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Drug Discovery: Natural Products and Compounds

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

Deadline for manuscript submissions: closed (20 March 2026) | Viewed by 8305

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Prof. Dr. Vincenzo Summa

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Department of Excellence of Pharmacy, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy
Interests: organic chemistry; analytical chemistry; antivirals; nutraceuticals; food chemistry
Special Issues, Collections and Topics in MDPI journals

Dr. Maria Maisto

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Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
Interests: nutraceuticals; bioactive compounds; antioxidant activity; mass spectrometry; chromatography
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Dr. Vincenzo Piccolo

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Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
Interests: food chemistry; nutraceuticals; antioxidants; chromatography; mass spectrometry; metabolomics; analytical chemistry; botanicals; phytochemistry; natural compounds; skin diseases; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue aims to highlight recent advances in drug discovery from natural products and bioactive compounds. Given their chemical diversity and biological activity, natural products from medicinal plants, marine organisms, and microorganisms continue to offer valuable scaffolds for the development of novel therapeutics against cancer, infections, inflammation, and metabolic diseases.

This Special Issue aims to gather high-quality research and review articles on the identification, structural characterization, biological evaluation, and molecular mechanisms of natural compounds. We particularly encourage studies involving advanced analytical techniques, in silico modeling, biosynthesis, synthetic modification, and innovative delivery systems. Topics such as metabolomics, dereplication, structure–activity relationship (SAR) studies, cheminformatics, sustainable sourcing, and biotechnological production are also of great interest. Interdisciplinary approaches integrating pharmacokinetics, toxicology, target identification, and system biology to elucidate mechanisms of action are especially valued. By providing a multidisciplinary dialog, this Special Issue aims to advance the field of natural product-based drug discovery and support the translation of natural compounds into effective therapeutic agents.

This Special Issue is supervised by Prof. Dr. Vincenzo Summa and Prof. Dr. Maria Maisto, with the assistance of our Topical Advisory Panel Member Dr. Vincenzo Piccolo (University of Naples Federico II, https://www.mdpi.com/journal/ijms/topical_advisory_panel?search=Vincenzo+Piccolo).

Prof. Dr. Vincenzo Summa
Dr. Maria Maisto
Dr. Vincenzo Piccolo
Guest Editors

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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 products
drug discovery
bioactive compounds
phytochemicals
marine natural compounds
microorganisms
structure–activity relationships (SARs)
pharmacological activity
cheminformatics
metabolomics

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Published Papers (8 papers)

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Research

21 pages, 4928 KB

Open AccessArticle

The Endogenous Metabolite TDCA Ameliorates LPS-Driven Liver Injury via Modulation of Caspase-11/GSDMD-Mediated Pyroptosis

by Deqing Ruan, Xing Yan, Yanmei Tang, Shunhua Yang, Xinxin Yang, Mei Zhang, Shibo Yu and Jie Yu

Int. J. Mol. Sci. 2026, 27(5), 2273; https://doi.org/10.3390/ijms27052273 - 28 Feb 2026

Viewed by 249

Abstract

The liver is a central immunometabolic organ during endotoxemia and a major target of sepsis-related injury. Intriguingly, the liver exhibits a notable resilience to endotoxemia or septic insults, suggesting the activation of endogenous protective mechanisms. The bile acid taurodeoxycholic acid (TDCA) demonstrates hepatoprotective properties; nonetheless, its role and mechanism in lipopolysaccharide (LPS)-driven inflammatory liver injury remain elusive. This study reveals that LPS challenge induces significant reprogramming of hepatic bile acid metabolism, with TDCA being markedly elevated in LPS-challenged mice. In vitro, TDCA dose-dependently attenuated pyroptosis in bone marrow-derived macrophages, as evidenced by reduced lactate dehydrogenase (LDH) release, decreased interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion, and suppressed dye Oxazole yellow uptake. Consistent with reduced non-canonical inflammasome signaling, TDCA treatment was associated with decreased activation of caspase-11 and its downstream targets Gasdermin D (GSDMD) and IL-1β. In a lethal D-Galactosamine (D-GalN)/LPS-induced toxin-sensitized inflammatory liver injury model, therapeutic administration of TDCA (3, 6 mg/kg) profoundly improved survival rates (40% and 80%, respectively), attenuated liver injury, reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST), suppressed systemic inflammation (IL-1β and IL-18), and ameliorated histopathological damage. Crucially, TDCA treatment reduced the activation of the caspase-11/GSDMD pathway in the septic liver. Our findings demonstrate that TDCA is an endogenously mobilized bile acid that confers protection against LPS-driven inflammatory liver injury, with effects supporting a role for modulation of the Caspase-11/GSDMD pyroptotic pathway. These observations provide hypothesis-generating implications for sepsis-associated liver injury that warrant further validation in clinically relevant sepsis models and pathway-necessity studies. Full article

(This article belongs to the Special Issue Drug Discovery: Natural Products and Compounds)

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21 pages, 3822 KB

Open AccessArticle

Characterization of Bacillus velezensis EV17 and K-3618 and Their Polyketide Antibiotic Oxydifficidin, an Inhibitor of Prokaryotic Translation with Low Cytotoxicity

by Alisa P. Chernyshova, Valeriya I. Marina, Andrey G. Tereshchenkov, Vladislava E. Sagitova, Maksim A. Kryakvin, Nikolai D. Dagaev, Eugeniya G. Yurchenko, Kseniya A. Arzamazova, Elena B. Guglya, Olga A. Belozerova, Sergey I. Kovalchuk, Margarita N. Baranova, Arsen M. Kudzhaev, Anton E. Shikov, Maria N. Romanenko, Alexander Yu. Rudenko, Vladimir K. Chebotar, Maria S. Gancheva, Maria E. Baganova, Mikhail V. Biryukov, Tatiana V. Panova, Maria G. Khrenova, Vadim N. Tashlitsky, Natalia V. Sumbatyan, Yulia V. Zakalyukina, Kirill S. Antonets, Anton A. Nizhnikov, Vladimir I. Polshakov, Stanislav S. Terekhov, Maria I. Zvereva, Olga A. Dontsova, Petr V. Sergiev, Vera A. Alferova and Dmitrii A. Lukianov Show full author list Hide full author list

Int. J. Mol. Sci. 2025, 26(24), 11777; https://doi.org/10.3390/ijms262411777 - 5 Dec 2025

Cited by 2 | Viewed by 730

Abstract

Oxydifficidin is a natural polyketide antibiotic that has long been recognized as a ribosome-targeting agent that inhibits protein synthesis. In this paper, we describe Bacillus velezensis strain EV17 and compare its complete genome sequence with that of the previously characterized B. velezensis strain K-3618 and the difficidin biosynthetic gene cluster (BGC) combined with mass spectrometry to elucidate the production of oxydifficidin by these strains. Toeprinting and small fluorescent peptide assays showed that isolated oxydifficidin induces a generalized inhibition of translation at every step of elongation in protein biosynthesis. In previous studies, it has been demonstrated that oxydifficidin targets bL12 protein. Although spontaneous mutations conferring resistance to oxydifficidin in ribosomal protein bL12 located relatively close to the thiostrepton binding site on uL11, our data show that oxydifficidin binding does not interfere with thiostrepton, thereby refining previous findings about its putative ribosomal target. We are the first to show that this compound does not affect eukaryotic translation and has two orders of magnitude lower effect on eukaryotic cells compared to bacteria. These facts are important to further investigate its potential as a bioprotectant against phytopathogens or even as a therapeutic agent. Full article

(This article belongs to the Special Issue Drug Discovery: Natural Products and Compounds)

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16 pages, 2395 KB

Open AccessArticle

Differential Gene Expression of Porphyromonas gingivalis in the Presence or Absence of Xanthohumol and Curcumin in a Dynamic In Vitro Biofilm Model

by Enrique Bravo, Cristina Chamorro, David Herrera and Mariano Sanz

Int. J. Mol. Sci. 2025, 26(23), 11315; https://doi.org/10.3390/ijms262311315 - 23 Nov 2025

Viewed by 710

Abstract

This study aimed to characterize the transcriptional response of Porphyromonas gingivalis biofilms to treatment with xanthohumol and curcumin. A validated dynamic in vitro biofilm model, based on microbial growth under flow and shear conditions resembling the oral cavity, was used to develop mature biofilms of P. gingivalis on sterile ceramic calcium hydroxyapatite discs. Transcriptional profiles of biofilms, treated and untreated with both extracts, were obtained through RNA-Sequencing (RNA-Seq). The biofilm development and the lack of phenotypic effects from sublethal concentrations of xanthohumol and curcumin were confirmed via Scanning Electron Microscopy (SEM) and Confocal Laser Scanning Microscopy (CLSM). Reverse transcription quantitative PCR (RT-qPCR) was employed to verify differentially expressed genes identified by RNA-Seq. Xanthohumol and curcumin caused extensive reprogramming of P. gingivalis biofilm gene expression. Out of 1,973 genes, xanthohumol activated 173 and repressed 286, whereas curcumin activated 170 and repressed 163. These changes affected genes involved in membrane integrity, oxidative stress, transmembrane transport, and virulence, suggesting a mechanism of action that involves membrane disruption. Full article

(This article belongs to the Special Issue Drug Discovery: Natural Products and Compounds)

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19 pages, 1686 KB

Open AccessArticle

Hybrid Poly(Lactic)-Chitosan Scaffold Intensifying In Situ Bioprocessing of Rindera graeca Transgenic Roots for Enhanced Rinderol Production

by Kamil Wierzchowski, Szymon Bober, Aleksandra Bandzerewicz, Miroslav Šlouf, Jiří Hodan, Agnieszka Gadomska-Gajadhur, Katarzyna Sykłowska-Baranek and Maciej Pilarek

Int. J. Mol. Sci. 2025, 26(21), 10668; https://doi.org/10.3390/ijms262110668 - 1 Nov 2025

Viewed by 652

Abstract

In vitro cultured biomass of Rindera graeca, a rare endemic plant, is an efficient renewable source of bioactive naphthoquinones, e.g., rinderol, a potential bioactive inducer of apoptosis in cancer cells. Bioengineering strategies, as biomass immobilization on functionalized biomaterial-based scaffolds, elicitation by chitosan, and in situ extraction of metabolites, are tested for intensifying naphthoquinones production in R. graeca hairy roots. The aim of the study was to investigate the effects of hybrid poly(lactic)–chitosan scaffolds on biomass proliferation and rinderol production in R. graeca hairy roots. Effects of chitosan origin (fungal or squid), molecular mass (350–1800 kDa), and concentration (up to 45%) in the developed hybrid scaffolds have been quantitatively identified, and the results were compared to the reference culture system containing an unmodified PLA-based construct. Applying PLA–chitosan scaffold containing 33% of fungal chitosan resulted in 635 times higher rinderol production (3660 µg g_DW⁻¹) than the application of reference scaffolds. Among the tested parameters, the chitosan concentration in the hybrid scaffolds revealed significant importance in rinderol production. To sum up, the developed hybrid PLA-chitosan scaffold may be recognized as a functional key element supporting the production of naphthoquinones in cultures of R. graeca biomass. Full article

(This article belongs to the Special Issue Drug Discovery: Natural Products and Compounds)

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31 pages, 4497 KB

Open AccessArticle

Cytotoxicity of Mimusops caffra-Based Ursolic Acid, Oleanolic Acid and Derivatives Against Human Cancerous and Non-Cancerous Cell Lines

by Sithenkosi Mlala, Opeoluwa Oyehan Oyedeji, Gbemisola Morounke Saibu, Mavuto Gondwe and Adebola Omowunmi Oyedeji

Int. J. Mol. Sci. 2025, 26(20), 9969; https://doi.org/10.3390/ijms26209969 - 13 Oct 2025

Viewed by 1076

Abstract

According to the World Health Organization, cancer is still the leading cause of death for humans worldwide. Although over 100 chemotherapeutic agents are currently available for the treatment of cancer patients, the overall long term clinical benefit is disappointing due to the lack of effectiveness or severe side effects from these drugs. The use of complementary and alternative medicinal products from plants has continued to increase in past decades, due to fewer side effects of bioactive compounds from medicinal plants of which pentacyclic triterpenoids have been identified as one class of secondary metabolites that could play an important role in the treatment and management of a number of non-communicable diseases. The main aim of this study is to extract, isolate, identify, and elucidate pentacyclic triterpenoid (ursolic acid, UA (1), and oleanolic acid, OA (2)) from Mimusops caffra. Semi-synthesis of UA was carried out to obtain some triterpenoid derivatives (3-O-acetyl ursolic acid, AUA (3), ursolic-28-methylate, UM (4), and 3-acetylursolic-methylate, AUM (5)), and we evaluated these compounds as anti-cancer therapeutic agents. Isolation of ursolic acid (UA) (1) from M. caffra is always accompanied by its isomer oleanolic acid (OA) (2) due to their similar retention factors (Rf) values. Acetylation and deacetylation techniques were used to isolate compounds 1 and 2. In vitro cytotoxicity activities of UA, AUA UM, and AUM were evaluated against various cancer cell lines, such as human breast adenocarcinoma cancer cell lines (MDA), human liver cancer cell lines (HepG2), human prostate cancer cell lines (PC3) and non-cancerous human fibroblast cell lines (KMST-6) using MTT assays. The UM exhibited remarkable cytotoxic activities against cancer cells, while little or no activities were observed on non-cancerous cell lines, which indicates that the addition of methyl at C-28 of UA is essential to enhance its activity as a therapeutic agent for cancer. The AUA showed moderate or no cytotoxicity against the different cancer cell lines, which is less than that of the UA parent compound. Moreover, these results suggest that ursolic acid and UA derivatives are potential therapeutic drugs for human breast, liver, and prostate cancers. Full article

(This article belongs to the Special Issue Drug Discovery: Natural Products and Compounds)

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17 pages, 1164 KB

Open AccessArticle

Larvicidal Effects and Phytochemical Analysis of Myrrh, Commiphora myrrh Chloroform, Methanol, and Acetone Extracts Against Dengue Vector Aedes aegypti L. (Diptera: Culicidae)

by Abadi M. Mashlawi, Hanan Bosly, Amal Naif Alshammari, Naimah Asid H. Alanazi, Mohammed A. Akeel, Amani Alhejely, Fahdah Ayed Alshammari, Mohammed Abdullah Jeraiby, Naser Ahmed Alkenani and Salama A. Salama

Int. J. Mol. Sci. 2025, 26(16), 8050; https://doi.org/10.3390/ijms26168050 - 20 Aug 2025

Viewed by 1213

Abstract

Mosquitoes pose a significant problem worldwide because of the diseases they transmit. Due to its antimicrobial and disinfectant properties, Commiphora myrrha (C. myrrha) has long been a popular choice in traditional medicine. This study aimed to extract C. myrrha using three different solvents—methanol, acetone, and chloroform—to identify their biochemical components and assess their larvicidal activity. The extracts were analyzed using gas chromatography–mass spectrometry, and their effects were evaluated against Aedes aegypti. We identified 29, 41, and 19 phytoconstituents in the acetone, methanol, and chloroform extracts, respectively, with most belonging to the sesquiterpene and phenol categories. Larval mortality rates were recorded as follows: chloroform (100%), methanol (90%), and acetone (95%) extracts of C. myrrha at a concentration of 1000 ppm, 24 h post-treatment. After 72 h, the C. myrrha extracts showed effectiveness with LC₅₀ values of 118.33, 127.67, and 142.13 ppm for chloroform, acetone, and methanol, respectively. The chloroform extract was the most effective in reducing the average number of eggs laid per day (234 eggs) compared to the untreated control group (1513 eggs) at 1000 ppm. These findings provide scientific evidence of the larvicidal efficacy of C. myrrha extracts and serve as valuable resources for developing plant-based pharmaceuticals. Full article

(This article belongs to the Special Issue Drug Discovery: Natural Products and Compounds)

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24 pages, 4816 KB

Open AccessArticle

Formulation of Honokiol- and Magnolol-Loaded Nanoemulsions for Head and Neck Cancer Adjuvant Therapy: Evaluation of Radiation Sterilization Effects on Active Substance Properties

by Katarzyna Dominiak, Aleksandra Gostyńska-Stawna, Agnieszka Sobczak, Jarosław Paluszczak, Aneta Woźniak-Braszak, Mikołaj Baranowski, Paweł Bilski, Barbara Wicher, Ewa Tykarska, Anna Jelińska and Maciej Stawny

Int. J. Mol. Sci. 2025, 26(16), 8032; https://doi.org/10.3390/ijms26168032 - 20 Aug 2025

Cited by 1 | Viewed by 1223

Abstract

Honokiol (HON) and magnolol (MAG), structural isomers from Magnolia officinalis, exhibit notable anticancer activity, particularly against head and neck squamous cell carcinoma (HNSCC). However, due to their high lipophilicity, their intravenous administration is challenging. This study aimed to develop HON- and MAG-loaded intravenous (IV) nanoemulsions using commercial lipid preparations with varying fatty acid compositions. The formulations were physicochemically characterized and evaluated in vitro using FaDu and SCC-040 HNSCC cell lines. HON and MAG were sterilized via ionizing radiation at doses of 25, 100, and 400 kGy. Their suitability for IV use was assessed through PXRD, DSC, TGA, EPR, FT-IR, NMR, and HPLC analyses. All formulations met safety criteria for IV administration, with mean droplet diameters below 241 nm and encapsulation efficiencies exceeding 95%. They significantly reduced cancer cell viability, with a synergistic effect observed in combined HON and MAG formulations compared to single-compound nanoemulsions. Clinoleic-based formulations showed enhanced anticancer efficacy, likely due to the pro-apoptotic properties of oleic acid. Notably, radiation sterilization at the standard 25 kGy dose preserved the thermal, crystalline, and structural stability of HON and MAG, whereas higher doses (400 kGy) induced degradation. Although free radicals were detected via EPR, their transient nature and rapid decay confirmed the method’s safety. HON/MAG-loaded nanoemulsions exhibited strong anticancer potential, while radiation sterilization at 25 kGy ensured sterility without compromising stability. These findings provide a preliminary in vitro basis for future in vivo studies investigating HON and MAG as potential adjuvant therapies for HNSCC. Full article

(This article belongs to the Special Issue Drug Discovery: Natural Products and Compounds)

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13 pages, 2783 KB

Open AccessArticle

Eggplant (Solanum spp.) Fruits Dietary Polyphenols Upregulate the Expression of Glucose Transporter Protein in Palmitate-Induced Diabetic Cell Line C2C12

by Esther E. Nwanna, Emmanuel Mukwevho, Emmanuel Okello, Ademola O. Ayeleso, Emmanuel O. Ibukun and Ganiyu Oboh

Int. J. Mol. Sci. 2025, 26(16), 7762; https://doi.org/10.3390/ijms26167762 - 11 Aug 2025

Cited by 1 | Viewed by 1551

Abstract

Studies utilizing cell-based systems to investigate plant-based diets for diabetes management are gaining attention due to the adverse effects associated with commercially available drugs. However, the molecular mechanisms underlying the anti-diabetic effects of specific plant-derived products remain inadequately explored. The major aim of our study was to elucidate the molecular mechanisms by which bioactive compounds in the fruit of Solanum spp. influence key proteins associated with type 2 diabetes. The expressions of genes such as glucose transporter protein 4 (GLUT4), myocyte enhancer factor-2 (MEF-2A), and nuclear respiratory factor-1 (NRF-1) were investigated in a palmitate-induced C2C12 cell model of type 2 diabetes mellitus. The structures of these proteins were retrieved from the protein database, while bioactive compounds previously identified in Solanum spp. were obtained from PubChem site. Drug-likeness properties of these compounds (ligands) were assessed. The docked protein-ligand complexes were further analyzed using the Protein-Ligand Profiler web server. Our results showed that the studied compounds from Solanum spp. profoundly upregulated GLUT4 expression (9–19-fold increase) in the C2C12 cell line, thus surpassing the effects of the standard anti-diabetic drug metformin. Additionally, activities of antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase were elevated. Molecular docking showed that rutin, an abundant flavonoid from Solanum spp., had the highest binding affinity for the active sites of the target proteins. These findings provide new mechanistic insight into the anti-diabetic effects of Solanum spp., primarily due to its high rutin content, which plays a major role in the plant’s glucose-regulating and antioxidant actions. Our findings underscore the potential use of Solanum spp. as an affordable functional food for managing type 2 diabetes, especially in developing countries with limited resources for purchasing drugs. Although promising, our findings should be further validated by clinical studies. Full article

(This article belongs to the Special Issue Drug Discovery: Natural Products and Compounds)

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