Coumarin Core Research Articles

Engineering coumarin-BODIPY thin-films and molecular crystals: Tailoring supramolecular self-assembly for organic electronic applications

Chromophoric coumarin-BODIPY derivatives bridged by an ethynyl π-bridge were investigated as supramolecular building blocks of organic semiconducting solids through X-ray analysis, UV/Vis and fluorescence measurements, and quantum chemical calculations of the frontier orbital energy depending on the chemical environment. Based on a push-pull architecture, the molecular properties of 7-(diethylamino)coumarin core end-capped with BODIPYs as well as the supramolecular self-assembly can be directed through the modification of the ethyny-aryl π-bridge and the intermolecular interactions it generates. Frontier orbital energy changes depending on chemical environment were performed, in particular, upon adsorption on a flat semiconducting surface. Coumarin-BODIPY building-blocks self-assemble into molecular crystals and highly-ordered thin-films with desirable periodic π-stacking interactions for semiconducting applications. The present work represents a convenient alternative to engineer organic semiconducting solids based on coumarin-BODIPY systems for organic electronics.

Demonstrating Ligandability of the LC3A and LC3B Adapter Interface.

Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).

Selenocysteinyl electrophiles efficiently promote the formation of coumarin and quinolinone cores by 6-endo-dig cyclization

Efficient methods have been disclosed for the construction of nitrogen and oxygen containing heterocyclic systems attached to selenocysteine or selenoglutathione.

Coumarins and Coumarin-Related Compounds in Pharmacotherapy of Cancer.

Cancer is one of the most common causes of disease-related deaths worldwide. Despite the discovery of many chemotherapeutic drugs that inhibit uncontrolled cell division processes for the treatment of various cancers, serious side effects of these drugs are a crucial disadvantage. In addition, multi-drug resistance is another important problem in anticancer treatment. Due to problems such as cytotoxicity and drug resistance, many investigations are being conducted to discover and develop effective anticancer drugs. In recent years, researchers have focused on the anticancer activity coumarins, due to their high biological activity and low toxicity. Coumarins are commonly used in the treatment of prostate cancer, renal cell carcinoma and leukemia, and they also have the ability to counteract the side effects caused by radiotherapy. Both natural and synthetic coumarin derivatives draw attention due to their photochemotherapy and therapeutic applications in cancer. In this review, a compilation of various research reports on coumarins with anticancer activity and investigation and a review of structure-activity relationship studies on coumarin core are presented. Determination of important structural features around the coumarin core may help researchers to design and develop new analogues with a strong anticancer effect and reduce the potential side effects of existing therapeutics.

Design and Synthesis of Novel Coumarin Conjugated Acetamides as Promising Anticancer Agents: An In Silico and In Vitro Approach.

Coumarin and benzophenone possess a vast sphere of biological activities, whereas thiazoles display various pharmacological properties. Hence, present study focused on the incorporation of coumarin and thiazole core to the benzophenone skeleton to enhance the bioactivity, anticipating their interesting biological properties. The objective of the current work is the synthesis and biological evaluation of a novel series of coumarin fused thiazole derivatives. A novel series of coumarin conjugated thiazolyl acetamide hybrid derivatives were synthesized by a multistep reaction sequence and were characterized by the FT-IR, LCMS, and NMR spectral techniques. The newly synthesized compounds were screened for anti-cancer activity by in silico and in vitro methods. The cytotoxicity of the synthesized unique compounds was executed for two different cancer cell lines, MCF-7 (Breast cancer) and KB (Oral cancer), in comparison with standard paclitaxel by MTT assay. The compound 7f is a potent motif with an acceptable range of IC50 values, for anti-cancer activity, i.e., 63.54μg/ml and 55.67μg/ml, against the MCF-7 and KB cell lines, respectively. Molecule docking model revealed that this compound formed three conventional hydrogen bonds with the active sites of the amino acids, MET 769, ARG 817, and LYS 721. Compound 7f with two methyl groups on the phenoxy ring and one 4-position methoxy group on the benzoyl ring, showed a significant cytotoxic effect. An advantageous level of low toxicity against normal cell line (L292) by MTT assay was determined.

SYNTHESIS AND COMPLETE NMR SPECTRAL ASSIGNMENTS OF NEW BENZYLAMINO COUMARIN DERIVATIVE

This research involves the reaction of 4-chloro-3-nitrocoumarin and (4-methoxyphenyl)methanamine, whereby a novel coumarin derivative 4-[(4-methoxybenzyl) amino]-3-nitro-2H-chromen-2-one was obtained in good yield. The reaction was carried out in ethyl acetate, in the presence of triethylamine. Also, a detailed spectral analysis of a new coumarin derivative is presented. Resonance assignment was achieved using one- (1H NMR and 13C NMR) and two-dimensional NMR techniques (1H-1H-COSY, NOESY, HSQC, and HMBC). The NOESY correlations of protons from arylamino substituent and coumarin core indicate their spatial orientation.

Novel coumarin-thiazolyl ester derivatives as potential DNA gyrase Inhibitors: Design, synthesis, and antibacterial activity.

The design and synthesis of novel coumarin-thiazolyl ester derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8p exhibited excellent antibacterial activity against four bacteria strains with MIC values of 0.05, 0.05, 8, and 0.05μg/mL, respectively. In vitro drug-resistant bacterial inhibition experiments indicated that compound 8p exhibited the best bacteriostatic effect in the selected compounds and four positive control drugs with MIC values of 4μg/mL. In vitro enzyme inhibitory assay showed that compound 8p exhibited potent inhibition against DNA gyrase with IC50 values of 0.13μM. The molecular docking model indicated that compounds 8p can bind well to the DNA gyrase by interacting with amino acid residues. This study demonstrated that the compound 8p can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.

Site-Specific Fluorogenic Protein Labelling Agent for Bioconjugation.

Many clinically relevant therapeutic agents are formed from the conjugation of small molecules to biomolecules through conjugating linkers. In this study, two novel conjugating linkers were prepared, comprising a central coumarin core, functionalized with a dimaleimide moiety at one end and a terminal alkyne at the other. In our first design, we developed a protein labelling method that site-specifically introduces an alkyne functional group to a dicysteine target peptide tag that was genetically fused to a protein of interest. This method allows for the subsequent attachment of azide-functionalized cargo in the facile synthesis of novel protein-cargo conjugates. However, the fluorogenic aspect of the reaction between the linker and the target peptide was less than we desired. To address this shortcoming, a second linker reagent was prepared. This new design also allowed for the site-specific introduction of an alkyne functional group onto the target peptide, but in a highly fluorogenic and rapid manner. The site-specific addition of an alkyne group to a protein of interest was thus monitored in situ by fluorescence increase, prior to the attachment of azide-functionalized cargo. Finally, we also demonstrated that the cargo can also be attached first, in an azide/alkyne cycloaddition reaction, prior to fluorogenic conjugation with the target peptide-fused protein.

Synthesis and complete NMR spectral assignments of new benzylamino coumarin derivative

This research involves the reaction of 4-chloro-3-nitrocoumarin and (4-methoxyphenyl)methanamine, whereby a novel coumarin derivative 4-[(4-methoxybenzyl) amino]-3-nitro-2H-chromen-2-one was obtained in good yield. The reaction was carried out in ethyl acetate, in the presence of triethylamine. Also, a detailed spectral analysis of a new coumarin derivative is presented. Resonance assignment was achieved using one( 1H NMR and 13C NMR) and two-dimensional NMR techniques (1H1H-COSY, NOESY, HSQC, and HMBC). The NOESY correlations of protons from arylamino substituent and coumarin core indicate their spatial orientation.

Molecular Docking and Recent Advances in the Design and Development of Cholinesterase Inhibitor Scaffolds: Coumarin Hybrids

AbstractAlzheimer is a deadly neurodegenerative disease that commonly attacks elderly people around the world. Therefore, this disease has drawn attention among the researchers to find new potent drugs to treat Alzheimer disease (AD) more efficiently. Coumarin containing scaffold is a potential AD agent. Coumarin hybrids are frequently used as a template to design novel therapeutic agent for the treatment of AD, which are designed based on using molecular docking. As a result of docking studies shown that coumarin cores can occupy PAS by making extensive hydrophobic interactions with the residues in that region (mainly Trp279, Tyr70, Tyr121, Asp72, Phe290, Trp84, Phe330). The present review compiles research literature on the recent design strategies of coumarin hybrids with anti‐Alzheimer's activities and outlined docking studies.

A Fluorescent False Neurotransmitter as a Dual Electrofluorescent Probe for Secretory Cell Models.

A dual electrofluorescent probe (FFN42) belonging to the fluorescent false neurotransmitter family was rationally designed for investigating cell secretion. This probe, which comprises a coumarin core with one amino and two hydroxy groups, is very promising due to its electroactive and fluorescent properties. The optimal excitation and emission wavelengths (380 nm and 470 nm respectively) make this probe adapted for use in fluorescence microscopy. FFN42 has a quantum yield of 0.18, a molar absorption coefficient of 12000 M-1 cm-1 and pKa values of 5.4 and 6.7 for the hydroxy groups. The electroactivity of FFN42 was evidenced on carbon fiber and ITO electrodes at relatively low oxidation potentials (0.24 V and 0.45 V vs Ag/AgCl respectively). Epifluorescence observations showed that FFN42 accumulated into secretory vesicles of PC12 and N13 cells. Toxicity tests further revealed that FFN42 had no lethal effect on these cells. Amperometric data obtained on carbon fiber electrodes proved that the probe is released by N13 cells.

Mapping the Biotransformation of Coumarins through Filamentous Fungi

Natural coumarins are present in remarkable amounts as secondary metabolites in edible and medicinal plants, where they display interesting bioactivities. Considering the wide enzymatic arsenal of filamentous fungi, studies on the biotransformation of coumarins using these microorganisms have great importance in green chemical derivatization. Several reports on the biotransformation of coumarins using fungi have highlighted the achievement of chemical analogs with high selectivity by using mild and ecofriendly conditions. Prompted by the enormous pharmacological, alimentary, and chemical interest in coumarin-like compounds, this study evaluated the biotransformation of nine coumarin scaffolds using Cunninghamella elegans ATCC 10028b and Aspergillus brasiliensis ATCC 16404. The chemical reactions which were catalyzed by the microorganisms were highly selective. Among the nine studied coumarins, only two of them were biotransformed. One of the coumarins, 7-hydroxy-2,3-dihydrocyclopenta[c]chromen-4(1H)-one, was biotransformed into the new 7,9-dihydroxy-2,3-dihydrocyclopenta[c]chromen-4(1H)-one, which was generated by selective hydroxylation in an unactivated carbon. Our results highlight some chemical features of coumarin cores that are important to biotransformation using filamentous fungi.

Ultrafast electron-transfer in a fully conjugated coumarin-ferrocene donor-acceptor dyads

A series of a fully conjugated ferrocene-containing coumarins and B,O-chelated coumarins was prepared and characterized by a variety of spectroscopic (UV–vis, NMR, and mass spectrometry), electrochemical (CV and DPV) and spectroelectrochemical methods. The photophysical properties of the target compounds were investigated by steady-state fluorescence and ultrafast transient absorption spectroscopy methods. Selective photoexcitation of the coumarin core was followed by ultrafast electron transfer from the ferrocene fragment, resulting in formation of a charge-separated Fc+-coumarin-. state. This charge-separated state undergoes ultrafast ground state recovery in 20–25 ps, shortening the excited state lifetime of the organic coumarin precursors (1.2–1.5 ns) by almost two orders of magnitude. Formation of the charge-separated states was supported by the experimental (steady-state fluorescence oxidative titrations) and theoretical DFT and TDDFT calculations.

Crystal structures, Hirsfeld surface analysis and a computational study of four ethyl 2-oxo-2H-chromene-3-carboxylate derivatives: a survey of organyl 2-oxo-2H-chromene-3-carboxylate structures

Abstract Crystal structures, Hirshfeld surface analysis and a computational study have been carried out on 2-oxo-2H-chromene-3-carboxylates. Crystal structures are reported for ethyl R-2-oxo-2H-chromene-3-carboxylate derivatives, 2a: R=6-Me, 2b: 7-Me, 2c: 7-Me, 2d: R=7-MeO. In contrast to 2-oxo-2H-chromene-3-carboxamides, 1, in which classical intramolecular N–H···O hydrogen bonds stabilize planar structures and hinder rotation of the amido group out of the coumarin plane in 2, without an equivalent hydrogen bond, there is a greater rotational freedom of the carboxylate group. The interplanar angles between the coumarin core and its attached –C(O)–R substituent in crystalline 2a, 2b, 2c and 2d are 10.41(6), 36.65(6), 10.4(2) and 5.64(6)°, respectively, with distances between the carbonyl oxygen atoms of 2.8255(16), 2.9278(16), 4.226(2) and 2.8328(14) Å, respectively. A theoretical study of molecular conformations was carried out at the M06-2X density level with the 6-31+G(d) and aug-cc-pVTZ basis sets, in methanol solution modeled by PCM, indicated that the most stable conformations had the carbonyl group of the ester in the plane of the coumarin core: the s-cis arrangement of the ester carbonyl and the 2-oxo moieties being the slightly more stable than the s-trans form by less than 0.5 kcal/mol. The experimental conformations of 2a and 2d match well the low energy s-cis arrangement, and 2c matches the slightly lesser stable s-trans arrangement found in the theoretical study. A survey of the molecular conformations of more than 50 2H-chromene-3-carboxylates derivatives in the CCDC data base indicated two distinct groupings of conformations, s-cis and s-trans, each with interplanar angles <30°.

Cooperation and competition of hydrogen and halogen bonds in 2D self-assembled nanostructures based on bromine substituted coumarins

Three coumarin derivatives (Co16, 6-Br-Co16 and 6,8-Br-Co16) with ester, ether, and carbonyl groups and different numbers of bromine substituents on the coumarin cores were synthesized.

Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors

Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.

Molecular docking, Hirshfeld surface, structural, spectroscopic, electronic, NLO and thermodynamic analyses on novel hybrid compounds containing pyrazole and coumarin cores

The target compound 3-(3-(4-chlorobenzoyl)-1-phenyl-1H-pyrazole-5-carbonyl)-7-methoxy-2H-chromen-2-one was characterized by FT-IR, Laser-Raman, NMR chemical shift, UV–Vis. and single-crystal X-Ray diffraction spectroscopic techniques. The molecular geometric structure, Hirshfeld surface, HOMO-LUMO, molecular electrostatic potential (MEP), non-linear optical, atomic charges, molecular docking and thermodynamic analyses were theoretically investigated to support the obtained data with experimental studies. The theoretical researches and evaluations were performed by DFT/B3LYP functional at the 6-311++G(d,p) basis set in the ground state of the compound. The assignments of computed harmonic vibrational wavenumbers were determined in terms of potential energy distribution (PED) analysis. Hirshfeld surface analysis was studied to examine intermolecular interactions in crystal packing of the compound. The experimental results on molecular geometry and spectral results were showed that the correlation between experimental and theoretical data is in good agreement. Additionally, for molecular docking study, macromolecule-ligand interactions between 3-(3-(4-chlorobenzoyl)-1-phenyl-1H-pyrazole-5-carbonyl)-7-methoxy-2H-chromen-2-one and interleukin-6 (IL-6) (PDB ID: 4NI9) were investigated by using AutoDock Vina program. All results related to title compound were evaluated in detail.

Viscosity sensitive fluorescent coumarin-carbazole chalcones and their BF2 complexes containing carboxylic acid – Synthesis and solvatochromism

Red emitting coumarin-carbazole chalcones of the D- π –A and D–π–A–π–D type were synthesized with the coumarin core as acceptor and carbazole with anchoring carboxylic group at the end of N-alkyl chain as donor. The introduction of extra donor on the coumarin core led to bathochromic shift. Further, the BF2 complexation of the synthesized chalcones led to emission in red region due to efficient increase in the electron attracting capacity of coumarin acceptor. A strong emission solvatochromism than absorption was observed for the studied dyes which is well understood with the help of the multi-linear regression analysis. The frontier molecular orbital analysis of the dyes suggest strong intramolecular charge transfer characteristics. Viscosity induced emission enhancement was observed for all dyes in polar-protic (ethanol: PEG 400) solvent mixtures. As the dyes 6 and 8 emit at 612 nm and 647 nm in polar solvents these can be used as red emitting fluorescent molecular rotors.

Coumarinyl Thiosemicarbazides as Antimicrobial Agents

Two series of coumarinyl thiosemicarbazides were synthesized: one, using the coumarin core substituted in position 7 and another, using same core substituted in position 4. All these compounds were obtained in reactions of the corresponding hydrazide and various isothiocyanates. The structures of all products were confirmed by the 1H and 13C NMR and mass spectrometry techniques. The antimicrobial properties of compounds were tested on four bacterial strains: Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. 2-(2-(7-Hydroxy-2-oxo-2H-chromen-4-yl)acetyl)-N-(2,4,6-trichlorophenyl)hydrazine-1-carbothioamide was found to be the most potent agent against B. subtilis.

Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives

A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-β-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced ≥62% HSD1 inhibition at 5 µM and, furthermore, three of them produced ≥68% inhibition at 1 µM. A docking-based structure-activity relationship analysis was done to determine the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues are only modestly active with 17-β-hydroxysteroid dehydrogenase 2 – a requirement for lowering effective oestradiol levels in vivo. Moreover, the analysis led to the synthesis and discovery of 3-imidazolecoumarin as a potent aromatase inhibitor. In short, coumarin core can be tailored with specific ring and polar moiety substitutions to block either the sulphatase pathway or the aromatase pathway for treating breast cancer and endometriosis.