Editorial

4 pages, 213 KiB

Open AccessEditorial

by Maria João Matos

Molecules 2021, 26(20), 6320; https://doi.org/10.3390/molecules26206320 - 19 Oct 2021

Cited by 7 | Viewed by 2338

Coumarins are widely distributed in nature and can be found in a large number of naturally occurring and synthetic bioactive molecules [...] Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

Research

Jump to: Editorial, Review

20 pages, 2876 KiB

Open AccessArticle

Synthesis of Ferulenol by Engineered Escherichia coli: Structural Elucidation by Using the In Silico Tools

by Anuwatchakij Klamrak, Jaran Nabnueangsap, Ploenthip Puthongking and Natsajee Nualkaew

Molecules 2021, 26(20), 6264; https://doi.org/10.3390/molecules26206264 - 16 Oct 2021

Cited by 7 | Viewed by 2181

Abstract

4-Hydroxycoumarin (4HC) has been used as a lead compound for the chemical synthesis of various bioactive substances and drugs. Its prenylated derivatives exhibit potent antibacterial, antitubercular, anticoagulant, and anti-cancer activities. In doing this, E. coli BL21(DE3)pLysS strain was engineered as the in [...] Read more.

4-Hydroxycoumarin (4HC) has been used as a lead compound for the chemical synthesis of various bioactive substances and drugs. Its prenylated derivatives exhibit potent antibacterial, antitubercular, anticoagulant, and anti-cancer activities. In doing this, E. coli BL21(DE3)pLysS strain was engineered as the in vivo prenylation system to produce the farnesyl derivatives of 4HC by coexpressing the genes encoding Aspergillus terreus aromatic prenyltransferase (AtaPT) and truncated 1-deoxy-D-xylose 5-phosphate synthase of Croton stellatopilosus (CstDXS), where 4HC was the fed precursor. Based on the high-resolution LC-ESI(±)-QTOF-MS/MS with the use of in silico tools (e.g., MetFrag, SIRIUS (version 4.8.2), CSI:FingerID, and CANOPUS), the first major prenylated product (named compound-1) was detected and ultimately elucidated as ferulenol, in which information concerning the correct molecular formula, chemical structure, substructures, and classifications were obtained. The prenylated product (named compound-2) was also detected as the minor product, where this structure proposed to be the isomeric structure of ferulenol formed via the tautomerization. Note that both products were secreted into the culture medium of the recombinant E. coli and could be produced without the external supply of prenyl precursors. The results suggested the potential use of this engineered pathway for synthesizing the farnesylated-4HC derivatives, especially ferulenol. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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16 pages, 1349 KiB

Open AccessArticle

Curcumin–Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders

by Elías Quezada, Fernanda Rodríguez-Enríquez, Reyes Laguna, Elena Cutrín, Francisco Otero, Eugenio Uriarte and Dolores Viña

Molecules 2021, 26(15), 4550; https://doi.org/10.3390/molecules26154550 - 28 Jul 2021

Cited by 7 | Viewed by 2478

Abstract

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of [...] Read more.

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin–coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11–18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H₂O₂ in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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12 pages, 1888 KiB

Open AccessArticle

Antiplatelet Activity of Coumarins: In Vitro Assays on COX-1

by Cristina Zaragozá, Francisco Zaragozá, Irene Gayo-Abeleira and Lucinda Villaescusa

Molecules 2021, 26(10), 3036; https://doi.org/10.3390/molecules26103036 - 19 May 2021

Cited by 8 | Viewed by 2194

Abstract

Atherosclerotic cardiovascular disease is the leading cause of death in developed countries. Therefore, there is an increasing interest in developing new potent and safe antiplatelet agents. Coumarins are a family of polyphenolic compounds with several pharmacological activities, including platelet aggregation inhibition. However, their [...] Read more.

Atherosclerotic cardiovascular disease is the leading cause of death in developed countries. Therefore, there is an increasing interest in developing new potent and safe antiplatelet agents. Coumarins are a family of polyphenolic compounds with several pharmacological activities, including platelet aggregation inhibition. However, their antiplatelet mechanism of action needs to be further elucidated. The aim of this study is to provide insight into the biochemical mechanisms involved in this activity, as well as to establish a structure–activity relationship for these compounds. With this purpose, the antiplatelet aggregation activities of coumarin, esculetin and esculin were determined in vitro in human whole blood and platelet-rich plasma, to set the potential interference with the arachidonic acid cascade. Here, the platelet COX activity was evaluated from 0.75 mM to 6.5 mM concentration by measuring the levels of metabolites derived from its activity (MDA and TXB₂), together with colorimetric assays performed with the pure recombinant enzyme. Our results evidenced that the coumarin aglycones present the greatest antiplatelet activity at 5 mM and 6.5 mM on aggregometry experiments and inhibiting MDA levels. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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16 pages, 11009 KiB

Open AccessArticle

New 3-Ethynylaryl Coumarin-Based Dyes for DSSC Applications: Synthesis, Spectroscopic Properties, and Theoretical Calculations

by João Sarrato, Ana Lucia Pinto, Gabriela Malta, Eva G. Röck, João Pina, João Carlos Lima, A. Jorge Parola and Paula S. Branco

Molecules 2021, 26(10), 2934; https://doi.org/10.3390/molecules26102934 - 14 May 2021

Cited by 12 | Viewed by 2906

Abstract

A set of 3-ethynylaryl coumarin dyes with mono, bithiophenes and the fused variant, thieno [3,2-b] thiophene, as well as an alkylated benzotriazole unit were prepared and tested for dye-sensitized solar cells (DSSCs). For comparison purposes, the variation of the substitution pattern [...] Read more.

A set of 3-ethynylaryl coumarin dyes with mono, bithiophenes and the fused variant, thieno [3,2-b] thiophene, as well as an alkylated benzotriazole unit were prepared and tested for dye-sensitized solar cells (DSSCs). For comparison purposes, the variation of the substitution pattern at the coumarin unit was analyzed with the natural product 6,7-dihydroxycoumarin (Esculetin) as well as 5,7-dihydroxycomarin in the case of the bithiophene dye. Crucial steps for extension of the conjugated system involved Sonogashira reaction yielding highly fluorescent molecules. Spectroscopic characterization showed that the extension of conjugation via the alkynyl bridge resulted in a strong red-shift of absorption and emission spectra (in solution) of approximately 73–79 nm and 52–89 nm, respectively, relative to 6,7-dimethoxy-4-methylcoumarin (λ_abs = 341 nm and λ_em = 410 nm). Theoretical density functional theory (DFT) calculations show that the Lowest Unoccupied Molecular Orbital (LUMO) is mostly centered in the cyanoacrylic anchor unit, corroborating the high intramolecular charge transfer (ICT) character of the electronic transition. Photovoltaic performance evaluation reveals that the thieno [3,2-b] thiophene unit present in dye 8 leads to the best sensitizer of the set, with a conversion efficiency (η = 2.00%), best V_OC (367 mV) and second best J_sc (9.28 mA·cm⁻²), surpassed only by dye 9b (J_sc = 10.19 mA·cm⁻²). This high photocurrent value can be attributed to increased donor ability of the 5,7-dimethoxy unit when compared to the 6,7 equivalent (9b). Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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19 pages, 3173 KiB

Open AccessArticle

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies

by Guillermo Moya-Alvarado, Osvaldo Yañez, Nicole Morales, Angélica González-González, Carlos Areche, Marco Tulio Núñez, Angélica Fierro and Olimpo García-Beltrán

Molecules 2021, 26(9), 2430; https://doi.org/10.3390/molecules26092430 - 22 Apr 2021

Cited by 16 | Viewed by 3524

Abstract

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among [...] Read more.

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson’s. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC₅₀ = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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15 pages, 2131 KiB

Open AccessArticle

Identification and Quantification of Coumarins by UHPLC-MS in Arabidopsis thaliana Natural Populations

by Izabela Perkowska, Joanna Siwinska, Alexandre Olry, Jérémy Grosjean, Alain Hehn, Frédéric Bourgaud, Ewa Lojkowska and Anna Ihnatowicz

Molecules 2021, 26(6), 1804; https://doi.org/10.3390/molecules26061804 - 23 Mar 2021

Cited by 8 | Viewed by 3615

Abstract

Coumarins are phytochemicals occurring in the plant kingdom, which biosynthesis is induced under various stress factors. They belong to the wide class of specialized metabolites well known for their beneficial properties. Due to their high and wide biological activities, coumarins are important not [...] Read more.

Coumarins are phytochemicals occurring in the plant kingdom, which biosynthesis is induced under various stress factors. They belong to the wide class of specialized metabolites well known for their beneficial properties. Due to their high and wide biological activities, coumarins are important not only for the survival of plants in changing environmental conditions, but are of great importance in the pharmaceutical industry and are an active source for drug development. The identification of coumarins from natural sources has been reported for different plant species including a model plant Arabidopsis thaliana. In our previous work, we demonstrated a presence of naturally occurring intraspecies variation in the concentrations of scopoletin and its glycoside, scopolin, the major coumarins accumulating in Arabidopsis roots. Here, we expanded this work by examining a larger group of 28 Arabidopsis natural populations (called accessions) and by extracting and analysing coumarins from two different types of tissues–roots and leaves. In the current work, by quantifying the coumarin content in plant extracts with ultra-high-performance liquid chromatography coupled with a mass spectrometry analysis (UHPLC-MS), we detected a significant natural variation in the content of simple coumarins like scopoletin, umbelliferone and esculetin together with their glycosides: scopolin, skimmin and esculin, respectively. Increasing our knowledge of coumarin accumulation in Arabidopsis natural populations, might be beneficial for the future discovery of physiological mechanisms of action of various alleles involved in their biosynthesis. A better understanding of biosynthetic pathways of biologically active compounds is the prerequisite step in undertaking a metabolic engineering research. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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20 pages, 6038 KiB

Open AccessArticle

3-Carboxylic Acid and Formyl-Derived Coumarins as Photoinitiators in Photo-Oxidation or Photo-Reduction Processes for Photopolymerization upon Visible Light: Photocomposite Synthesis and 3D Printing Applications

by Mahmoud Rahal, Bernadette Graff, Joumana Toufaily, Tayssir Hamieh, Guillaume Noirbent, Didier Gigmes, Frédéric Dumur and Jacques Lalevée

Molecules 2021, 26(6), 1753; https://doi.org/10.3390/molecules26061753 - 21 Mar 2021

Cited by 27 | Viewed by 3495

Abstract

In this paper, nine organic compounds based on the coumarin scaffold and different substituents were synthesized and used as high-performance photoinitiators for free radical photopolymerization (FRP) of meth(acrylate) functions under visible light irradiation using LED at 405 nm. In fact, these compounds showed [...] Read more.

In this paper, nine organic compounds based on the coumarin scaffold and different substituents were synthesized and used as high-performance photoinitiators for free radical photopolymerization (FRP) of meth(acrylate) functions under visible light irradiation using LED at 405 nm. In fact, these compounds showed a very high initiation capacity and very good polymerization profiles (both high rate of polymerization (Rp) and final conversion (FC)) using two and three-component photoinitiating systems based on coum/iodonium salt (0.1%/1% w/w) and coum/iodonium salt/amine (0.1%/1%/1% w/w/w), respectively. To demonstrate the efficiency of the initiation of photopolymerization, several techniques were used to study the photophysical and photochemical properties of coumarins, such as: UV-visible absorption spectroscopy, steady-state photolysis, real-time FTIR, and cyclic voltammetry. On the other hand, these compounds were also tested in direct laser write experiments (3D printing). The synthesis of photocomposites based on glass fiber or carbon fiber using an LED conveyor at 385 nm (0.7 W/cm²) was also examined. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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12 pages, 1953 KiB

Open AccessArticle

Synthesis and Biological Activity Evaluation of Coumarin-3-Carboxamide Derivatives

by Weerachai Phutdhawong, Apiwat Chuenchid, Thongchai Taechowisan, Jitnapa Sirirak and Waya S. Phutdhawong

Molecules 2021, 26(6), 1653; https://doi.org/10.3390/molecules26061653 - 16 Mar 2021

Cited by 25 | Viewed by 3693

Abstract

A series of novel coumarin-3-carboxamide derivatives were designed and synthesized to evaluate their biological activities. The compounds showed little to no activity against gram-positive and gram-negative bacteria but specifically showed potential to inhibit the growth of cancer cells. In particular, among the tested [...] Read more.

A series of novel coumarin-3-carboxamide derivatives were designed and synthesized to evaluate their biological activities. The compounds showed little to no activity against gram-positive and gram-negative bacteria but specifically showed potential to inhibit the growth of cancer cells. In particular, among the tested compounds, 4-fluoro and 2,5-difluoro benzamide derivatives (14b and 14e, respectively) were found to be the most potent derivatives against HepG2 cancer cell lines (IC₅₀ = 2.62–4.85 μM) and HeLa cancer cell lines (IC₅₀ = 0.39–0.75 μM). The activities of these two compounds were comparable to that of the positive control doxorubicin; especially, 4-flurobenzamide derivative (14b) exhibited low cytotoxic activity against LLC-MK2 normal cell lines, with IC₅₀ more than 100 μM. The molecular docking study of the synthesized compounds revealed the binding to the active site of the CK2 enzyme, indicating that the presence of the benzamide functionality is an important feature for anticancer activity. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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10 pages, 492 KiB

Open AccessArticle

Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study

by Danilo Menichelli, Daniela Poli, Emilia Antonucci, Vittoria Cammisotto, Sophie Testa, Pasquale Pignatelli, Gualtiero Palareti, Daniele Pastori and the Italian Federation of Anticoagulation Clinics (FCSA)

Molecules 2021, 26(5), 1425; https://doi.org/10.3390/molecules26051425 - 06 Mar 2021

Cited by 10 | Viewed by 2437

Abstract

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide [...] Read more.

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081–1.927, p = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, p < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones (p < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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11 pages, 2780 KiB

Open AccessCommunication

Chiral Tertiary Amine Catalyzed Asymmetric [4 + 2] Cyclization of 3-Aroylcoumarines with 2,3-Butadienoate

by Jun-Lin Li, Xiao-Hui Wang, Jun-Chao Sun, Yi-Yuan Peng, Cong-Bin Ji and Xing-Ping Zeng

Molecules 2021, 26(2), 489; https://doi.org/10.3390/molecules26020489 - 18 Jan 2021

Cited by 4 | Viewed by 2063

Abstract

Coumarins and 2H-pyran derivatives are among the most commonly found structural units in natural products. Therefore, the introduction of 2H-pyran moiety into the coumarin structural unit, i.e., dihydrocoumarin-fused dihydropyranones, is a potentially successful route for the identification of novel [...] Read more.

Coumarins and 2H-pyran derivatives are among the most commonly found structural units in natural products. Therefore, the introduction of 2H-pyran moiety into the coumarin structural unit, i.e., dihydrocoumarin-fused dihydropyranones, is a potentially successful route for the identification of novel bioactive structures, and the synthesis of these structures has attracted continuing research interest. Herein, a chiral tertiary amine catalyzed [4 + 2] cyclization of 3-aroylcoumarines with benzyl 2,3-butadienoate was reported. In the presence of Kumar’s 6’-(4-biphenyl)-β-iso-cinchonine, the desired dihydrocoumarin-fused dihydropyranone products could be obtained in up to 97% yield and 90% ee values. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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18 pages, 3368 KiB

Open AccessArticle

Synthesis and Biochemical Evaluation of Warhead-Decorated Psoralens as (Immuno)Proteasome Inhibitors

by Eva Shannon Schiffrer, Matic Proj, Martina Gobec, Luka Rejc, Andrej Šterman, Janez Mravljak, Stanislav Gobec and Izidor Sosič

Molecules 2021, 26(2), 356; https://doi.org/10.3390/molecules26020356 - 12 Jan 2021

Cited by 4 | Viewed by 2620

Abstract

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for [...] Read more.

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure–activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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10 pages, 1356 KiB

Open AccessArticle

Coumarin’s Anti-Quorum Sensing Activity Can Be Enhanced When Combined with Other Plant-Derived Small Molecules

by Dmitry Deryabin, Kseniya Inchagova, Elena Rusakova and Galimzhan Duskaev

Molecules 2021, 26(1), 208; https://doi.org/10.3390/molecules26010208 - 03 Jan 2021

Cited by 12 | Viewed by 2632

Abstract

Coumarins are class of natural aromatic compounds based on benzopyrones (2H-1-benzopyran-2-ones). They are identified as secondary metabolites in about 150 different plant species. The ability of coumarins to inhibit cell-to-cell communication in bacterial communities (quorum sensing; QS) has been previously described. Coumarin and [...] Read more.

Coumarins are class of natural aromatic compounds based on benzopyrones (2H-1-benzopyran-2-ones). They are identified as secondary metabolites in about 150 different plant species. The ability of coumarins to inhibit cell-to-cell communication in bacterial communities (quorum sensing; QS) has been previously described. Coumarin and its derivatives in plant extracts are often found together with other small molecules that show anti-QS properties too. The aim of this study was to find the most effective combinations of coumarins and small plant-derived molecules identified in various plants extracts that inhibit QS in Chromobacterium violaceum ATCC 31532 violacein production bioassay. The coumarin and its derivatives: 7-hydroxycoumarin, 7.8-dihydroxy-4-methylcoumarin, were included in the study. Combinations of coumarins with gamma-octalactone, 4-hexyl-1.3-benzenediol, 3.4.5-trimethoxyphenol and vanillin, previously identified in oak bark (Quercus cortex), and eucalyptus leaves (Eucalyptus viminalis) extracts, were analyzed in a bioassay. When testing two-component compositions, it was shown that 7.8-dihydroxy-4-methylcoumarin, 4-hexyl-1.3-benzendiol, and gamma-octalactone showed a supra-additive anti-QS effect. Combinations of all three molecules resulted in a three- to five-fold reduction in the concentration of each compound needed to achieve EC₅₀ (half maximal effective concentration) against QS in C. violaceum ATCC 31532. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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18 pages, 4352 KiB

Open AccessArticle

Studies of Coumarin Derivatives for Constitutive Androstane Receptor (CAR) Activation

by Shin-Hun Juang, Min-Tsang Hsieh, Pei-Ling Hsu, Ju-Ling Chen, Hui-Kang Liu, Fong-Pin Liang, Sheng-Chu Kuo, Chen-Yuan Chiu, Shing-Hwa Liu, Chen-Hsi Chou, Tian-Shung Wu and Hsin-Yi Hung

Molecules 2021, 26(1), 164; https://doi.org/10.3390/molecules26010164 - 31 Dec 2020

Cited by 4 | Viewed by 2512

Abstract

Constitutive androstane receptor (CAR) activation has found to ameliorate diabetes in animal models. However, no CAR agonists are available clinically. Therefore, a safe and effective CAR activator would be an alternative option. In this study, sixty courmarin derivatives either synthesized or purified from [...] Read more.

Constitutive androstane receptor (CAR) activation has found to ameliorate diabetes in animal models. However, no CAR agonists are available clinically. Therefore, a safe and effective CAR activator would be an alternative option. In this study, sixty courmarin derivatives either synthesized or purified from Artemisia capillaris were screened for CAR activation activity. Chemical modifications were on position 5,6,7,8 with mono-, di-, tri-, or tetra-substitutions. Among all the compounds subjected for in vitro CAR activation screening, 6,7-diprenoxycoumarin was the most effective and was selected for further preclinical studies. Chemical modification on the 6 position and unsaturated chains were generally beneficial. Electron-withdrawn groups as well as long unsaturated chains were hazardous to the activity. Mechanism of action studies showed that CAR activation of 6,7-diprenoxycoumarin might be through the inhibition of EGFR signaling and upregulating PP2Ac methylation. To sum up, modification mimicking natural occurring coumarins shed light on CAR studies and the established screening system provides a rapid method for the discovery and development of CAR activators. In addition, one CAR activator, scoparone, did showed anti-diabetes effect in db/db mice without elevation of insulin levels. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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17 pages, 1948 KiB

Open AccessArticle

Antiglioma Potential of Coumarins Combined with Sorafenib

by Joanna Sumorek-Wiadro, Adrian Zając, Ewa Langner, Krystyna Skalicka-Woźniak, Aleksandra Maciejczyk, Wojciech Rzeski and Joanna Jakubowicz-Gil

Molecules 2020, 25(21), 5192; https://doi.org/10.3390/molecules25215192 - 08 Nov 2020

Cited by 20 | Viewed by 2732

Abstract

Coumarins, which occur naturally in the plant kingdom, are diverse class of secondary metabolites. With their antiproliferative, chemopreventive and antiangiogenetic properties, they can be used in the treatment of cancer. Their therapeutic potential depends on the type and location of the attachment of [...] Read more.

Coumarins, which occur naturally in the plant kingdom, are diverse class of secondary metabolites. With their antiproliferative, chemopreventive and antiangiogenetic properties, they can be used in the treatment of cancer. Their therapeutic potential depends on the type and location of the attachment of substituents to the ring. Therefore, the aim of our study was to investigate the effect of simple coumarins (osthole, umbelliferone, esculin, and 4-hydroxycoumarin) combined with sorafenib (specific inhibitor of Raf (Rapidly Accelerated Fibrosarcoma) kinase) in programmed death induction in human glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells lines. Osthole and umbelliferone were isolated from fruits: Mutellina purpurea L. and Heracleum leskowii L., respectively, while esculin and 4-hydroxycoumarin were purchased from Sigma Aldrich (St. Louis, MO, USA). Apoptosis, autophagy and necrosis were identified microscopically after straining with specific fluorochromes. The level of caspase 3, Beclin 1, PI3K (Phosphoinositide 3-kinase), and Raf kinases were estimated by immunoblotting. Transfection with specific siRNA (small interfering RNA) was used to block Bcl-2 (B-cell lymphoma 2), Raf, and PI3K expression. Cell migration was tested with the wound healing assay. The present study has shown that all the coumarins eliminated the MOGGCCM and T98G tumor cells mainly via apoptosis and, to a lesser extent, via autophagy. Osthole, which has an isoprenyl moiety, was shown to be the most effective compound. Sorafenib did not change the proapoptotic activity of this coumarin; however, it reduced the level of autophagy. At the molecular level, the induction of apoptosis was associated with a decrease in the expression of PI3K and Raf kinases, whereas an increase in the level of Beclin 1 was observed in the case of autophagy. Inhibition of the expression of this protein by specific siRNA eliminated autophagy. Moreover, the blocking of the expression of Bcl-2 and PI3K significantly increased the level of apoptosis. Osthole and sorafenib successfully inhibited the migration of the MOGGCCM and T98G cells. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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10 pages, 2357 KiB

Open AccessCommunication

4-Hydroxy-7-Methoxycoumarin Inhibits Inflammation in LPS-activated RAW264.7 Macrophages by Suppressing NF-κB and MAPK Activation

by Jin Kyu Kang and Chang-Gu Hyun

Molecules 2020, 25(19), 4424; https://doi.org/10.3390/molecules25194424 - 26 Sep 2020

Cited by 19 | Viewed by 2958

Abstract

Coumarins are natural products with promising pharmacological activities owing to their anti-inflammatory, antioxidant, antiviral, anti-diabetic, and antimicrobial effects. Coumarins are present in many plants and microorganisms and have been widely used as complementary and alternative medicines. To date, the pharmacological efficacy of 4-hydroxy-7-methoxycoumarin [...] Read more.

Coumarins are natural products with promising pharmacological activities owing to their anti-inflammatory, antioxidant, antiviral, anti-diabetic, and antimicrobial effects. Coumarins are present in many plants and microorganisms and have been widely used as complementary and alternative medicines. To date, the pharmacological efficacy of 4-hydroxy-7-methoxycoumarin (4H-7MTC) has not been reported yet. Therefore, in this study, we investigated the anti-inflammatory effects of 4H-7MTC in LPS-stimulated RAW264.7 cells as well as its mechanisms of action. Cells were treated with various concentrations of 4H-7MTC (0.3, 0.6, 0.9, and 1.2 mM) and 40 μM L-N⁶-(1-iminoethyl)-L-lysine (L-NIL) were used as controls. LPS-stimulated RAW264.7 cells showed that 4H-7MTC significantly reduced nitric oxide (NO) and prostaglandin E₂ (PGE₂) production without cytotoxic effects. In addition, 4H-7MTC strongly decreased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Furthermore, 4H-7MTC reduced the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. We also found that 4H-7MTC strongly exerted its anti-inflammatory actions by downregulating nuclear factor kappa B (NF-κB) activation by suppressing inhibitor of nuclear factor kappa B alpha (IκBα) degradation in macrophages. Moreover, 4H-7MTC decreased phosphorylation of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK), but not that of p38 MAPK. These results suggest that 4H-7MTC may be a good candidate for the treatment or prevention of inflammatory diseases such as dermatitis, psoriasis, and arthritis. Ultimately, this is the first report describing the effective anti-inflammatory activity of 4H-7MTC. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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14 pages, 1372 KiB

Open AccessArticle

Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of hARs

by Saleta Vazquez-Rodriguez, Santiago Vilar, Sonja Kachler, Karl-Norbert Klotz, Eugenio Uriarte, Fernanda Borges and Maria João Matos

Molecules 2020, 25(18), 4306; https://doi.org/10.3390/molecules25184306 - 19 Sep 2020

Cited by 10 | Viewed by 2570

Abstract

Adenosine receptors (ARs) play an important role in neurological and psychiatric disorders such as Alzheimer’s disease, Parkinson’s disease, epilepsy and schizophrenia. The different subtypes of ARs and the knowledge on their densities and status are important for understanding the mechanisms underlying the pathogenesis [...] Read more.

Adenosine receptors (ARs) play an important role in neurological and psychiatric disorders such as Alzheimer’s disease, Parkinson’s disease, epilepsy and schizophrenia. The different subtypes of ARs and the knowledge on their densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Looking for new scaffolds for selective AR ligands, coumarin–chalcone hybrids were synthesized (compounds 1–8) and screened in radioligand binding (hA₁, hA_2A and hA₃) and adenylyl cyclase (hA_2B) assays in order to evaluate their affinity for the four human AR subtypes (hARs). Coumarin–chalcone hybrid has been established as a new scaffold suitable for the development of potent and selective ligands for hA₁ or hA₃ subtypes. In general, hydroxy-substituted hybrids showed some affinity for the hA₁, while the methoxy counterparts were selective for the hA₃. The most potent hA₁ ligand was compound 7 (K_i = 17.7 µM), whereas compound 4 was the most potent ligand for hA₃ (K_i = 2.49 µM). In addition, docking studies with hA₁ and hA₃ homology models were established to analyze the structure–function relationships. Results showed that the different residues located on the protein binding pocket could play an important role in ligand selectivity. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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16 pages, 2507 KiB

Open AccessArticle

Inhibition of Butyrylcholinesterase and Human Monoamine Oxidase-B by the Coumarin Glycyrol and Liquiritigenin Isolated from Glycyrrhiza uralensis

by Geum Seok Jeong, Myung-Gyun Kang, Joon Yeop Lee, Sang Ryong Lee, Daeui Park, MyoungLae Cho and Hoon Kim

Molecules 2020, 25(17), 3896; https://doi.org/10.3390/molecules25173896 - 26 Aug 2020

Cited by 26 | Viewed by 3190

Abstract

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC₅₀ values of 7.22 and 14.77 µM, respectively, and [...] Read more.

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC₅₀ values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC₅₀ = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC₅₀ = 0.098 µM) and MAO-A (IC₅₀ = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (>40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a K_i value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a K_i value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (−7.8 kcal/mol) was greater than its affinity for AChE (−7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (−8.8 kcal/mol) was greater than its affinity for MAO-A (−7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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20 pages, 3524 KiB

Open AccessArticle

Structural Characterization of Mono and Dihydroxylated Umbelliferone Derivatives

by Rubén Seoane-Rivero, Estibaliz Ruiz-Bilbao, Rodrigo Navarro, José Manuel Laza, José María Cuevas, Beñat Artetxe, Juan M. Gutiérrez-Zorrilla, José Luis Vilas-Vilela and Ángel Marcos-Fernandez

Molecules 2020, 25(15), 3497; https://doi.org/10.3390/molecules25153497 - 31 Jul 2020

Cited by 9 | Viewed by 2990

Abstract

Coumarin derivatives are a class of compounds with a pronounced wide range of applications, especially in biological activities, in the medicine, pharmacology, cosmetics, coatings and food industry. Their potential applications are highly dependent on the nature of the substituents attached to their nucleus. [...] Read more.

Coumarin derivatives are a class of compounds with a pronounced wide range of applications, especially in biological activities, in the medicine, pharmacology, cosmetics, coatings and food industry. Their potential applications are highly dependent on the nature of the substituents attached to their nucleus. These substituents modulate their photochemical and photophysical properties, as well as their interactions in their crystalline form, which largely determines the final field of application. Therefore, in this work a series of mono and dihydroxylated coumarin derivatives with different chemical substituents were synthesized and characterized by UV-Visible spectroscopy, thermal analysis (differential scanning calorimetry (DSC) and TGA), ¹H NMR and X-Ray Diffraction to identify limitations and possibilities as a function of the molecular structure for expanding their applications in polymer science. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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Review

Jump to: Editorial, Research

20 pages, 5900 KiB

Open AccessReview

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms

by Eslam Reda El-Sawy, Ahmed Bakr Abdelwahab and Gilbert Kirsch

Molecules 2021, 26(11), 3409; https://doi.org/10.3390/molecules26113409 - 04 Jun 2021

Cited by 8 | Viewed by 2956

Abstract

Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in [...] Read more.

Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in assembling information about fused five-membered aromatic heterocycles, and after having presented mono-hetero-atomic five-membered aromatic heterocycles in Part I. The current review Part II is intended to present an overview of the different synthetic routes to coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring, covering the literature from 1945 to 2021. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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12 pages, 583 KiB

Open AccessFeature PaperReview

Chalepin and Chalepensin: Occurrence, Biosynthesis and Therapeutic Potential

by Lutfun Nahar, Shaymaa Al-Majmaie, Afaf Al-Groshi, Azhar Rasul and Satyajit D. Sarker

Molecules 2021, 26(6), 1609; https://doi.org/10.3390/molecules26061609 - 14 Mar 2021

Cited by 13 | Viewed by 2968

Abstract

Dihydrofuranocoumarin, chalepin (1) and furanocoumarin, chalepensin (2) are 3-prenylated bioactive coumarins, first isolated from the well-known medicinal plant Ruta chalepensis L. (Fam: Rutaceae) but also distributed in various species of the genera Boenminghausenia, Clausena and Ruta. The [...] Read more.

Dihydrofuranocoumarin, chalepin (1) and furanocoumarin, chalepensin (2) are 3-prenylated bioactive coumarins, first isolated from the well-known medicinal plant Ruta chalepensis L. (Fam: Rutaceae) but also distributed in various species of the genera Boenminghausenia, Clausena and Ruta. The distribution of these compounds appears to be restricted to the plants of the family Rutaceae. To date, there have been a considerable number of bioactivity studies performed on coumarins 1 and 2, which include their anticancer, antidiabetic, antifertility, antimicrobial, antiplatelet aggregation, antiprotozoal, antiviral and calcium antagonistic properties. This review article presents a critical appraisal of publications on bioactivity of these 3-prenylated coumarins in the light of their feasibility as novel therapeutic agents and investigate their natural distribution in the plant kingdom, as well as a plausible biosynthetic route. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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15 pages, 1640 KiB

Open AccessReview

Trending Topics on Coumarin and Its Derivatives in 2020

by Aitor Carneiro, Maria João Matos, Eugenio Uriarte and Lourdes Santana

Molecules 2021, 26(2), 501; https://doi.org/10.3390/molecules26020501 - 19 Jan 2021

Cited by 83 | Viewed by 7446

Abstract

Coumarins are naturally occurring molecules with a versatile range of activities. Their structural and physicochemical characteristics make them a privileged scaffold in medicinal chemistry and chemical biology. Many research articles and reviews compile information on this important family of compounds. In this overview, [...] Read more.

Coumarins are naturally occurring molecules with a versatile range of activities. Their structural and physicochemical characteristics make them a privileged scaffold in medicinal chemistry and chemical biology. Many research articles and reviews compile information on this important family of compounds. In this overview, the most recent research papers and reviews from 2020 are organized and analyzed, and a discussion on these data is included. Multiple electronic databases were scanned, including SciFinder, Mendeley, and PubMed, the latter being the main source of information. Particular attention was paid to the potential of coumarins as an important scaffold in drug design, as well as fluorescent probes for decaging of prodrugs, metal detection, and diagnostic purposes. Herein we do an analysis of the trending topics related to coumarin and its derivatives in the broad field of drug discovery. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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21 pages, 5816 KiB

Open AccessFeature PaperReview

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom

by Eslam Reda El-Sawy, Ahmed Bakr Abdelwahab and Gilbert Kirsch

Molecules 2021, 26(2), 483; https://doi.org/10.3390/molecules26020483 - 18 Jan 2021

Cited by 12 | Viewed by 3461

Abstract

This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin(benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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26 pages, 3468 KiB

Open AccessReview

Coumarin Derivatives in Inflammatory Bowel Disease

by Luiz C. Di Stasi

Molecules 2021, 26(2), 422; https://doi.org/10.3390/molecules26020422 - 15 Jan 2021

Cited by 40 | Viewed by 5655

Abstract

Inflammatory bowel disease (IBD) is a non-communicable disease characterized by a chronic inflammatory process of the gut and categorized into Crohn’s disease and ulcerative colitis, both currently without definitive pharmacological treatment and cure. The unclear etiology of IBD is a limiting factor for [...] Read more.

Inflammatory bowel disease (IBD) is a non-communicable disease characterized by a chronic inflammatory process of the gut and categorized into Crohn’s disease and ulcerative colitis, both currently without definitive pharmacological treatment and cure. The unclear etiology of IBD is a limiting factor for the development of new drugs and explains the high frequency of refractory patients to current drugs, which are also related to various adverse effects, mainly after long-term use. Dissatisfaction with current therapies has promoted an increased interest in new pharmacological approaches using natural products. Coumarins comprise a large class of natural phenolic compounds found in fungi, bacteria, and plants. Coumarin and its derivatives have been reported as antioxidant and anti-inflammatory compounds, potentially useful as complementary therapy of the IBD. These compounds produce protective effects in intestinal inflammation through different mechanisms and signaling pathways, mainly modulating immune and inflammatory responses, and protecting against oxidative stress, a central factor for IBD development. In this review, we described the main coumarin derivatives reported as intestinal anti-inflammatory products and its available pharmacodynamic data that support the protective effects of these products in the acute and subchronic phase of intestinal inflammation. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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23 pages, 4091 KiB

Open AccessReview

Naturally Occurring Calanolides: Occurrence, Biosynthesis, and Pharmacological Properties Including Therapeutic Potential

by Lutfun Nahar, Anupam Das Talukdar, Deepa Nath, Sushmita Nath, Aman Mehan, Fyaz M. D. Ismail and Satyajit D. Sarker

Molecules 2020, 25(21), 4983; https://doi.org/10.3390/molecules25214983 - 28 Oct 2020

Cited by 18 | Viewed by 3138

Abstract

Calanolides are tetracyclic 4-substituted dipyranocoumarins. Calanolide A, isolated from the leaves and twigs of Calophyllum lanigerum var. austrocoriaceum (Whitmore) P. F. Stevens, is the first member of this group of compounds with anti-HIV-1 activity mediated by reverse transcriptase inhibition. Calanolides are classified pharmacologically [...] Read more.

Calanolides are tetracyclic 4-substituted dipyranocoumarins. Calanolide A, isolated from the leaves and twigs of Calophyllum lanigerum var. austrocoriaceum (Whitmore) P. F. Stevens, is the first member of this group of compounds with anti-HIV-1 activity mediated by reverse transcriptase inhibition. Calanolides are classified pharmacologically as non-nucleoside reverse transcriptase inhibitors (NNRTI). There are at least 15 naturally occurring calanolides distributed mainly within the genus Calophyllum, but some of them are also present in the genus Clausena. Besides significant anti-HIV properties, which have been exploited towards potential development of new NNRTIs for anti-HIV therapy, calanolides have also been found to possess anticancer, antimicrobial and antiparasitic potential. This review article provides a comprehensive update on all aspects of naturally occurring calanolides, including their chemistry, natural occurrence, biosynthesis, pharmacological and toxicological aspects including mechanism of action and structure activity relationships, pharmacokinetics, therapeutic potentials and available patents. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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