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Versatile Coumarins

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (15 August 2017) | Viewed by 45562

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Prof. Dr. Perry T. Kaye

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Department of Chemistry, Rhodes University, Grahamstown, South Africa
Interests: synthetic methodology: Applications of the Baylis–Hillman reaction in the synthesis of benzannulated heterocyclic systems and their elaboration to biologically active compounds; medicinal chemistry: Design, synthesis and in silico and in vitro evaluation of the medicinal potential of novel compounds as anti-parasitic (anti-malarial and anti-trypanosomal), HIV-1 PR, IN and RT inhibitors and anti-TB agents; physical organic chemistry: Kinetic-mechanistic studies of organic reaction mechanisms using spectroscopic and computational methods

Special Issue Information

Dear Colleagues,

Since the isolation of Daphnin from Daphne alpina in 1812 and of coumarin itself from the Tonka bean (Dipteryx odorata) shortly afterwards in 1820; coumarin derivatives have been discovered in a wide variety of plants. Coupled with the variety of natural sources has been the remarkable range of biological activities that coumarin-containing phytochemicals have been observed to exhibit, and such activities have undoubtedly contributed to their use in herbal remedies. Various classes of coumarin derivatives, including 4-hydroxycoumarins, furanocoumarins, and pyranocoumarins, have been identified and synthetic methods continue to be developed to access both the natural products and structural analogues. The broad medicinal potential of coumarin derivatives as, inter alia, anti-coagulant, anti-inflammatory, anti-oxidant, antibiotic, anti-fungal, anti-cancer, anti-diabetic and anti-HIV agents, makes the coumarin nucleus an attractive platform for the development of novel therapeutic agents.

This Special Issue will focus on recent developments in the synthesis or isolation of new coumarin derivatives and their potential as drug discovery lead compounds. Colleagues are invited to submit contributions to research in this area.

Emeritus Prof. Perry T. Kaye
Guest Editor

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Keywords

Coumarin
2H-Chromene-2-one
Hydroxycoumarin
Furanocoumarin
Pyranocoumarin
Drug discovery
Medicinal Chemistry
Phytochemistry

Published Papers (5 papers)

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Research

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2865 KiB

Open AccessArticle

New Metabolites of Coumarin Detected in Human Urine Using Ultra Performance Liquid Chromatography/Quadrupole-Time-of-Flight Tandem Mass Spectrometry

by Letícia Paula Leonart, João Cleverson Gasparetto, Flávia Lada Degaut Pontes, Letícia Bonancio Cerqueira, Thais Martins Guimarães De Francisco and Roberto Pontarolo

Molecules 2017, 22(11), 2031; https://doi.org/10.3390/molecules22112031 - 22 Nov 2017

Cited by 15 | Viewed by 5547

Abstract

Coumarin (1,2-benzopyrone) is a natural compound whose metabolism in humans was established in the 1970s. However, a new metabolite was recently identified in human plasma, indicating that the metabolism of coumarin has not been completely elucidated. To complement the knowledge of its metabolism, a rapid and sensitive method using UPLC-QTOF-MS was developed. A total of 12 metabolites was identified using MetaboLynxTM software, including eight metabolites not previously reported in human urine. The identified biotransformation included hydroxylation, glucuronidation, sulfation, methylation, and conjugation with N-acetylcysteine. The present work demonstrates that the metabolism study of coumarin was incomplete, possibly due to limitations of old techniques. The identification of eight inedited metabolites of such a simple molecule suggests that the information regarding the metabolism of other drugs may also be incomplete, and therefore, new investigations are necessary. Full article

(This article belongs to the Special Issue Versatile Coumarins)

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2736 KiB

Open AccessArticle

Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

by Erika Kapp, Hanri Visser, Samantha L. Sampson, Sarel F. Malan, Elizabeth M. Streicher, Germaine B. Foka, Digby F. Warner, Sylvester I. Omoruyi, Adaze B. Enogieru, Okobi E. Ekpo, Frank T. Zindo and Jacques Joubert

Molecules 2017, 22(10), 1644; https://doi.org/10.3390/molecules22101644 - 30 Sep 2017

Cited by 22 | Viewed by 5908

Abstract

A medium-throughput screen using Mycobacterium tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. In this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at 50 µM. This prompted further exploration of all the 7-substituted coumarins in our library. Four compounds showed promising MIC₉₉ values of 8.31–29.70 µM and 44.15–57.17 µM on M. tuberculosis H37Rv in independent assays using GAST-Fe and 7H9+OADC media, respectively. These compounds were found to bind to albumin, which may explain the variations in MIC between the two assays. Preliminary data showed that they were able to maintain their activity in fluoroquinolone resistant mycobacteria. Structure-activity relationships indicated that structural modification on position 4 and/or 7 of the coumarin scaffold could direct the selectivity towards either the inhibition of neuronal enzymes or the antimycobacterial effect. Moderate cytotoxicities were observed for these compounds and slight selectivity towards mycobacteria was indicated. Further neuroprotective assays showed significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and neuroprotective agents. Full article

(This article belongs to the Special Issue Versatile Coumarins)

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2215 KiB

Open AccessArticle

Kinetics and Molecular Docking Studies of 6-Formyl Umbelliferone Isolated from Angelica decursiva as an Inhibitor of Cholinesterase and BACE1

by Md Yousof Ali, Su Hui Seong, Machireddy Rajeshkumar Reddy, Sung Yong Seo, Jae Sue Choi and Hyun Ah Jung

Molecules 2017, 22(10), 1604; https://doi.org/10.3390/molecules22101604 - 24 Sep 2017

Cited by 30 | Viewed by 6684

Abstract

Coumarins, which have low toxicity, are present in some natural foods, and are used in various herbal remedies, have attracted interest in recent years because of their potential medicinal properties. In this study, we report the isolation of two natural coumarins, namely umbelliferone (1) and 6-formyl umbelliferone (2), from Angelica decursiva, and the synthesis of 8-formyl umbelliferone (3) from 1. We investigated the anti-Alzheimer disease (anti-AD) potential of these coumarins by assessing their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Among these coumarins, 2 exhibited poor inhibitory activity against AChE and BChE, and modest activity against BACE1. Structure–activity relationship analysis showed that 2 has an aldehyde group at the C-6 position, and exhibited strong anti-AD activity, whereas the presence or absence of an aldehyde group at the C-8 position reduced the anti-AD activity of 3 and 1, respectively. In addition, 2 exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. A kinetic study revealed that 2 and 3 non-competitively inhibited BACE1. To confirm enzyme inhibition, we predicted the 3D structures of AChE and BACE1, and used AutoDock 4.2 to simulate binding of coumarins to these enzymes. The blind docking studies demonstrated that these molecules could interact with both the catalytic active sites and peripheral anionic sites of AChE and BACE1. Together, our results indicate that 2 has an interesting inhibitory activity in vitro, and can be used in further studies to develop therapeutic modalities for the treatment of AD. Full article

(This article belongs to the Special Issue Versatile Coumarins)

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2687 KiB

Open AccessArticle

Deep Eutectic Solvents as Convenient Media for Synthesis of Novel Coumarinyl Schiff Bases and Their QSAR Studies

by Maja Molnar, Mario Komar, Harshad Brahmbhatt, Jurislav Babić, Stela Jokić and Vesna Rastija

Molecules 2017, 22(9), 1482; https://doi.org/10.3390/molecules22091482 - 05 Sep 2017

Cited by 23 | Viewed by 5904

Abstract

Deep eutectic solvents, as green and environmentally friendly media, were utilized in the synthesis of novel coumarinyl Schiff bases. Novel derivatives were synthesized from 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide and corresponding aldehyde in choline chloride:malonic acid (1:1) based deep eutectic solvent. In these reactions, deep eutectic solvent acted as a solvent and catalyst as well. Novel Schiff bases were synthesized in high yields (65–75%) with no need for further purification, and their structures were confirmed by mass spectra, ¹H and ¹³C NMR. Furthermore, their antioxidant activity was determined and compared to antioxidant activity of previously synthesized derivatives, thus investigating their structure–activity relationship utilizing quantitative structure-activity relationship QSAR studies. Calculation of molecular descriptors has been performed by DRAGON software. The best QSAR model (R_tr = 0.636; R_ext = 0.709) obtained with three descriptors (MATS3m, Mor22u, Hy) implies that the pairs of atoms higher mass at the path length 3, three-dimensional arrangement of atoms at scattering parameter s = 21 Å⁻¹, and higher number of hydrophilic groups (-OH, -NH) enhanced antioxidant activity. Electrostatic potential surface of the most active compounds showed possible regions for donation of electrons to 1,1-diphenyl-2-picryhydrazyl (DPPH) radicals. Full article

(This article belongs to the Special Issue Versatile Coumarins)

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Review

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34 pages, 16824 KiB

Open AccessReview

Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds

by Angela Stefanachi, Francesco Leonetti, Leonardo Pisani, Marco Catto and Angelo Carotti

Molecules 2018, 23(2), 250; https://doi.org/10.3390/molecules23020250 - 27 Jan 2018

Cited by 406 | Viewed by 20857

Abstract

Many naturally occurring substances, traditionally used in popular medicines around the world, contain the coumarin moiety. Coumarin represents a privileged scaffold for medicinal chemists, because of its peculiar physicochemical features, and the versatile and easy synthetic transformation into a large variety of functionalized coumarins. As a consequence, a huge number of coumarin derivatives have been designed, synthesized, and tested to address many pharmacological targets in a selective way, e.g., selective enzyme inhibitors, and more recently, a number of selected targets (multitarget ligands) involved in multifactorial diseases, such as Alzheimer’s and Parkinson’s diseases. In this review an overview of the most recent synthetic pathways leading to mono- and polyfunctionalized coumarins will be presented, along with the main biological pathways of their biosynthesis and metabolic transformations. The many existing and recent reviews in the field prompted us to make some drastic selections, and therefore, the review is focused on monoamine oxidase, cholinesterase, and aromatase inhibitors, and on multitarget coumarins acting on selected targets of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Versatile Coumarins)

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