Research into Bioactive Natural Compounds: New Molecules, Bioinspired Syntheses, Biotechnological Methods and Bioassays—Celebrating the Pioneering Work of Prof. Alejandro Fernandez Barrero

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-derived Molecules".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 8039

Special Issue Editors


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Guest Editor
Department of Organic Chemistry, University of Granada, 18071 Granada, Spain
Interests: natural products (terpenes); organic synthesis; pest control
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Special Issue Information

Dear Colleagues,

In 2020, Professor Alejandro F. Barrero retired after devoting more than 45 years to teaching and research activities. During these years. Prof. Barrero focused his efforts on the field of natural products chemistry, including the isolation, structural elucidation, chemical synthesis, and pharmacology of compounds derived from natural sources. Prof. Barrero’s team discovered more than two hundred new natural molecules and, in parallel, a number of biomimetic syntheses of natural products, employing new protocols based on both radical and cationic chemistry. Furthermore, he pioneered the use of innovative natural compounds as starting materials, thus favoring isolation methodologies. He also performed biosynthetic studies of terpenes using genetically modified fungi. Honoring the work of Prof. Barrero, this Special Issue is dedicated to the study of the chemistry of natural products.

Historically, natural products and their structural analogues have played a significant role in many fields that contribute to human welfare, including human and veterinary medicine, agriculture, and the food and the cosmetic industries.

The research into natural products is currently an efficient and safe approach to worldwide problems. In particular, there is a need for improved agricultural practices and strategies to address population explosion and climate change in tandem with stricter regulations for insecticide use. Similarly, the demand for new drugs including new antibiotics is enormous; according to the WHO, one of the greatest threats that we face as a global community is antibiotic resistance, which is revitalizing interest in the use of natural products as drug leads.

In parallel to these needs, the development of improved analytical tools, genome mining, and advances in microbial culturing are creating new opportunities for natural product-based bioactive compound discovery.

Finally, the fact that many of these natural products can be obtained from renewable sources may enable the study of their potential contributions to the circular economy.

This Special Issue aims to perform an overall survey of the research into bioactive natural compounds, including the description of new naturally occurring molecules, as well as the synthesis of these bioactive compounds, including biomimetic synthesis, microbial culturing production and the preparation of new active derivatives. Studies carried out to test the bioactivity of these natural compounds will also be considered. This subject fits the scope of this journal, particularly in the area of “Natural and Bio-inspired Molecules”

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following areas:

  • Processes used for the extraction-fractioning of bioactive natural terpenoids and new natural products;
  • Biotechnology: the study of biosynthetic routes and production of bioactive natural products from fungi and bacteria, known as biotransformation;
  • Synthesis of bioactive natural products using bioinspired synthetic approaches and the use of natural synthons and bioconversions;
  • Search for pharmacologically active natural products, biopesticides, etc.

We look forward to receiving your contributions.

Dr. José Francisco Quílez del Moral
Dr. Azucena González Coloma
Guest Editors

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Keywords

  • natural products
  • bioactivity
  • organic synthesis
  • biotecnnology
  • structural elucidation

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Published Papers (6 papers)

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Research

22 pages, 2510 KiB  
Article
The Epiphyte Bacillus sp. G2112 Produces a Large Diversity of Nobilamide Peptides That Promote Biofilm Formation in Pseudomonads and Mycobacterium aurum
by Kenechukwu Iloabuchi and Dieter Spiteller
Biomolecules 2024, 14(10), 1244; https://doi.org/10.3390/biom14101244 - 1 Oct 2024
Viewed by 795
Abstract
Bacillus sp. G2112, an isolate from cucumber plants that inhibited plant pathogens, produces not only surfactins, iturins, and fengycins common to many Bacillus spp., but also a large variety of N-acyl-(depsi)peptides related to A-3302-B and nobilamides. Four known and fourteen previously unreported [...] Read more.
Bacillus sp. G2112, an isolate from cucumber plants that inhibited plant pathogens, produces not only surfactins, iturins, and fengycins common to many Bacillus spp., but also a large variety of N-acyl-(depsi)peptides related to A-3302-B and nobilamides. Four known and fourteen previously unreported nobilamide peptides were characterized using high-resolution mass spectrometry, tandem mass spectrometry, and NMR. The stereochemistry of the amino acids of nobilamide peptides was determined using Marfey’s method. The diversity of nobilamide peptides from Bacillus sp. G2112 resulted from the incorporation of different acyl groups and amino acids in the sequence. The peptides occur in linear or cyclic form. In addition, a truncated N-acetylpentapeptide was produced. Agar diffusion assays with selected nobilamide peptides against plant pathogens and human pathogens revealed that A-3302-B and its N-acyl homologs, A-3302-A and nobilamide J, exhibited powerful antibiotic activity (at 5 µg/hole) against Lysinibacillus sphaericus that can cause severe sepsis and bacteremia in patients. Moreover, nobilamide peptides from Bacillus sp. G2112 strongly promoted biofilm formation in the Gram-positive Mycobacterium aurum and Gram-negative pseudomonads. Structurally diverse nobilamides from Bacillus sp. G2112, whether linear or cyclic, penta and heptapeptides, induced biofilm formation, suggesting that the common N-acetyl-D-Phe-D-Leu-L-Phe-D-allo-Thr-L-Val amino acid sequence motif is important for the biofilm-inducing activity. Full article
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20 pages, 2271 KiB  
Article
Genome Mining for Diazo-Synthesis-Related Genes in Streptomyces sp. CS057 Unveiled the Cryptic Biosynthetic Gene Cluster crx for the Novel 3,4-AHBA-Derived Compound Crexazone 2
by Laura Prado-Alonso, Suhui Ye, Ignacio Pérez-Victoria, Ignacio Montero, Pedro Riesco, Francisco Javier Ortiz-López, Jesús Martín, Carlos Olano, Fernando Reyes and Carmen Méndez
Biomolecules 2024, 14(9), 1084; https://doi.org/10.3390/biom14091084 - 29 Aug 2024
Viewed by 1286
Abstract
Natural products play a crucial role in drug development, addressing the escalating microbial resistance to antibiotics and the treatment of emerging diseases. Progress in genome sequencing techniques, coupled with the development of bioinformatics tools and the exploration of uncharted habitats, has highlighted the [...] Read more.
Natural products play a crucial role in drug development, addressing the escalating microbial resistance to antibiotics and the treatment of emerging diseases. Progress in genome sequencing techniques, coupled with the development of bioinformatics tools and the exploration of uncharted habitats, has highlighted the biosynthetic potential of actinomycetes. By in silico screening for diazo-related gene genomes from twelve Streptomyces strains isolated from Attini leaf-cutting ants, the new crx biosynthetic gene cluster (BGC) was identified in Streptomyces sp. CS057. This cluster, highly conserved in several Streptomyces strains, contains genes related to diazo group formation and genes for the biosynthesis of 3,4-AHBA. By overexpressing the LuxR-like regulatory gene crxR1, we were able to activate the crx cluster, which encodes the biosynthesis of three 3,4-AHBA-derived compounds that we named crexazones (CRXs). The chemical structure of crexazones (CRXs) was determined by LC-DAD-HRMS-based dereplication and NMR spectroscopic analyses and was found to correspond to two known compounds, 3-acetamido-4-hydroxybenzoic acid (CRX1) and the phenoxazinone texazone (CRX3), and a novel 3,4-AHBA-containing compound herein designated as CRX2. Experimental proof linking the crx BGC to their encoded compounds was achieved by generating mutants in selected crx genes. Full article
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20 pages, 10882 KiB  
Article
Planarian Mucus: A Novel Source of Pleiotropic Cytotoxic and Cytostatic Agents against Cancer Cells
by Gaetana Gambino, Eleonora Da Pozzo, Alessandra Salvetti and Leonardo Rossi
Biomolecules 2024, 14(9), 1075; https://doi.org/10.3390/biom14091075 - 28 Aug 2024
Viewed by 903
Abstract
Biological evolution has generated a vast array of natural compounds produced by organisms across all domains. Among these, secondary metabolites, selected to enhance an organism’s competitiveness in its natural environment, make them a reservoir for discovering new compounds with cytotoxic activity, potentially useful [...] Read more.
Biological evolution has generated a vast array of natural compounds produced by organisms across all domains. Among these, secondary metabolites, selected to enhance an organism’s competitiveness in its natural environment, make them a reservoir for discovering new compounds with cytotoxic activity, potentially useful as novel anticancer agents. Slime secretions, the first barrier between epithelial surfaces and the surrounding environment, frequently contain cytotoxic molecules to limit the growth of parasitic organisms. Planarians, freshwater Triclads, continuously secrete a viscous mucus with multiple physiological functions. The chemical composition of planarian mucus has been only partially elucidated, and there are no studies reporting its cytotoxic or cytostatic effects. In this study, we developed a protocol for collecting mucus from Dugesia japonica specimens and we demonstrated that it inhibits the growth of cancer cells by activating cytostatic and ROS-dependent cytotoxic mechanisms inducing lipid droplet accumulation and mitochondrial membrane reorganization. Although further research is needed to identify the specific chemicals responsible for the anticancer activity of planarian mucus, this work opens up numerous research avenues aimed at better understanding the mechanisms of action of this product for potential therapeutic applications. Full article
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17 pages, 4250 KiB  
Article
Molecular Diversity from Longipinenes of Santolina viscosa Lag. through Acid Catalysis: Biocidal Activity
by Irene Torres-García, José F. Quílez del Moral, Alejandro F. Barrero, Azucena González-Coloma, María Fe Andrés, José L. López-Pérez, Miriam Álvarez-Corral, Ignacio Rodríguez-García and Manuel Muñoz-Dorado
Biomolecules 2024, 14(7), 780; https://doi.org/10.3390/biom14070780 - 30 Jun 2024
Viewed by 948
Abstract
The search for new compounds with biocidal potential was carried out, focusing on the longipinenes 17 from the plant species Santolina viscosa Lag. Compounds 1, 2, and 5 showed remarkable molecular diversity when treated in acidic reaction conditions. Protonic, [...] Read more.
The search for new compounds with biocidal potential was carried out, focusing on the longipinenes 17 from the plant species Santolina viscosa Lag. Compounds 1, 2, and 5 showed remarkable molecular diversity when treated in acidic reaction conditions. Protonic, Lewis, and heterogeneous compounds were used in the treatment. Three main models of reaction have been observed: isomerization of the double bond (810); rearrangements to longibornane-based skeleton (1115) and ring-opening to himachalane-based skeleton (1618). Secolongibornane aldehydes 23 and 24 were obtained after epoxide opening under the same reaction conditions. The elucidation of the structures of the new compounds was carried out using spectroscopic data and was supported by computational theoretical calculations of 13C NMR spectra. Additionally, high-resolution mass spectrometry and single-crystal X-ray diffraction analysis were employed for certain compounds. Natural longipinenes 47, methyl esters 13 of corresponding natural carboxylic acids and the isomerized and derivatives compounds 819 exhibit moderate to high insecticidal activity against R. padi and M. persicae insects. Longipinene 5 shows potent inhibition against the root growth of the plants L. perenne and L. sativa, as well as compound 2 on the leaves of L. perenne. Furthermore, significant ixocidal and nematicidal activity was found for this latter compound. Full article
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21 pages, 5750 KiB  
Article
Anti-Biofilm Perspectives of Propolis against Staphylococcus epidermidis Infections
by Virginia Vadillo-Rodríguez, Irene Fernández-Babiano, Ciro Pérez-Giraldo and María Coronada Fernández-Calderón
Biomolecules 2024, 14(7), 779; https://doi.org/10.3390/biom14070779 - 29 Jun 2024
Cited by 1 | Viewed by 1701
Abstract
Staphylococcus epidermis has emerged as the main causative agent of medical device-related infections. Their major pathogenicity factor lies in its ability to adhere to surfaces and proliferate into biofilms, which increase their resistance to antibiotics. The main objective of this study was to [...] Read more.
Staphylococcus epidermis has emerged as the main causative agent of medical device-related infections. Their major pathogenicity factor lies in its ability to adhere to surfaces and proliferate into biofilms, which increase their resistance to antibiotics. The main objective of this study was to evaluate the use and the mechanism of action of an ethanolic extract of Spanish propolis (EESP) as a potential alternative for preventing biofilm-related infections caused by S. epidermidis. The chemical composition of propolis is reported and its antibacterial activity against several strains of S. epidermidis with different biofilm-forming capacities evaluated. The influence of sub-inhibitory concentrations (sub-MICs) of EESP on their growth, physicochemical surface properties, adherence, and biofilm formation were studied. EESP interferes with planktonic cells, homogenizing their physicochemical surface properties and introducing a significant delay in their growth. The adherence and biofilms at the EESP concentrations investigated were decreased up to 90.5% among the strains. Microscopic analysis indicated that the planktonic cells that survived the treatment were the ones that adhere and proliferate on the surfaces. The results obtained suggest that the EESP has a high potential to be used as an inhibitor of both the adhesion and biofilm formation of S. epidermidis. Full article
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15 pages, 4248 KiB  
Article
Globospiramine Exhibits Inhibitory and Fungicidal Effects against Candida albicans via Apoptotic Mechanisms
by Joe Anthony H. Manzano, Simone Brogi, Vincenzo Calderone, Allan Patrick G. Macabeo and Nicanor Austriaco
Biomolecules 2024, 14(6), 610; https://doi.org/10.3390/biom14060610 - 22 May 2024
Viewed by 1385
Abstract
Candidiasis is considered an emerging public health concern because of the occurrence of drug-resistant Candida strains and the lack of an available structurally diverse antifungal drug armamentarium. The indole alkaloid globospiramine from the anticandidal Philippine medicinal plant Voacanga globosa exhibits a variety of [...] Read more.
Candidiasis is considered an emerging public health concern because of the occurrence of drug-resistant Candida strains and the lack of an available structurally diverse antifungal drug armamentarium. The indole alkaloid globospiramine from the anticandidal Philippine medicinal plant Voacanga globosa exhibits a variety of biological activities; however, its antifungal properties remain to be explored. In this study, we report the in vitro anticandidal activities of globospiramine against two clinically relevant Candida species (C. albicans and C. tropicalis) and the exploration of its possible target proteins using in silico methods. Thus, the colony-forming unit (CFU) viability assay revealed time- and concentration-dependent anticandidal effects of the alkaloid along with a decrease in the number of viable CFUs by almost 50% at 60 min after treatment. The results of the MIC and MFC assays indicated inhibitory and fungicidal effects of globospiramine against C. albicans (MIC = 8 µg/mL; MFC = 8 µg/mL) and potential fungistatic effects against C. tropicalis at lower concentrations (MIC = 4 µg/mL; MFC > 64 µg/mL). The FAM-FLICA poly-caspase assay showed metacaspase activation in C. albicans cells at concentrations of 16 and 8 µg/mL, which agreed well with the MIC and MFC values. Molecular docking and molecular dynamics simulation experiments suggested globospiramine to bind strongly with 1,3-β-glucan synthase and Als3 adhesin—enzymes indirectly involved in apoptosis-driven candidal inhibition. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Bovistols E and F, new Terpenoids Isolated from Psathyrella microrhiza CF-117891
Authors: Fernando Reyes et al.
Affiliation: Fundación MEDINA, Avda del Conocimiento 34, 18016, Armilla, Granada, Spain
Abstract: Bioactivity-based purification of the acetone extract of a culture of the fungus Psathyrella microrhiza CF-117891 led to the isolation of the newbis-sesquiterpenes bovistols E and F (1 and 2) together with the anti-plasmodial macrolide coriolide (3). The structures of the compounds were determined by a combination of (+)-ESI-TOF mass spectrometry and NMR spectroscopy. Of the three compounds isolated, coriolide displayed previously unreported moderate anti-Plasmodiun falciparum 3 D7 activity, with an EC50 value 17.8 µM, whereas the new bovistols did not show any biological activity in their pure forms against this parasite nor against Tripanosoma cruzi Tulahuen parasites. This work further demonstrates that fungal extracts can be a rich source of new chemistry for possible future applications.

Title: Terpenes with Cyclic Anhydride Scaffolds: Occurrence, Biosynthesis and Bioactivity
Authors: Jose Francisco Quilez del Moral
Affiliation: Department of Organic Chemistry, University of Granada, 18071 Granada, Spain

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