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Nature-Inspired and Synthetic Compounds: New Frontiers in Bioactivity and Drug Discovery

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 3757

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Special Issue Editors

Dr. Alina Bora

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Computational Chemistry, “Coriolan Dragulescu” Institute of Chemistry, Romanian Academy, 24 Mihai Viteazu Ave., 300223 Timisoara, Romania
Interests: computational chemistry; chemoinformatics; drug discovery; molecular simulation; medicinal chemistry; drug repurposing; molecular docking; natural product-based drug discovery; QSAR modeling; artificial intelligence in drug discovery
Special Issues, Collections and Topics in MDPI journals

Dr. Luminita Crisan

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Guest Editor

“Coriolan Dragulescu” Institute of Chemistry, Romanian Academy, 24 Mihai Viteazu Ave., 300223 Timisoara, Romania
Interests: computational chemistry; chemoinformatics; drug discovery; QSAR modeling; molecular simulation; drug repurposing; molecular docking; natural products-based drug discovery; and artificial intelligence in drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Natural products and their synthetic analogues have long played a fundamental role in the discovery of new therapeutic candidates. Nature-inspired molecules continue to influence drug design, while recent advances in synthetic chemistry, biotechnology, and computational tools have significantly improved the bioactivity, stability, and selectivity of drug candidates.

This Special Issue aims to present high-quality research on bioactive compounds—whether derived from natural sources or synthetically engineered—with promising pharmacological potential against a broad spectrum of diseases. These include cancer, infectious and neurodegenerative disorders, metabolic syndromes, autoimmune and inflammatory diseases, cardiovascular and dermatological conditions, and age-related ailments.

This Special Issue showcases innovative strategies tackling global health challenges through drug discovery and development. Topics of interest include the elucidation of molecular and cellular mechanisms of action, the discovery and profiling of novel natural or synthetic products, the improvement of drug efficacy and safety, and the development of advanced, eco-friendly delivery systems to improve bioavailability and therapeutic targeting. Special attention will be given to the integration of emerging technologies—such as artificial intelligence, machine learning, digital twin modeling, and the Internet of Things—in optimizing drug design, disease modeling, and personalized medicine. This multidisciplinary platform supports the transition toward more sustainable and efficient pharmaceutical innovation.

Dr. Alina Bora
Dr. Luminita Crisan
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

natural and synthetic products
drug discovery and development
drug repurposing
artificial intelligence and machine learning
biological evaluation
healthcare
green and sustainable chemistry
natural and synthetic drug applications

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Published Papers (5 papers)

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Research

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17 pages, 3263 KB

Open AccessArticle

10-epi-Protectin DX and Resolvin D5_{n-3 DPA} Attenuate Multi-Organ Inflammatory Injury in an LPS-Induced Murine Endotoxemia Model

by Suyeon Kim, Uijin Kim, Nahyun Kim, Tae-Eui Lee, Jin Lee, Deok-Kun Oh and Ha Youn Shin

Int. J. Mol. Sci. 2026, 27(8), 3356; https://doi.org/10.3390/ijms27083356 - 8 Apr 2026

Viewed by 414

Abstract

Sepsis is a life-threatening syndrome driven by dysregulated immune activation and multi-organ dysfunction, with limited effective therapies. Oxylipins are endogenous lipid mediators that promote the resolution of inflammation and tissue repair, yet their therapeutic potential in systemic inflammatory diseases remains incompletely understood. In this study, we evaluated the effects of two oxylipins, 10-epi-Protectin DX (10-epi-PDX) and Resolvin D5_{n-3 DPA} (RvD5_{n-3 DPA}), in a lipopolysaccharide (LPS)-induced murine endotoxemia model. Given that this model recapitulates key features of systemic inflammation and multi-organ injury relevant to sepsis-associated conditions, oxylipin effects were assessed across major organs implicated in systemic inflammatory pathology. Administration of either oxylipin significantly reduced systemic tissue injury and inflammatory damage in the lungs, kidneys, and liver. These protective effects were accompanied by suppression of inflammatory responses and marked improvements in histopathological outcomes. These findings indicate that 10-epi-PDX and RvD5_{n-3 DPA} possess organ-protective, anti-inflammatory properties in endotoxemia and support further investigation of their potential as therapeutic candidates for limiting systemic inflammatory injury. Full article

(This article belongs to the Special Issue Nature-Inspired and Synthetic Compounds: New Frontiers in Bioactivity and Drug Discovery)

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24 pages, 9129 KB

Open AccessArticle

Soloxolone N-3-(Dimethylamino)propylamide Suppresses Tumor Growth and Mitigates Doxorubicin-Induced Hepatotoxicity in RLS40 Lymphosarcoma-Bearing Mice

by Arseny D. Moralev, Aleksandra V. Sen’kova, Alina A. Firsova, Daria E. Solomina, Artem D. Rogachev, Oksana V. Salomatina, Nariman F. Salakhutdinov, Marina A. Zenkova and Andrey V. Markov

Int. J. Mol. Sci. 2025, 26(24), 11912; https://doi.org/10.3390/ijms262411912 - 10 Dec 2025

Viewed by 651

Abstract

Multidrug resistance (MDR) remains a significant obstacle to effective cancer chemotherapy, primarily due to overexpression of P-glycoprotein (P-gp), which reduces intracellular accumulation of cytotoxic drugs. This study evaluated the pharmacological potential of the glycyrrhetinic acid derivative soloxolone N-3-(dimethylamino)propylamide (Sol-DMAP) as a biocompatible P-gp inhibitor with hepatoprotective properties. Using a murine model of P-gp-overexpressing RLS40 lymphosarcoma, we demonstrated that Sol-DMAP significantly enhanced the antitumor efficacy of doxorubicin (DOX) by increasing its intratumoral concentration 4.7-fold without enhancing systemic toxicity. Independently, Sol-DMAP exhibited direct antitumor activity, reducing tumor growth in vivo and inducing apoptosis and G1-phase arrest in RLS40 cells in vitro. In addition, Sol-DMAP mitigated DOX-induced hepatic injury by reducing necrotic and dystrophic changes in liver tissue and restoring heme oxygenase 1 (Hmox1) expression. Further studies in HepG2 cells confirmed that Sol-DMAP activated the NRF2-dependent antioxidant response, upregulating HMOX1, GCLC, GCLM, and NQO1 genes. Molecular docking revealed that Sol-DMAP can disrupt the KEAP1-NRF2 interaction, likely leading to NRF2 activation. Collectively, these findings demonstrate that Sol-DMAP effectively reverses P-gp-mediated MDR while protecting the liver from oxidative stress, highlighting its potential as a multifunctional scaffold for the development of safer and more effective chemotherapeutic adjuvants. Full article

(This article belongs to the Special Issue Nature-Inspired and Synthetic Compounds: New Frontiers in Bioactivity and Drug Discovery)

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27 pages, 2873 KB

Open AccessArticle

A Comprehensive Environmental and Molecular Strategy for the Evaluation of Fluroxypyr and Nature-Derived Compounds

by Ion Valeriu Caraba, Luminita Crisan and Marioara Nicoleta Caraba

Int. J. Mol. Sci. 2025, 26(17), 8209; https://doi.org/10.3390/ijms26178209 - 24 Aug 2025

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Abstract

This study evaluated the effects of different doses of the herbicide fluroxypyr on soil microbial communities under controlled laboratory conditions. Specific enzymatic activities ((dehydrogenase (DA), urease (UA), catalase (CA), phosphatase (PA)) and quantitative variations in bacterial and fungal populations were measured regarding key physico-chemical soil parameters (temperature, pH, electrical conductivity, moisture, organic matter, ammonium, nitrate nitrogen, and available phosphate content). The effects of the herbicide on the targeted parameters were dose- and time-dependent. Fluroxypyr induced a clear decrease in DA, CA, and PA during the first 14 days after administration, while UA showed a decrease in the first 7 days, followed by a slight increase starting on day 14, closely related to the applied dose. Microbial populations decreased in direct relation to the fluroxypyr dose. Organic matter content exhibited a positive correlation with DA, UA, CA, as well as with microbial populations. In addition, three natural compounds structurally similar to fluroxypyr were identified via 3D virtual screening, demonstrating potential herbicidal activity. Fluroxypyr can alter soil metabolic activity and disrupt microbial communities, thereby affecting soil fertility. Used as a reference in 3D screening, fluroxypyr helped identify three natural compounds with potential herbicidal activity as safer alternatives to synthetic herbicides. Full article

(This article belongs to the Special Issue Nature-Inspired and Synthetic Compounds: New Frontiers in Bioactivity and Drug Discovery)

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Review

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65 pages, 4279 KB

Open AccessReview

Plant-Derived Compounds as Potential Sensitizers to Immunotherapy in Melanoma

by Oana Bătrîna, Roxana Negrea-Ghiulai, Liana Suciu, Roxana Racoviceanu, Elisabeta Atyim, Mihaela Jorgovan, Tamara Maksimovic, Alexandra Mioc, Cristina Trandafirescu, Codruța Șoica and Marius Mioc

Int. J. Mol. Sci. 2026, 27(10), 4423; https://doi.org/10.3390/ijms27104423 - 15 May 2026

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Abstract

Compounds of plant origin have increasingly emerged as anticancer agents through direct cytotoxicity and sensitizing mechanisms. Melanoma remains the most aggressive form of skin cancer that exhibits a steadily increasing number of new cases globally each year, thus urgently requiring more effective therapeutic strategies. Therefore, phytochemicals can be considered promising candidates, particularly when used in combination with immune checkpoint inhibitors. Their ability to optimize therapeutic efficacy and strengthen antitumor immune responses is mediated through various mechanisms that include the stimulation of T cell activity, the regulation of the TME, the activation of intrinsic immune responses and cytokine signaling, and the regulation of immune checkpoints such as PD-1/PD-L1, CTLA-4, and LAG-3. Additionally, these compounds can alter key signaling pathways that control immune regulation. Nevertheless, the extrapolation of preclinical studies to clinical applications remains limited by insufficient clinical evidence, the lack of standardized therapeutic protocols, and poor pharmacokinetic behavior. Consequently, further studies are required in order to clarify their actual efficacy and to better define their role in modern oncology. This article aims to review the mechanisms that underlie the anticancer sensitizing activity of major classes of plant-derived compounds such as polyphenols, flavonoids, terpenoids, alkaloids, and isothiocyanates. The available preclinical and clinical evidence were reported together with their potential synergistic effects when combined with immune checkpoint inhibitors. An important aspect related to the anticancer effects of these compounds lies in their ability to simultaneously target multiple signaling pathways. Furthermore, advanced formulations such as nanoparticulated delivery systems are discussed as strategies to optimize their clinical application and therapeutic outcomes. Full article

(This article belongs to the Special Issue Nature-Inspired and Synthetic Compounds: New Frontiers in Bioactivity and Drug Discovery)

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13 pages, 551 KB

Open AccessReview

Interleukin 13 (IL-13) Signalling as a Potential Target for Cell Therapies in Liver Fibrosis

by Adam Mazurski, Alicja Bednarz and Piotr Czekaj

Int. J. Mol. Sci. 2026, 27(6), 2735; https://doi.org/10.3390/ijms27062735 - 17 Mar 2026

Viewed by 592

Abstract

Liver fibrosis is a regenerative mechanism, but it pathologically intensifies in the course of various diseases, leading to progressive impairment of organ function. This process involves parenchymal cells (hepatocytes) and non-parenchymal cells (Kupffer cells, stellate cells, and endothelial cells). Its classic mechanism is based on the activation of stellate cells, the main effector of fibrosis, by transforming growth factor β (TGF-β), which stimulates excessive collagen production. The role of interleukin 13 (IL-13), which enters the liver parenchyma from resident lymphoid cells, seems to be equally important. By binding to the IL-13Rα receptor on stellate cells, IL-13 initiates their activation and increases the production of type I collagen. This process is supported by the Erk1/2 pathway, which induces the expression of genes promoting extracellular matrix deposition. Due to its role as an initiator of the fibrotic cascade, IL-13 represents a promising therapeutic target for inhibiting progressive scarring. In this context, cell therapies are considered to be of great importance. Mesenchymal and epithelial stem cell secretions contain, among others, exosomes that carry paracrine mediators that can inhibit the profibrotic effects of IL-13 by modulating IL-13 signalling, limiting the development of organ scarring. However, the data on clinical applications of this molecular pathway is scarce, as there are no significant studies focusing on IL-13 influence in liver fibrosis. This review emphasizes the lack of clear clinical data linking the beneficial effects of cell therapy with modulation of the IL-13 pathway, which highlights the need for such studies. Full article

(This article belongs to the Special Issue Nature-Inspired and Synthetic Compounds: New Frontiers in Bioactivity and Drug Discovery)

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