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Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: 25 April 2024 | Viewed by 16652

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Dr. Anita Kornicka

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Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdansk, Gen. J. Hallera Av. 107, 80-416 Gdansk, Poland
Interests: medicinal chemistry; heterocyclic compounds; design and synthesis; anticancer activity; antimicrobial activity; structure-activity relationship

Dr. Łukasz Balewski

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Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdansk, Gen. J. Hallera Av. 107, 80-416 Gdansk, Poland
Interests: medicinal chemistry; nitrogen-containing heterocyclic compounds; Cu(II) complexes; design and synthesis; anticancer activity; structure-activity relationship

Special Issue Information

Dear Colleagues,

Coumarins belong to a large family of extensively studied compounds containing the 2H-1-benzopyran-2-one core structure. They are widely distributed in the natural kingdom and occur as secondary metabolites in the seeds, flowers, fruits, leaves, roots, and stems of various plant species used as spices, herbal teas, or medicines. In addition to plant sources, coumarins are also present in some bacteria and fungi, as well as marine organisms. The history of coumarins can be traced back to 1820, when H. A. Vogel first isolated the simplest member of this family—coumarin from the plant Coumarouna odorata Aubl. (syn. Dipteryx odorata (Aubl.) Forsyth f.). Regarding their chemical structures, natural coumarins can be divided into different groups, from simple coumarins and bis-coumarins to several other types of polycyclic coumarins, such as furanocoumarins, pyranocoumarins, benzocoumarins, and coumestans. These naturally derived compounds exhibit a broad spectrum of biological properties, including anticoagulant, anti-inflammatory, antioxidant, antimicrobial (antibacterial, antiviral, antifungal, and antiparasitic), antitumor, neuroprotective, antidiabetic, and enzyme inhibitory effects. Their multi-faceted pharmacological activities along with their high bioavailability, low toxicity, and minor side effects make them attractive lead compounds for the development of novel therapeutic agents. Many strategies have been developed for the synthesis and modification of coumarin structural scaffolds, providing the possibility of designing new coumarin-based compounds as potential drug candidates against various diseases. Coumarins have also been investigated as supramolecular medicinal agents, diagnostic and pathological probes, and biological stains.

In this Special Issue, original research and review articles on the role of natural coumarins as important phytochemicals and lead compounds in drug research, their applications, as well as the development of their synthetic analogues, are highly welcome.

Dr. Anita Kornicka
Dr. Łukasz Balewski
Guest Editors

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Keywords

coumarin
coumarin derivatives
natural products
synthesis
biological activity
drug discovery
drug candidates

Published Papers (9 papers)

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Research

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22 pages, 6994 KiB

Open AccessArticle

Examining the Antioxidant and Superoxide Radical Scavenging Activity of Anise, (Pimpinella anisum L. Seeds), Esculetin, and 4-Methyl-Esculetin Using X-ray Diffraction, Hydrodynamic Voltammetry and DFT Methods

by Miriam Rossi, Francesco Caruso, Natalie Thieke, Stuart Belli, Alana Kim, Elisabetta Damiani, Camilla Morresi and Tiziana Bacchetti

Pharmaceuticals 2024, 17(1), 67; https://doi.org/10.3390/ph17010067 - 31 Dec 2023

Viewed by 896

Abstract

Pimpinella anisum L., or anise, is a plant that, besides its nutritional value, has been used in traditional medical practices and described in many cultures in the Mediterranean region. A possible reason for anise’s therapeutic value is that it contains coumarins, which are known to have many biomedical and antioxidant properties. HPLC analysis in our laboratory of the anise extract shows the presence of the coumarin esculetin. We used a hydrodynamic voltammetry rotating ring–disk electrode (RRDE) method to measure the superoxide scavenging abilities of anise seeds and esculetin, which has marked scavenging activity. A related coumarin, 4-methyl-esculetin, also showed strong antioxidant activity as measured by RRDE. Moreover, this study includes the X-ray crystal structure of esculetin and 4-methyl-esculetin, which reveal the H-bond and the stacking intermolecular interactions of the two coumarins. Coordinates of esculetin crystal structure were used to perform a DFT study to arrive at the mechanism of superoxide scavenging. Besides performing a H(hydroxyl) abstraction in esculetin position 6 by superoxide, the scavenging also includes the presence of a second superoxide radical in a π–π approach. Both rings of esculetin were explored for this attack, but only the pyrone ring was effective. As a result, one product of esculetin scavenging is H₂O₂ formation, while the second superoxide remains π–π trapped within the pyrone ring to form an esculetin-η-O₂ complex. Comparison with other coumarins shows that subtle structural differences in the coumarin framework can imply marked differences in scavenging. For instance, when the catechol moiety of esculetin (position 6,7) is shifted to position 7,8 in 4-methyl-7,8-dihydroxy coumarin, that coumarin shows a superoxide dismutase action, which, beside H₂O₂ formation, includes the formation and elimination of a molecule of O₂. This is in contrast with the products formed through esculetin superoxide scavenging, where a second added superoxide remains trapped, and forms an esculetin-η-O₂ complex. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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27 pages, 9363 KiB

Open AccessArticle

Sesquiterpene Coumarin Ethers with Selective Cytotoxic Activities from the Roots of Ferula huber-morathii Peşmen (Apiaceae) and Unequivocal Determination of the Absolute Stereochemistry of Samarcandin

by Fatma Memnune Eruçar, Fadıl Kaan Kuran, Gülsüm Altıparmak Ülbegi, Süheyla Özbey, Şule Nur Karavuş, Gülşah Gamze Arcan, Seçil Yazıcı Tütüniş, Nur Tan, Pınar Aksoy Sağırlı and Mahmut Miski

Pharmaceuticals 2023, 16(6), 792; https://doi.org/10.3390/ph16060792 - 26 May 2023

Cited by 5 | Viewed by 1652

Abstract

Ancient physicians frequently used the resin of Ferula species to treat cancer. Today, some folkloric recipes used for cancer treatment also contain the resin of Ferula species. The dichloromethane extract of the roots of Ferula huber-morathii exhibited cytotoxic activities against COLO 205 (colon), K-562 (lymphoblast), and MCF-7 (breast) cancer cell lines (IC₅₀ = 52 µg/mL, 72 µg/mL, and 20 µg/mL, respectively). Fifteen sesquiterpene coumarin ethers with cytotoxic activity were isolated from the dichloromethane extract of the roots of F. huber-morathii using bioactivity-directed isolation studies. Extensive spectroscopic analyses and chemical transformations have elucidated the structures of these sesquiterpene coumarin ethers as conferone (1), conferol (2), feselol (3), badrakemone (4), mogoltadone (5), farnesiferol A (6), farnesiferol A acetate (7), gummosin (8), ferukrin (9), ferukrin acetate (10), deacetylkellerin (11), kellerin (12), samarcandone (13), samarcandin (14), and samarcandin acetate (15). The absolute configuration of samarcandin (14) was unequivocally determined by the X-ray crystallographic analysis of the semi-synthetic (R)-MTPA ester of samarcandin (24). Conferol (2) and mogoltadone (5) were found to be the most potent cytotoxic compounds against all three cancer cell lines; furthermore, these compounds exhibit low cytotoxic activity against the non-cancerous human umbilical vein epithelial cells (HUVEC) cell line. Investigation of the biological activity mechanisms of mogoltadone (5) revealed that while suppressing the levels of Bcl-XL and procaspase-3 in the COLO 205 cancer cell line, it did not have a significant effect on the Bcl-XL, caspase-3, and β-catenin protein levels of the HUVEC cell line, which may explain the cytotoxic selectivity of mogoltadone (5) on cancer cell lines. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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19 pages, 5444 KiB

Open AccessArticle

Anti-Alopecia Activity of Coumarin Derivatives Isolated from Merremia peltata Leaves and Computational Study of Their Binding to Androgen Receptors Using Molecular Docking and Molecular Dynamic Simulation

by Syawal Abdurrahman, Ruslin Ruslin, Aliya Nur Hasanah, Mus Ifaya and Resmi Mustarichie

Pharmaceuticals 2023, 16(5), 669; https://doi.org/10.3390/ph16050669 - 28 Apr 2023

Cited by 2 | Viewed by 1664

Abstract

Alopecia is a condition in which hair on the scalp or other areas of the body is lost or falls out excessively. Nutritional deficiency causes blood flow to the head to decrease causing the hormone testosterone to be changed by the enzyme 5-α-reductase to dihydrotestosterone, which inhibits the growth phase and accelerates the death phase. One of the methods developed to treat alopecia is through inhibition of the 5-α-reductase enzyme, which converts testosterone to its more potent metabolite, dihydrotestosterone (DHT). Ethnomedicinally, Merremia peltata leaf is used by the people of Sulawesi as a remedy for baldness. Therefore, in this research, an in vivo study was conducted on rabbits to determine the anti-alopecia activity of M. peltata leaf compounds. The structure of the compounds isolated from the M. peltata leaf ethyl acetate fraction was determined by analysis of NMR and LC-MS data. An in silico study was then carried out using minoxidil as a comparison ligand; scopolin (1) and scopoletin (2) isolated from M. peltata leaf were identified as anti-alopecia compounds by predicting docking, simulating molecular dynamics and predicting absorption, distribution, metabolism, excretion, and toxicology (ADME-Tox). Compounds 1 and 2 had a better effect on hair growth compared to positive controls, and NMR and LC-MS analysis showed that they had comparable binding energies to receptors in the molecular docking interaction study: −4.51 and −4.65 kcal/mol, respectively, compared to −4.8 kcal/mol for minoxidil. Molecular dynamics simulation analysis with the parameters binding free energy calculated using the MM-PBSA method and complex stability based on SASA, PCA, RMSD, and RMSF showed that scopolin (1) has a good affinity for androgens receptors. The ADME-Tox prediction for scopolin (1) showed good results for the parameters of skin permeability, absorption and distribution. Therefore, scopolin (1) is a potential antagonist to androgen receptors and could be useful in the treatment of alopecia. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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13 pages, 2431 KiB

Open AccessArticle

Acenocoumarol, an Anticoagulant Drug, Prevents Melanogenesis in B16F10 Melanoma Cells

by Hyunju Han and Changgu Hyun

Pharmaceuticals 2023, 16(4), 604; https://doi.org/10.3390/ph16040604 - 17 Apr 2023

Cited by 7 | Viewed by 1597

Abstract

Hyperpigmentation can occur in abnormal skin conditions such as melanomas, as well as in conditions including melasma, freckles, age spots, seborrheic keratosis, and café-au-lait spots (flat brown spots). Thus, there is an increasing need for the development of depigmenting agents. We aimed to repurpose an anticoagulant drug as an effective ingredient against hyperpigmentation and apply cosmeceutical agents. In the present study, the anti-melanogenic effects of two anticoagulant drugs, acenocoumarol and warfarin, were investigated. The results showed that both acenocoumarol and warfarin did not cause any cytotoxicity and resulted in a significant reduction in intracellular tyrosinase activity and melanin content in B16F10 melanoma cells. Additionally, acenocoumarol inhibits the expression of melanogenic enzymes such as tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, suppressing melanin synthesis through a cAMP-dependent, protein kinase (PKA)-dependent downregulation of microphthalmia-associated transcription factor (MITF), a master transcription factor in melanogenesis. Furthermore, anti-melanogenic effects were exerted by acenocoumarol through downregulation of the p38 and JNK signaling pathway and upregulation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthesis kinase-3β (GSK-3β) cascades. In addition, the β-catenin content in the cell cytoplasm and nucleus was increased by acenocoumarol through a reduction in the phosphorylated β-catenin (p-β-catenin content). Finally, we tested the potential of acenocoumarol for topical applications by conducting primary human skin irritation tests. Acenocoumarol did not induce any adverse reactions during these tests. Based on the results, it can be concluded that acenocoumarol regulates melanogenesis through various signaling pathways such as PKA, MAPKs, PI3K/Akt/GSK-3β, and β-catenin. These findings suggest that acenocoumarol has the potential to be repurposed as a drug for treating hyperpigmentation symptoms and could provide new insights into the development of therapeutic approaches for hyperpigmentation disorders. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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12 pages, 1198 KiB

Open AccessArticle

Structures of Mammeasins P and Q, Coumarin-Related Polysubstituted Benzofurans, from the Thai Medicinal Plant Mammea siamensis (Miq.) T. Anders.: Anti-Proliferative Activity of Coumarin Constituents against Human Prostate Carcinoma Cell Line LNCaP

by Fenglin Luo, Yoshiaki Manse, Saowanee Chaipech, Yutana Pongpiriyadacha, Osamu Muraoka and Toshio Morikawa

Pharmaceuticals 2023, 16(2), 231; https://doi.org/10.3390/ph16020231 - 03 Feb 2023

Cited by 1 | Viewed by 1622

Abstract

A methanol extract of the flowers of Mammea siamensis (Miq.) T. Anders. (Calophyllaceae) showed anti-proliferative activity against human prostate carcinoma LNCaP cells (IC₅₀ = 2.0 µg/mL). Two new coumarin-related polysubstituted benzofurans, mammeasins P (1) and Q (2), and a known polysubstituted coumarin mammea B/AC cyclo F (39) were isolated from the extract along with 44 previously reported polysubstituted coumarin constituents (3–38 and 40–47). The structures of two new compounds (1 and 2) were determined based on their spectroscopic properties derived from the physicochemical evidence including NMR and MS analyses and taking the plausible generative pathway into account. Among the coumarin constituents, mammeasins A (3, IC₅₀ = 1.2 µM) and B (4, 0.63 µM), sugangin B (18, 1.5 µM), kayeassamins E (24, 3.0 µM) and G (26, 3.5 µM), and mammeas E/BA (40, 0.88 µM), E/BB (41, 0.52 µM), and E/BC (42, 0.12 µM) showed relatively potent anti-proliferative activity. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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20 pages, 10471 KiB

Open AccessArticle

Synthesis and Cytotoxicity Evaluation of Novel Coumarin–Palladium(II) Complexes against Human Cancer Cell Lines

by Edina H. Avdović, Marko Antonijević, Dušica Simijonović, Sunčica Roca, Dražen Vikić Topić, Nađa Grozdanić, Tatjana Stanojković, Ivana Radojević, Radiša Vojinović and Zoran Marković

Pharmaceuticals 2023, 16(1), 49; https://doi.org/10.3390/ph16010049 - 29 Dec 2022

Cited by 2 | Viewed by 1693

Abstract

Two newly synthesized coumarin–palladium(II) complexes (C1 and C2) were characterized using elemental analysis, spectroscopy (IR and ¹H-¹³C NMR), and DFT methods at the B3LYP-D3BJ/6-311+G(d,p) level of theory. The in vitro and in silico cytotoxicity of coumarin ligands and their corresponding Pd(II) complexes was examined. For in vitro testing, five cell lines were selected, namely human cervical adenocarcinoma (HeLa), the melanoma cell line (FemX), epithelial lung carcinoma (A549), the somatic umbilical vein endothelial cell line (EA.hi926), and pancreatic ductal adenocarcinoma (Panc-1). In order to examine the in silico inhibitory potential and estimate inhibitory constants and binding energies, molecular docking studies were performed. The inhibitory activity of C1 and C2 was investigated towards epidermal growth factor receptor (EGFR), receptor tyrosine kinase (RTK), and B-cell lymphoma 2 (BCL-2). According to the results obtained from the molecular docking simulations, the inhibitory activity of the investigated complexes towards all the investigated proteins is equivalent or superior in comparison with current therapeutical options. Moreover, because of the low binding energies and the high correlation rate with experimentally obtained results, it was shown that, out of the three, the inhibition of RTK is the most probable mechanism of the cytotoxic activity of the investigated compounds. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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Review

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61 pages, 30929 KiB

Open AccessReview

Umbelliferone and Its Synthetic Derivatives as Suitable Molecules for the Development of Agents with Biological Activities: A Review of Their Pharmacological and Therapeutic Potential

by Anita Kornicka, Łukasz Balewski, Monika Lahutta and Jakub Kokoszka

Pharmaceuticals 2023, 16(12), 1732; https://doi.org/10.3390/ph16121732 - 15 Dec 2023

Viewed by 1537

Abstract

Umbelliferone (UMB), known as 7-hydroxycoumarin, hydrangine, or skimmetine, is a naturally occurring coumarin in the plant kingdom, mainly from the Umbelliferae family that possesses a wide variety of pharmacological properties. In addition, the use of nanoparticles containing umbelliferone may improve anti-inflammatory or anticancer therapy. Also, its derivatives are endowed with great potential for therapeutic applications due to their broad spectrum of biological activities such as anti-inflammatory, antioxidant, neuroprotective, antipsychotic, antiepileptic, antidiabetic, antimicrobial, antiviral, and antiproliferative effects. Moreover, 7-hydroxycoumarin ligands have been implemented to develop 7-hydroxycoumarin-based metal complexes with improved pharmacological activity. Besides therapeutic applications, umbelliferone analogues have been designed as fluorescent probes for the detection of biologically important species, such as enzymes, lysosomes, and endosomes, or for monitoring cell processes and protein functions as well various diseases caused by an excess of hydrogen peroxide. Furthermore, 7-hydroxy-based chemosensors may serve as a highly selective tool for Al³⁺ and Hg²⁺ detection in biological systems. This review is devoted to a summary of the research on umbelliferone and its synthetic derivatives in terms of biological and pharmaceutical properties, especially those reported in the literature during the period of 2017–2023. Future potential applications of umbelliferone and its synthetic derivatives are presented. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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26 pages, 15042 KiB

Open AccessReview

Antioxidant Activity of Coumarins and Their Metal Complexes

by Lozan Todorov, Luciano Saso and Irena Kostova

Pharmaceuticals 2023, 16(5), 651; https://doi.org/10.3390/ph16050651 - 26 Apr 2023

Cited by 12 | Viewed by 2119

Abstract

Ubiquitously present in plant life, coumarins, as a class of phenolic compounds, have multiple applications—in everyday life, in organic synthesis, in medicine and many others. Coumarins are well known for their broad spectrum of physiological effects. The specific structure of the coumarin scaffold involves a conjugated system with excellent charge and electron transport properties. The antioxidant activity of natural coumarins has been a subject of intense study for at least two decades. Significant research into the antioxidant behavior of natural/semi-synthetic coumarins and their complexes has been carried out and published in scientific literature. The authors of this review have noted that, during the past five years, research efforts seem to have been focused on the synthesis and examination of synthetic coumarin derivatives with the aim to produce potential drugs with enhanced, modified or entirely novel effects. As many pathologies are associated with oxidative stress, coumarin-based compounds could be excellent candidates for novel medicinal molecules. The present review aims to inform the reader on some prominent results from investigations into the antioxidant properties of novel coumarin compounds over the past five years. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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26 pages, 8953 KiB

Open AccessReview

Natural Coumarin Derivatives Activating Nrf2 Signaling Pathway as Lead Compounds for the Design and Synthesis of Intestinal Anti-Inflammatory Drugs

by Luiz C. Di Stasi

Pharmaceuticals 2023, 16(4), 511; https://doi.org/10.3390/ph16040511 - 30 Mar 2023

Cited by 11 | Viewed by 2589

Abstract

Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor related to stress response and cellular homeostasis that plays a key role in maintaining the redox system. The imbalance of the redox system is a triggering factor for the initiation and progression of non-communicable diseases (NCDs), including Inflammatory Bowel Disease (IBD). Nrf2 and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) are the main regulators of oxidative stress and their activation has been recognized as a promising strategy for the treatment or prevention of several acute and chronic diseases. Moreover, activation of Nrf2/keap signaling pathway promotes inhibition of NF-κB, a transcriptional factor related to pro-inflammatory cytokines expression, synchronically promoting an anti-inflammatory response. Several natural coumarins have been reported as potent antioxidant and intestinal anti-inflammatory compounds, acting by different mechanisms, mainly as a modulator of Nrf2/keap signaling pathway. Based on in vivo and in vitro studies, this review focuses on the natural coumarins obtained from both plant products and fermentative processes of food plants by gut microbiota, which activate Nrf2/keap signaling pathway and produce intestinal anti-inflammatory activity. Although gut metabolites urolithin A and urolithin B as well as other plant-derived coumarins display intestinal anti-inflammatory activity modulating Nrf2 signaling pathway, in vitro and in vivo studies are necessary for better pharmacological characterization and evaluation of their potential as lead compounds. Esculetin, 4-methylesculetin, daphnetin, osthole, and imperatorin are the most promising coumarin derivatives as lead compounds for the design and synthesis of Nrf2 activators with intestinal anti-inflammatory activity. However, further structure–activity relationships studies with coumarin derivatives in experimental models of intestinal inflammation and subsequent clinical trials in health and disease volunteers are essential to determine the efficacy and safety in IBD patients. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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