-driven strategy to stabilize quercetin by encapsulating it in lipid nanoparticles (QLNs) and embedding these in a Carbopol hydrogel, providing comprehensive physicochemical and functional stability data. A fully validated HPLC-PDA assay was used to quantify quercetin in the nanoparticle–hydrogel matrix. In vitro bioactivity testing showed notable antioxidant activity (DPPH IC₅₀ 6.84 ± 0.12 µg/mL; ABTS IC₅₀ 4.04 ± 0.08 µg/mL; FRAP 301.46 ± 3.68 µg/mL) and an anti-inflammatory effect in LPS-stimulated RAW264.7 macrophages (1 µM quercetin reduced NO from 50.72 ± 2.00 µM to 41.57 ± 3.12 µM, p < 0.05). Forced degradation mapping across acidic, basic, oxidative, and photolytic conditions defined degradation pathways (complete loss in 1 N NaOH at 24 h; greater retention in 1 N HCl, 3% H₂O₂, and UV-254). QLN–hydrogel formulations remained physically and chemically stable through heating–cooling cycles and 180-day storage at multiple temperatures, retaining >90% quercetin and preserving antioxidant and anti-inflammatory activities (<10% reduction). These results establish a robust, application-ready approach for maintaining quercetin’s chemical integrity and bioactivity in topical formulations. Full article

(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)

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21 pages, 2746 KB

Open AccessArticle

Effects of Ilex aquifolium Polyphenols on Cardiovascular, Renal and Liver Structure in a Rat Model of Metabolic Syndrome: A Biochemical and Histological Study

by Renata Nowaczyk, Piotr Kuropka, Antoni Szumny, Natalia Pachura-Hanusek, Anna Zwyrzykowska-Wodzińska, Krystyna Pogoda-Sewrniak and Robert Kupczyński

Molecules 2026, 31(14), 2487; https://doi.org/10.3390/molecules31142487 - 16 Jul 2026

Viewed by 332

Abstract

Metabolic syndrome (MetS) is a major driver of cardiovascular disease, renal injury, and hepatic steatosis, largely through chronic low-grade inflammation and oxidative stress. This study evaluated the cardioprotective, nephroprotective, and hepatoprotective potential of a polyphenol-rich fraction (PP) isolated from Ilex aquifolium leaves in obese Zucker (fa/fa) rats—a well-established model of MetS. Male rats (8 weeks old) were randomly assigned to receive either a standard diet (CTRL, n = 8) or the same diet supplemented with 10 mg/kg body weight/day of the polyphenol fraction (PP, n = 8) for 8 weeks. The fraction was dominated by chlorogenic acid (59.33 mg/g), neochlorogenic acid (35.39 mg/g), and rutin (9.23 mg/g). At the end of the experiment, biochemical markers of oxidative stress, inflammation, and metabolic status were assessed, together with detailed histopathological examination of the heart, kidneys, and liver. Supplementation with Ilex aquifolium polyphenols significantly increased (p < 0.01) total antioxidant status, reduced circulating IL-6 and increased MCP-1 levels. These changes were accompanied by clear cardioprotective effects. However, the intervention also produced organ-specific adverse effects. In the kidneys, polyphenol-treated rats exhibited histopathological features consistent with early-stage nephropathy. In the liver, supplementation exacerbated hepatic steatosis compared to controls. In conclusion, the polyphenol-rich fraction from Ilex aquifolium exerts potent antioxidant and anti-inflammatory effects that translate into substantial cardioprotection in obese Zucker rats. Nevertheless, its capacity to worsen renal injury and hepatic steatosis highlights the need for caution and further dose- and duration-dependent studies before considering therapeutic application in metabolic syndrome. Full article

(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)

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23 pages, 3754 KB

Open AccessArticle

Stability of Polyphenols and Antioxidant Activity of Cellulose-Based Encapsulates Enriched with Tart Cherry Juice Polyphenols

by Josipa Krezić, Ivana Buljeta, Anita Pichler and Mirela Kopjar

Molecules 2026, 31(14), 2449; https://doi.org/10.3390/molecules31142449 - 13 Jul 2026

Cited by 1 | Viewed by 305

Abstract

This study investigated the potential of cellulose as a carrier for bioactive phenolic compounds from tart cherry juice. Using a freeze-drying method, encapsulates were prepared by varying cellulose content (2.5%, 5%, 7.5%, and 10%) and complexation times (15 and 60 min) while maintaining a constant juice volume. The prepared encapsulates were characterized by determining the concentrations of total phenols, monomeric anthocyanins, and proanthocyanidins, alongside antioxidant activity by spectrophotometric methods, individual polyphenols by HPLC, color parameters and structural changes via IR spectroscopy. Additionally, the stability of these parameters was evaluated after one year of storage at room temperature. Results indicated that the highest concentrations of phenolic compounds and the strongest antioxidant potential were achieved with 2.5% cellulose content (the lowest content) after 15 min of complexation (shorter time). Concentrations of polyphenols decreased as the cellulose contents increased. Although changes in chemical parameters occurred during storage, the results confirm that cellulose is a viable carrier for tart cherry phenolics, particularly at lower contents, offering a promising approach for formulating stable bioactive delivery systems. Full article

(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)

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23 pages, 1492 KB

Open AccessArticle

Encapsulation of Verbascum sinaiticum Leaf Extract as a Natural Antimicrobial for Controlling Microbial Growth in Beef During Refrigerated Storage

by Alemu Belay Legesse, Shimelis Admassu Emire, Timilehin Martins Oyinloye and Won Byong Yoon

Molecules 2026, 31(12), 2063; https://doi.org/10.3390/molecules31122063 - 12 Jun 2026

Viewed by 440

Abstract

The efficacy of plant-derived antimicrobials in meat systems is frequently limited by interactions with proteins, lipids, and other food matrix components that reduce the bioavailability and antimicrobial activity of phytochemicals. This study evaluated the antimicrobial effectiveness of Verbascum sinaiticum (V. sinaiticum) leaf extract encapsulated using maltodextrin (MD), gum arabic (GA), and a maltodextrin–gum arabic blend (MDGA, 8:2 w/w) through freeze-drying for application in raw beef during refrigerated storage (4 °C). The encapsulation systems exhibited process yields of 42.5–54.7%, encapsulation efficiencies of 78.3–92.5%, and loading capacities of 18.5–24.3 mg GAE/g DW, with MDGA showing the highest encapsulation efficiency. The effects of encapsulation on microbial inhibition, physicochemical properties, and sensory quality were investigated over 15 days of storage. Aerobic plate counts in the control increased from 3.04 to 8.26 log CFU/g, whereas encapsulated treatments showed significantly lower final counts (p < 0.05), reaching 7.89 log CFU/g (MD), 7.96 log CFU/g (MDGA), and 7.95 log CFU/g (GA). Similarly, encapsulated treatments reduced Escherichia coli counts during storage, with maltodextrin (MD) exhibiting the greatest inhibitory effect (6.23 × 10⁵ CFU/g) compared with the control (6.93 × 10⁵ CFU/g) on day 15. However, reductions in Staphylococcus aureus, E. coli, Candida albicans, and Bacillus cereus remained below 1 log CFU/g, indicating limited antimicrobial efficacy under the tested conditions. All encapsulated treatments slowed pH increases during storage (6.20–6.34) relative to the control (6.62) on day 15 and preserved aroma quality throughout the storage period. Overall, encapsulation improved the antimicrobial performance of V. sinaiticum extract compared with the free extract, particularly in MD-based systems; however, the antimicrobial effects in beef remained modest. These findings highlight both the potential and current limitations of encapsulated plant-derived antimicrobials for meat preservation and emphasize the need for optimized delivery systems to enhance efficacy in complex food matrices. Full article

(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)

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27 pages, 7659 KB

Open AccessArticle

Modulation of Selective Extraction of Phenolic Compounds from Capsicum chinense By-Products via UAE/NADES: Effects of Hydrogen Bond Acceptor, Extraction Time and Drying Method

by Kevin Alejandro Avilés-Betanzos, Dayra Priscila Turrén-Gutiérrez, Manuel Octavio Ramírez-Sucre, Juan Valerio Cauich-Rodríguez and Ingrid Mayanin Rodríguez-Buenfil

Molecules 2026, 31(11), 1931; https://doi.org/10.3390/molecules31111931 - 3 Jun 2026

Viewed by 348

Abstract

Habanero pepper (Capsicum chinense Jacq. var. Jaguar) leaves are an underutilized by-product with potential as a source of polyphenols. This study evaluated UAE/NADES extraction as a tunable strategy to modulate selective polyphenol recovery rather than only maximizing total yield. A 2 × 3 × 2 factorial design was used to assess the hydrogen-bond acceptor (HBA) in fructose-based NADES, choline chloride (ChCl) or malic acid (MAc), ultrasound-assisted extraction (UAE) time (10, 20, and 30 min), and leaf drying method: freeze-drying (FzD) or oven-drying (OvD). Total phenolic content (TPC, Folin–Ciocalteu), antioxidant capacity (Ax, DPPH assay), and individual polyphenols by UPLC-DAD were determined. The highest TPC was obtained with ChCl from FzD leaves after 10 min of UAE (36.18 ± 0.70 mg GAE/g dry leaf). Maximum Ax was observed in OvD leaves after 30 min and was similar between HBAs (ChCl: 86.43 ± 0.65%; MAc: 86.95 ± 0.18%). UPLC-DAD confirmed compound-dependent selectivity, with catechin favored in MAc-FzD at 20 min (51.14 ± 1.07 mg/g dry leaf), chlorogenic acid in MAc-OvD at 10 min (16.05 ± 0.09 mg/g dry leaf), and quercetin + luteolin in MAc-FzD at 10 min (5.37 ± 0.05 mg/g dry leaf). This selective behavior may be associated with HBA-dependent solvent–solute affinity, polarity, hydrogen-bonding interactions, UAE-driven mass transfer, and drying-induced matrix changes. It is important to note that TPC, antioxidant capacity, and individual polyphenols showed a decoupled response, indicating that the overall spectrophotometric parameters did not necessarily reflect the polyphenol profile. Overall, the results show that UAE/NADES conditions can be directed toward target polyphenol profiles, supporting the valorization of C. chinense leaves as a source of tailored polyphenol extracts for future food, cosmetic, pharmaceutical, or nutraceutical applications. Full article

(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)

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21 pages, 1193 KB

Open AccessArticle

Rambutan (Nephelium lappaceum L.) Shell as a Source of Polyphenols: Chemical Characterization and Biological Activities

by Carlos Barba-Ostria, Arianna Mayorga-Ramos, Johana Zúñiga-Miranda, Rebeca Gonzalez-Pastor, Elena Coyago-Cruz, Antonella Viteri, Ana Belén Peñaherrera-Pazmiño, Orestes López, Diana Celi, Eduardo Tejera and Linda P. Guamán

Molecules 2026, 31(11), 1925; https://doi.org/10.3390/molecules31111925 - 3 Jun 2026

Viewed by 502

Abstract

This study investigates the valorization of Nephelium lappaceum (rambutan) shell, an agro-industrial byproduct, as a sustainable source of bioactive compounds through comprehensive chemical and functional characterization. Phytochemical profiles were determined using spectrophotometrics and HPLC-DAD-MS/MS, revealing a composition dominated by ellagitannins (e.g., geraniin, corilagin, chebulagic acid) and ellagic acid derivatives, alongside significant levels of total phenolics (25,982.2 mg/100 g DW) and anthocyanins. The extract exhibited strong antioxidant activity (DPPH IC₅₀ = 8.02 μg/mL; TEAC = 5703.92 μmol TE/g), consistent with its high phenolic content. Biological evaluation demonstrated antimicrobial activity against a broad panel of Gram-positive and Gram-negative bacteria, including multidrug-resistant strains, with greater efficacy against Gram-positive species (Staphylococcus aureus, MIC = 2.5 mg/mL). The extract also showed significant antibiofilm activity, achieving up to 93% inhibition. Antitumoral assays revealed selective cytotoxicity, particularly against HeLa cells (IC₅₀ = 260 μg/mL; TI = 11.5), indicating preferential effects on tumor over non-tumor cells. Importantly, hemolytic assays confirmed low toxicity, with negligible erythrocyte membrane disruption across tested concentrations. Overall, these findings highlight rambutan shell as a rich source of phenolic bioactives with multifunctional biological properties and favorable safety profile, supporting its potential application in nutraceutical and pharmaceutical formulations within a circular economy framework. This study aligns with SDG 3 and SDG 9 by promoting the valorization of agro-industrial waste as a source of safe bioactive compounds for health-related applications. Full article

(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)

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20 pages, 4652 KB

Open AccessArticle

Structure-Based Drug Design Targeting Topoisomerase II Alpha: Discovery of Potential Antitumor Xanthone Derivatives

by Thi Thuy Huong Le, Thi Nguyet Hang Nguyen, Minh Quan Pham, Thi Thu Thuy Tran, Tu Thi Dinh, Thi Hoai Van Tran, Van Lang Tran and Quoc Long Pham

Molecules 2026, 31(10), 1670; https://doi.org/10.3390/molecules31101670 - 15 May 2026

Viewed by 586

Abstract

Cancer represents a major global health challenge, contributing to an estimated 19 million new cases annually. While conventional chemotherapeutic approaches continue to advance, target-based therapeutic strategies are increasingly recognized as effective pathways in modern drug development. A prominent biological target in current anticancer research is the selective inhibition of Topoisomerase II alpha (TOP2A). TOP2A, a crucial DNA topoisomerase, is vital for maintaining genomic integrity by mediating the cleavage and re-ligation of double-stranded DNA during essential cellular processes, such as DNA replication and transcription. Inhibiting TOP2A effectively disrupts these processes, leading to cell death. This study employed computer-aided drug design approaches to virtually screen a library of 3000 xanthone derivatives against the TOP2A target, and the results were preliminarily validated through cytotoxicity assays on the A549 and HepG2 cancer cell lines. The computational methods utilized included molecular docking, pharmacological modeling, molecular dynamics simulations, and steered molecular dynamics simulations. The virtual screening identified two highly promising HIT compounds, CID162372098 and CID156619937, that exhibited the most favorable interactions and stability profiles in relation to the TOP2A active site. The experimental results demonstrated that both hit compounds effectively exhibited significant anti-proliferative activities against the HepG2 cell line, with IC50 values of 9.54 ± 0.26 µg mL⁻¹ (CID162372098) and 10.03 ± 0.36 12.69 ± 0.31 µg mL⁻¹ (CID156619937), respectively. Collectively, these findings demonstrate the potential of xanthone-based scaffolds as inhibitors of TOP2A and provide a rational framework for the screening and development of novel anticancer agents. Full article

(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)

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Review

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58 pages, 48313 KB

Open AccessReview

Therapeutic Potential of Kuwanon G: From Bioactivities to Network-Level Mechanisms

by Esra Aydemir, Beyzanur Şimşek, Ayşe Acar, A. Cansu Kilit and Elif Odabaş Köse

Molecules 2026, 31(13), 2292; https://doi.org/10.3390/molecules31132292 - 1 Jul 2026

Viewed by 340

Abstract

Natural products like the isoprenylated flavonoid Kuwanon G (KWG), isolated primarily from Morus alba, offer promising pleiotropic effects against multifactorial diseases, overcoming the limitations of conventional single-target synthetic drugs. This study aims to systematically review the pharmacological activities of KWG and evaluate its underlying molecular mechanisms. A comprehensive literature review was integrated with network pharmacology, protein–protein interaction (PPI) profiling, and KEGG/GO pathway enrichment analyses to identify shared targets across different pathologies. Experimental data demonstrate that KWG exhibits antimicrobial, anti-inflammatory, antidiabetic, neuroprotective, anti-obesity, and anticancer properties. Bioinformatics analyses revealed that KWG exerts these effects by modulating core targets (e.g., TNF, IL-6, SRC, RELA) and key signaling pathways, including NF-κB, PI3K/AKT/mTOR, and Toll-like receptors, which govern inflammation, oxidative stress, and metabolic regulation. In conclusion, KWG is a potent, multi-target compound with significant therapeutic potential for managing chronic and infectious diseases. However, future structure–activity relationship studies and clinical trials are required to address its pharmacokinetic limitations, such as low bioavailability, to facilitate its clinical translation. Full article

(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)

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