Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition

Topic Information

Dear Colleagues,

Bioactive compounds can serve as drugs or inspire novel synthetic structures to be employed for treating numerous human illnesses, including cancer and COVID-19. Natural products, as well as synthetic compounds, represent a massive group of biologically active factors with potential roles in medical fields. For example, the antioxidant properties of phytomolecules may imply therapeutic agents. Nonetheless, significant attention is being devoted to the repositioning of ‘orphan drugs’ and repurposing existing drugs for novel medical scopes. In this context, dissecting the molecular connections with treatment and the metabolic response of a system are fundamental aspects to investigate. These strategies allow for the identification of pathways related to specific metabolites or proteins with a role in pathogenesis or the discovery of mechanistic insights important to preventing cellular damage and sequelae in patients. Nonetheless, the support offered by the latest state-of-the-art omics technologies can provide a global view of the effects generated by bioactive compounds in health and disease.

This Topic aims to collect experimental outcomes concerning the effects of molecules extracted from natural sources or chemically modified in synthetic/semisynthetic derivatives, with potential effects on human health. It will also welcome research papers, reviews, communications, etc., based on in vitro and in vivo molecular and biochemical assays, including biomolecular interactions, antioxidant analyses, proteomic and metabolomic profiling, and in silico investigations.

Dr. Michele Costanzo
Dr. Giovanni N. Roviello
Dr. Armando Cevenini
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Cells cells	5.2	10.5	2012	16 Days	CHF 2700
Chemistry chemistry	2.4	3.9	2019	18.5 Days	CHF 1800
International Journal of Molecular Sciences ijms	4.9	9.0	2000	20.5 Days	CHF 2900
Molecules molecules	4.6	8.6	1996	16.1 Days	CHF 2700
Metabolites metabolites	3.7	6.9	2011	14.4 Days	CHF 2700

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Published Papers (7 papers)

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All Cells Chemistry IJMS Molecules Metabolites

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22 pages, 5839 KB  

Open AccessArticle

Novel Nitrogen Heterocycle–Hydroxamic Acid Conjugates Demonstrating Potent Anti-Acute Lymphoblastic Leukemia Activity: Induction of Endogenous Apoptosis and G0/G1 Arrest via Regulation of Histone H3 Acetylation and AKT Phosphorylation in Jurkat Cells

by Lingjie Wu, Li Zhao, Liping Wang, Yi Lu, Gaojie Lou, Bin Zhang and Ning Wang

Cells 2025, 14(22), 1822; https://doi.org/10.3390/cells14221822 - 20 Nov 2025

Abstract

Epigenetics garnered significant scientific interest in recent decades, with histone acetylation emerging as the most prevalent epigenetic deregulation process observed in malignancies. The clinical application of histone deacetylase (HDAC) inhibitors faced challenges, including complex therapeutic mechanisms and inconsistent treatment outcomes. In Acute Lymphoblastic [...] Read more.

Epigenetics garnered significant scientific interest in recent decades, with histone acetylation emerging as the most prevalent epigenetic deregulation process observed in malignancies. The clinical application of histone deacetylase (HDAC) inhibitors faced challenges, including complex therapeutic mechanisms and inconsistent treatment outcomes. In Acute Lymphoblastic Leukemia (ALL), the dysregulation of HDAC activity presents a promising therapeutic target. To investigate cellular-level tumor suppression by HDAC inhibitors possessing potent target engagement, we developed two novel azetidine-hydroxamic acid conjugates. Compared to N-hydroxy-4-((quinolin-4-ylamino)methyl)benzamide (NBU-1), N-hydroxy-6-((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl)amino)hexanamide (NBU-2) demonstrated enhanced inhibitory activity against HDAC1 (class I) and HDAC6 (class II) with IC₅₀ values of 7.75 nM and 7.34 nM, respectively, consistent with binding mode analysis and docking energy calculations. In vitro evaluation across 12 tumor cell lines revealed NBU-2’s potent antiproliferative effects, particularly against the ALL-derived Jurkat cells (IC₅₀ = 0.86 μM). Subsequent mechanistic studies were therefore conducted in this ALL model. Proteomic profiling indicated its potential involvement in modulating AKT signaling and histone modification pathways in Jurkat cells. Mechanistic investigations demonstrated that NBU-2 elevated histone acetylation while suppressing AKT phosphorylation. This compound altered apoptotic regulators by downregulating Bcl-2 and Bcl-XL expression while upregulating BAX, ultimately activating Caspase-9 and Caspase-3 to induce apoptosis. Cell cycle analysis revealed NBU-2-mediated G0/G1 arrest through reduced expression of Cyclin D1 and CDK4, diminished Rb protein phosphorylation, and increased p21 expression. These findings propose a strategic framework for developing next-generation HDAC inhibitors for ALL treatment and elucidating their mechanism-specific anti-cancer actions. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition)

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38 pages, 7643 KB  

Open AccessArticle

Investigation of Antithrombotic Activity and In Vivo Effective Forms of Kaempferitrin Using FeCl₃-Induced Rat Arterial Thrombosis and UHPLC-Q-Exactive Orbitrap MS

by Jingjing Zhou, Ruixin Wang, Jingchen Hou, Yitong Qi, Yanglu Liu, Linying Niu, Xinyu Xia, Jinchen Shao, Yizhou Liu, Chunyan Liu and Hongfu Li

Molecules 2025, 30(22), 4434; https://doi.org/10.3390/molecules30224434 - 16 Nov 2025

Viewed by 346

Abstract

Kaempferitrin (KAE) is a natural flavonol dirhamnopyranoside with various pharmacological activities, isolated from the antithrombotic fraction of Celastrus orbiculatus Thunb. This study aimed to investigate the antithrombotic activity and “effective forms” of KAE. The results showed that KAE significantly prolonged rabbit plasma recalcification [...] Read more.

Kaempferitrin (KAE) is a natural flavonol dirhamnopyranoside with various pharmacological activities, isolated from the antithrombotic fraction of Celastrus orbiculatus Thunb. This study aimed to investigate the antithrombotic activity and “effective forms” of KAE. The results showed that KAE significantly prolonged rabbit plasma recalcification time in vitro. In the FeCl₃-induced rat arterial thrombosis model, KAE demonstrated antithrombotic effects by inhibiting coagulation, platelet aggregation, and fibrinolysis, with a lesser risk of bleeding compared to aspirin. KAE was orally administered to rats, and a total of 192 metabolites were characterized. These included 25 phase I metabolites, 8 hydroxylated and methylated metabolites, 57 sulfated metabolites, 74 glucuronidated metabolites, 26 sulfated and glucuronidated metabolites, and 2 glycosylated metabolites. Twenty-eight compounds were considered the in vivo “effective forms” of KAE for their antithrombotic activity. Network pharmacology, molecular docking, and molecular dynamics simulations collectively predict that these “effective forms” may exert antithrombotic effects by suppressing the SRC/PI3K/AKT pathway. This study provides a foundation for a better understanding of the in vivo “effective forms” and mechanisms underlying KAE’s antithrombotic activity, which is essential for understanding of “hexue” traditional efficacy of C. orbiculatus. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition)

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12 pages, 383 KB  

Open AccessArticle

Synthesis and Biological Activity of Novel Polyazaheterocyclic Derivatives of Quinine

by Gulim K. Mukusheva, Nurizat N. Toigambekova, Roza B. Seidakhmetova, Roza I. Jalmakhanbetova, Mukhlissa N. Babakhanova, Oralgazy A. Nurkenov, Ekaterina A. Akishina, Evgenij A. Dikusar, Irina A. Kolesnik, Hongwei Zhou and Vladimir I. Potkin

Molecules 2025, 30(15), 3301; https://doi.org/10.3390/molecules30153301 - 7 Aug 2025

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Abstract

A synthetic methodology of the CuAAC “click” approach was exploited for the construction of 1,2-azolyltriazole quinine derivatives by the reaction of O-propargylquinine with azidomethyl-1,2-azoles in methanol. Quinine–piperidine and quinine–anabasine conjugates were obtained using a chloroacetate linker by reacting quinine chloroacetate with piperidine or [...] Read more.

A synthetic methodology of the CuAAC “click” approach was exploited for the construction of 1,2-azolyltriazole quinine derivatives by the reaction of O-propargylquinine with azidomethyl-1,2-azoles in methanol. Quinine–piperidine and quinine–anabasine conjugates were obtained using a chloroacetate linker by reacting quinine chloroacetate with piperidine or anabasine in a diethyl ether medium. Cinchophene ester was obtained by the acylation of quinine with cinchophen acid chloride in methylene chloride. The antibacterial, fungicidal, analgesic and cytotoxic properties of the obtained compounds were examined. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition)

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26 pages, 4256 KB  

Open AccessReview

Progress in Pharmacokinetics, Pharmacological Effects, and Molecular Mechanisms of Swertiamarin: A Comprehensive Review

by Hao-Xin Yang, Ying-Yue Hu, Rui Liang, Hong Zheng and Xuan Zhang

Cells 2025, 14(15), 1173; https://doi.org/10.3390/cells14151173 - 30 Jul 2025

Viewed by 1545

Abstract

Swertiamarin (SW), a natural iridoid glycoside primarily isolated from the genus Swertia, Gentianaceae family, has been extensively utilized in traditional medicine systems, including Ayurveda, Traditional Chinese Medicine, and Tibetan medicine, for treating fever, diabetes, liver disorders, and inflammatory conditions. Pharmacokinetic studies reveal [...] Read more.

Swertiamarin (SW), a natural iridoid glycoside primarily isolated from the genus Swertia, Gentianaceae family, has been extensively utilized in traditional medicine systems, including Ayurveda, Traditional Chinese Medicine, and Tibetan medicine, for treating fever, diabetes, liver disorders, and inflammatory conditions. Pharmacokinetic studies reveal that SW exhibits rapid absorption but demonstrates low oral bioavailability due to the first-pass effect. Pharmacological studies have demonstrated that SW possesses a wide range of pharmacological activities, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and neuroprotective activities. Our analysis demonstrates that SW exerts remarkable therapeutic potential across multiple pathological conditions through coordinated modulation of key signaling cascades, including Nrf2/HO-1, NF-κB, MAPK, PI3K/Akt, and PPAR pathways. This comprehensive review systematically consolidates current knowledge on SW’s pharmacokinetic characteristics, toxicity, diverse biological activities, and underlying molecular mechanisms based on extensive preclinical evidence, establishing a scientific foundation for future drug development strategies and potential clinical applications of the potential natural lead compound. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition)

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17 pages, 1633 KB  

Open AccessArticle

Iodinated Salicylhydrazone Derivatives as Potent α-Glucosidase Inhibitors: Synthesis, Enzymatic Activity, Molecular Modeling, and ADMET Profiling

by Seema K. Bhagwat, Fabiola Hernandez-Rosas, Abraham Vidal-Limon, J. Oscar C. Jimenez-Halla, Balasaheb K. Ghotekar, Vivek D. Bobade, Enrique Delgado-Alvarado, Sachin V. Patil and Tushar Janardan Pawar

Chemistry 2025, 7(4), 117; https://doi.org/10.3390/chemistry7040117 - 23 Jul 2025

Cited by 1 | Viewed by 873

Abstract

Type 2 diabetes mellitus (T2DM) demands safer and more effective therapies to control postprandial hyperglycemia. Here, we report the synthesis and in vitro evaluation of ten salicylic acid-derived Schiff base derivatives (4a–4j) as α-glucosidase inhibitors. Compounds 4e, 4g [...] Read more.

Type 2 diabetes mellitus (T2DM) demands safer and more effective therapies to control postprandial hyperglycemia. Here, we report the synthesis and in vitro evaluation of ten salicylic acid-derived Schiff base derivatives (4a–4j) as α-glucosidase inhibitors. Compounds 4e, 4g, 4i, and 4j exhibited potent enzyme inhibition, with IC₅₀ values ranging from 14.86 to 18.05 µM—substantially better than acarbose (IC₅₀ = 45.78 µM). Molecular docking and 500 ns molecular dynamics simulations revealed stable enzyme–ligand complexes driven by π–π stacking, halogen bonding, and hydrophobic interactions. Density Functional Theory (DFT) calculations and molecular electrostatic potential (MEP) maps highlighted key electronic factors, while ADMET analysis confirmed favorable drug-like properties and reduced nephrotoxicity. Structure–activity relationship (SAR) analysis emphasized the importance of halogenation and aromaticity in enhancing bioactivity. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition)

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19 pages, 3851 KB  

Open AccessArticle

Neuroprotective Terpenoids Derived from Hericium erinaceus Fruiting Bodies: Isolation, Structural Elucidation, and Mechanistic Insights

by Ying Cao, Qiaona Wang, Lu Li, Haitao Jiang, Bianjiang Zhang, Yulong Wu, Feng Zhou, Chun Hua, Guangming Huo, Shengjie Li and Jianmei Li

Int. J. Mol. Sci. 2025, 26(14), 6606; https://doi.org/10.3390/ijms26146606 - 10 Jul 2025

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Abstract

Hericium erinaceus, a medicinal macrofungus, is renowned for its potential neuroprotective benefits. Here, we isolated and characterized secondary metabolites from H. erinaceus fruiting bodies and explored their neuroprotective effects and primary mechanisms of action. A novel terpenoid (4) and four known compounds [...] Read more.

Hericium erinaceus, a medicinal macrofungus, is renowned for its potential neuroprotective benefits. Here, we isolated and characterized secondary metabolites from H. erinaceus fruiting bodies and explored their neuroprotective effects and primary mechanisms of action. A novel terpenoid (4) and four known compounds (1, 2, 3, and 5) were identified. Their chemical structures were determined using nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), and x-ray diffraction (XRD). Bioactivity screening using PC12 cells indicated that (3R,4R)-4-acetyl-3,4-dihydro-6,8-dihydroxy-3-methoxy-5-methyl-1H-2-benzopyran (3) and the terpenoid, (1R,4S,8aS)-1,4-dihydroxy-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde (4), demonstrated protective properties against hydrogen peroxide (H₂O₂)-induced damage. Transcriptomics, network pharmacology, and molecular docking showed that compound 4 counteracted H₂O₂-induced oxidative stress and inflammation by substantially attenuating pro-inflammatory cytokine (IL-1β, IL-6) expression, downregulating pro-oxidant factors (Aoc3, Dusp3), and decreasing reactive oxygen species levels, while boosting superoxide dismutase activity. Compound 4 exerted neuroprotective effects via the NF-κB pathway. H. erinaceus represents a valuable natural reservoir of bioactive compounds for treating and preventing neurodegenerative diseases. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition)

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15 pages, 1767 KB  

Open AccessBrief Report

β-Hydroxybutyrate Reduces Body Weight by Modulating Fatty Acid Oxidation and Beiging in the Subcutaneous Adipose Tissue of DIO Mice

by Violeta Heras, Virginia Mela, Pallavi Kompella, Elena Rojano, Guillermo Paz-López, Lucia Hurtado-García, Almudena Ortega-Gomez, Maria José García-López, María Luisa García-Martín, Juan A. G. Ranea, Francisco J. Tinahones and Isabel Moreno-Indias

Int. J. Mol. Sci. 2025, 26(11), 5064; https://doi.org/10.3390/ijms26115064 - 24 May 2025

Cited by 1 | Viewed by 1990

Abstract

β-hydroxybutyrate (BHB) serves as an alternative cellular fuel during states of low glucose availability, such as fasting or carbohydrate restriction, when the body shifts to using fats and ketone bodies for energy. While BHB has shown potential metabolic benefits, its mechanisms of action [...] Read more.

β-hydroxybutyrate (BHB) serves as an alternative cellular fuel during states of low glucose availability, such as fasting or carbohydrate restriction, when the body shifts to using fats and ketone bodies for energy. While BHB has shown potential metabolic benefits, its mechanisms of action in the context of obesity are not fully understood. In this study, we examined the effects of BHB supplementation on subcutaneous adipose tissue (SAT) metabolism in a diet-induced obesity (DIO) mouse model. Adult male mice were first fed a high-fat diet for six weeks, followed by a standard diet with or without BHB supplementation for an additional six weeks. BHB supplementation led to significant body weight loss independent of food intake. This weight reduction was associated with decreased adipocyte differentiation, reflected by reduced peroxisome proliferator-activated receptor gamma (PPARγ) protein levels and lower uncoupling protein 1 (UCP1) expression, indicating altered SAT function. Transcriptomic analysis of SAT revealed upregulation of genes involved in fatty acid activation and transport (e.g., Slc27a2, Plin5, Acot4, Acsm3, Rik). Functional enrichment highlighted the activation of the PPAR signaling pathway and enrichment of peroxisomal components in the BHB group. Together, these results suggest that BHB promotes lipid remodeling in SAT, enhancing fatty acid metabolism while suppressing thermogenic pathways, and thus may represent a novel mechanism contributing to adiposity reduction and metabolic improvement. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition)

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