Coumarin Ring Research Articles

Synthesis and Pharmacological Evaluation of Novel Coumarin Derivatives

The current work focuses on new architecture, synthesis of coumarin-oxadiazole hybrid derivative products as both these (coumarin ring and oxadiazole) have a wide variety of biological behavior, Compounds containing the nucleus of coumarin (2H-1-benzopyran-2-one) are an interesting class of hetero cycles which hold an important role in the field of natural ingredients and synthetic organic chemistry. It has been exciting medicinal chemists to study native coumarins or synthetic analogs for their application for decades. And they can be further modified to synthesize more effective and potent drugs. Compounds have been characterized by spectrophotometry of physicochemical properties and their structures verified by infrared spectroscopy (FTIR) and nuclear magnetic resonance (1H-NMR) Such new derivatives of coumarinyl-oxadiazole was qualified to estimate the lethal dose, anticancer, anticoagulant and antioxidant activity. Their pharmacological properties depend on their pattern of substitution, compound S4F proved significant anticoagulant activity in concentration (50, 100, 200 mg/ml) similar for heparin, and monitor the coagulation effect on plasma, while compound S4CO give significant anticancer activity against MCF-7 a breast cancer cell. Specific compounds have strong antioxidants with the effective action of radical scavengers; the S4Cl compound with IC50 1.49 is the most potent antioxidant activity note. Basically, all the formulations tested reported satisfactory behavior. The review shows that varieties of coumarin derivatives have synthesized and shown anti-cancer, antioxidant and anti-coagulant potentials. These derivatives synthesis and its biological assay can be further modified in the future to improve the anti-cancer, anti-oxidant and anticoagulant potentials of the versatile coumarin nucleus.

Review on fluorescent donor–acceptor conjugated system as molecular probes

In a donor–acceptor conjugated system, donor and acceptor mesomeric units associated with π-conjugated chromophores provide simple operational, sensitive, selective and non-destructive methods of detection. In this article, we reviewed certain donor–acceptor conjugated fluorescent probes including fluorescein, acridine, cyanine, rhodamine,boron‐dipyrromethenes, coumarin, squarine, bipyridine, and thiophene ring. Along with this photophysical and optical properties have also been discussed. We also talk over the significance of these probes in the biological system. We summarized the significance of these sensors in monitoring, imaging or sensing for in vitro and in vivo examination. We discussed certain probes to examine their synthetic route, detection properties and advantages over pre-established techniques. We summarized the various type of probes including intensity-based, turn on/off type and colorimetric probes.

Synthesis, Spectrometric Characterization (ESI-MS, NMR, IRTF), X-Ray Study and Quantum Chemical Calculations of 2-oxo-2H-chromen-7-yl Benzoate

The paper presents a combined experimental and computational study of 7-substituted coumarin derivative, the 2-oxo-2H-chromen-7-yl benzoate (I). The compound was prepared in the laboratory by linking the coumarin system (7-hydroxycoumarin) to benzoyl chloride and crystallized in the monoclinic space group P2 1 with = 3.86010(10), = 27.7876(9), = 5.7453(2) A, = = 90, =91.063(3)° and = 2. The compound has been characterized structurally by spectroscopy and by single-crystal X-Ray diffraction. In the latter, the structure of (I) was solved by direct methods and refined to a final R value of 0.038 for 2260 independent reflections. Its structure is stabilized by intramolecular C-H•••O and intermolecular C-H•••O hydrogen bonds that extended as infinite 1D chain along [001]. Stabilization is also ensured by oxygen-π stacking interaction between the aromatic ring and oxygen of the benzoate moiety. The analysis of intermolecular interactions through the mapping of d norm and shape-index revel that the most significant contributions to the Hirshfeld surface 36.2 and 27.9% are from H•••H and O•••H contacts, respectively. Besides, the molecular geometry of (I) was also optimized using density functional theory (DFT/RB3LYP), the basic ab initio model i.e the restricted Hartree-Fock (RHF) methods with the 6-311 ++ G(d, p) basis set in ground state and frequency calculations with RB3LYP method using 6-31G(d,p) basis set. The theoretical data resulting from these quantum chemical calculations are generally in good agreement with the observed structure. The only significant observed difference is in the torsion angles between the coumarin ring system and the benzoate ring, where the observed CO -CC value (59.6 (4)°) is slightly lower than the DFT/RB3LYP calculated value (54.32°) and the frequency calculations (41.23°) value and larger than that of the RHF computed value (110.63°). The non-linear optical effects (NLO), molecular electrostatic potential (MEP), frontier molecular orbitals (FMO), and the Mulliken charge distribution were also investigated theoretically. The theoretical HOMO-LUMO energy gap values originating from these calculations are 4.465 eV (DFT/RB3LYP/6-311++G(d,p)) and 4.434 eV (FREQ/ RB3LYP/6-31G(d,p)).

Design, Synthesis and Antimicrobial Evaluations of Novel 3,7-Disubstituted 2H-1-Benzopyran-2-ones

In present study, a novel class of 3,7-disubstituted 2H-1-benzopyran-2-one derivatives (3xa-3zc) bearing a basic ether side chain at C-7 and a substituted phenyl ring at C-3 of the coumarin ring is synthesized. These compounds have been evaluated for antimicrobial (antibacterial/antifungal) activities. Some of the compounds viz. 3xc, 3xe, 3xf, 3yb, 3yc and 3yf have shown significant antifungal activities against selective strains. Compounds 3xe, 3yb and 3yc with the MIC values of 1.56 μg/mL displayed better antifungal activity than fluconazole against Trichophyton mentagrophytes

Coumarin incorporated 1,2,4–triazole derived silver(I) N–heterocyclic carbene complexes as efficient antioxidant and antihaemolytic agents

Three series of structurally and electronically varied silver complexes of coumarin and allyl substituted N–heterocyclic carbene (NHC) ligands derived from 1,2,4–triazole core have been prepared and characterized. The ionic 1,2,4–triazolium salts have been prepared by successive N–alkylation method using allyl bromide and appropriately substituted 4–bromomethylcoumarin derivatives. Further, in–situ deprotonation method for triazolium salts was followed with different silver sources (silver oxide and silver acetate) and reaction conditions to obtain structurally diverse silver NHC coordination architectures. Furthermore, the structure of 4–bromomethyl–6–chlorocoumarin, a triazolium salt and two silver complexes has been established by single crystal X–ray diffraction technique. The silver NHC complexes displayed a linear coordination geometry with monoclinic crystal system. Supramolecular assembly of the salt and the complexes evidenced moderate π − π stacking interactions between adjacent coumarin rings. Since silver(I) NHC complexes are well known for medicinal properties, present complexes have been studied for their potent antioxidant and antihaemolytic abilities. Bis–NHC coordinated silver hexafluorophosphate complexes displayed DPPH radical scavenging activity with an IC50 value in the range 61 ± 14 to 131 ± 7 μM, while others displayed moderate to poor activity. Similarly, antihaemolytic activity has been carried out at 100 μM concentration, and the complexes exhibited lysis of red blood cells as low as 2.32 ± 0.05%.

Discovering the structure–activity relationships of different O-prenylated coumarin derivatives as effective anticancer agents in human cervical cancer cells

Cervical cancer remains one of the greatest life threatening diseases for women worldwide. Although chemotherapy is considered as a standard treatment for advanced cervical cancers, there are still some drawbacks in this procedure including side effects and acquired drug resistance, which necessitate further research on development of more effective agents with less side effects. Among natural compounds, coumarin derivatives have shown anticancer properties on various cancerous cells and coumarin ring has proven to have a paramount role in development of anticancer drugs.Here, we aimed to establish the structure-activity relationships of eighteen O-prenylated coumarin derivatives and determined their anticancer properties on HeLa cervical cancer and HDF normal cells by MTT assay. Moreover, the mechanism of cell death induced by these compounds and their effects on cell cycle were studied using flow cytometry. MTT results indicated that twelve O-prenylated coumarin derivatives exhibited selective toxicity on HeLa cells, while they had no significant toxic effects on normal cells. Besides, flow cytometric analyses, showed that the selected compounds induced apoptosis in HeLa cells, and could also result to G1 cell cycle arrest.In conclusion, analyzing structural–activity relationships revealed that a prenylation substitution at position 6 of the coumarin ring greatly improved anticancer properties of these agents. As these derivatives exerted their cytotoxic effects via apoptosis and were not toxic on normal cells, they can be considered as effective anticancer agents for further preclinical experiments.

Crystal structure of a new polymorph of 3-acetyl-8-meth-oxy-2H-chromen-2-one.

A new polymorphic form of the title compound, C12H10O4, is described in the ortho-rhom-bic space group Pbca and Z = 8, as compared to polymorph I, which crystallizes in the monoclinic space group C2/c and Z = 8 [Li et al. (2012). Chin. J. Struct. Chem. 31, 1003-1007.]. In polymorph II, the coumarin ring system is almost planar (r.m.s. deviation = 0.00129 Å). In the crystal, mol-ecules are connected by Csp 3-H⋯O and Car-H⋯O hydrogen bonds, forming mol-ecular sheets linked into zigzag shaped layers along the b-axis direction. The three-dimensional lattice is assembled through stacking of the zigzag layers by π-π inter-actions with a centroid-to-centroid distance of 3.600 (9) Å and anti-parallel C=O⋯C=O inter-actions with a distance of 3.1986 (17) Å, which give rise to a helical supra-molecular architecture.

Structural, spectroscopic and first-principles studies of new aminocoumarin derivatives.

The new aminocoumarin derivatives 3-[1-(3-hydroxyanilino)ethylidene]-3H-chromene-2,4-dione, (1), 3-[1-(4-hydroxyanilino)ethylidene]-3H-chromene-2,4-dione, (2), and 3-[1-(2-hydroxyanilino)ethylidene]-3H-chromene-2,4-dione, (3), all C17H13NO4, were synthesized by reacting an equimolar amount of 3-acetyl-4-hydroxycoumarin and the corresponding aminophenol in absolute ethanol. Structural and spectroscopic analysis of these phases revealed that derivatives (1) and (2) are isomers of previously reported (3) [Brahmia et al. (2013). Acta Cryst. E69, o1296]. The crystal structures of meta derivative (1) and para derivative (2) were ab initio determined from powder X-ray diffraction data using the direct-space approach. Both (1) and (2) adopt the orthorhombic space group P212121. These isomers show hydrogen bonds and rich π-π stacking, together with π...H interactions, which are built by conjugated systems of coumarin and phenol rings. In the crystalline lattice, the packing of (1) and (3) are mainly stabilized through O-H...O hydrogen bonding between neighbouring coumarin molecules, while hydrogen bonds between coumarin and water molecules build the stable crystal structure of derivative (2). A big similarity in the skeletons of the IR spectra of these isomers was noticed. Derivative (2) exhibits two weak bands which were not present in the spectra of the other two derivatives, at 2370 and 2948 cm-1, which can be assigned to the O-H vibrations of the solvent (H2O) trapped in the structure of (2). These aminocoumarin derivatives display absorption maxima in the visible region, attributed to π-π delocalization involving the whole electronic system of the compounds with a considerable charge-transfer character originating from the aminophenyl ring and pointing towards the coumarin system which is characterized by a high electron-accepting character. Additionally, the isolated molecular ground-state geometries were optimized at the PBE0/TZP level and the electronic properties, molecular electrostatic potential and Hirshfeld charges were determined.

A colorimetric and fluorometric probe for hydrazine through subsequent ring-opening and closing reactions: Its environmental applications

Hydrazine (N2H4), as one of the essential industrial chemicals, is main water contaminant and highly toxic for human health. Therefore, the rapid, selective and sensitive detection strategies for hydrazine are needed. The present study describes the first example of a receptor based on pyrazolone and hydrazide formation by subsequent ring-opening and closing reactions displayed distinct naked eye colorimetric and visual fluorescence sensing towards hydrazine with rapid reactivity and very good selectivity over various anions, cations and amines. The probe BC was obtained in good yield by three stages. The sensing mechanism was confirmed by 1H NMR and 13C NMR spectra. Upon interaction with hydrazine, coumarin ring was easily opened and pink color followed by purple was formed. The more hydrazine addition triggered pyrazolone ring formation with yellow colored solution in company with the remarkable cyan blue turn-on fluorescence output. An easy-to-produce TLC test strip enables to determine hydrazine in the solution. The results were successfully shown to be convenient and efficient for hydrazine detection. Therefore, the present strategy is supposed to be widely applied to fabricate fluorescent sensors for detection of hydrazine.

A Dual Emissive Coumarin-urea Derivative with an Electron-withdrawing Substituent in the Presence of Acetate Anion.

We investigated the fluorescent properties, including the excited-state intermolecular proton transfer, of urea derivatives comprising a coumarin ring, which is a widely used fluorophore. We prepared two different coumarin-urea derivatives, 6CU and 7CU, which bear a urea-based substituent at the 6 and 7 positions of a coumarin ring, respectively. In the presence of the acetate ion, 7CU showed additional tautomer fluorescence emission with respect to 6CU, indicating that tautomer formation depends on the positions of the urea-based substituent on the coumarin ring. Thus, the resonance structures of urea derivatives might play an important role in the behavior of dual fluorescence, which is an important phenomenon applicable to photochemical anion sensing. Moreover, in order to further improve the fluorescence properties of the mentioned derivatives, a CF3 group was introduced in a phenyl ring opposite to a coumarin ring. The fluorescence quantum yield of 7CUCF3 thus synthesized was 65 times as large as that of 7CU, an observation that renders 7CUCF3 a suitable anion sensor candidate. The results of this study will contribute to the development of new molecular designs for highly fluorescent sensing.

Synthesis and kinetics studies of N'-(2-(3,5-disubstituted-4H-1,2,4-triazol-4-yl)acetyl)-6/7/8-substituted-2-oxo-2H-chromen-3-carbohydrazide derivatives as potent antidiabetic agents.

A novel series of N'-(2-(3,5-disubstituted-4H-1,2,4-triazol-4-yl)acetyl)-6/7/8-substituted-2-oxo-2H-chromen-3-carbohydrazides were synthesized and studied for their α-glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α-glucosidase inhibition activity with IC50 values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e, having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC50 = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver-Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d, and 4e, on the α-glucosidase activity, was found to be in the competitive mode.

Synthesis, characterization, crystal structure and antibacterial properties of N– and O–functionalized (benz)imidazolium salts and their N–heterocyclic carbene silver(I) complexes

Here, two series of structurally and electronically varied benzonitrile and coumarin substituted imidazolium (2–5) and benzimidazolium (7–10) hexafluorophosphate salts and corresponding NHC silver(I) complexes (11–18) are reported. Substituents on the coumarin ring are varied with an intention of bringing appropriate electronic changes in the complex, which facilitates the targeted activity. Additionally, the structure of two azolium salts (2 and 7) has been established by SCXRD technique. Extended structure of these salts witnessed a series of hydrogen bonds between the azolium cations and the hexafluorophosphate anions along with moderate π–π stacking interactions operating between the adjacent heterocyclic and/or aromatic rings such as coumarin, (benz)imidazole and benzonitrile phenyl systems. Further, a preliminary antibacterial study of the representative salts and silver complexes against a Gram positive (S. aureus, ATCC 29213) and a Gram negative (E. coli, ATCC 25922) bacteria has been carried out. Both the series of silver complexes demonstrated potent antibacterial activity with a MIC of 8/16 μg/mL against E. coli, while there activity against S. aureus found moderate with a MIC in the range 32–128 μg/mL. Furthermore, the salts evidenced no activity in the working concentration range against tested bacteria, indicating that the activity of the complexes is due to the metal center.

Crystal structure and in vitro antimicrobial activity studies of Robustic acid and other Alpinumisoflavones isolated from Millettia thonningii

Abstract We report a systematic study of the antibacterial inhibitory potential of isoflavone natural products isolated from the seeds extracts of Millettia thonningii. In an effort to gain bond topological information which may have consequences for the observed bioactivities, the crystal structure of robustic acid was solved and refined using the independent atom as well as the invariom model, and the structures were compared. Robustic acid contains a fused tricyclic unit with a benzopyran moiety, with a phenylene ring substitution on the coumarin ring similar to the alpinumisoflavones isolated from this plant. At a minimum inhibitory concentration of ~1 mg/mL, alpinumisoflavone and robustic acid were found to be cytotoxic to Staphylococcus aureus (ATCC 25923) showing a zone of inhibition (ZOI) of ~9 mm. On the other hand, at ~2 mg/mL, these compounds were found to be bacteriostatic to a hospital isolate of Salmonella typhi with about 7 mm ZOI. Taken together, these compounds offer potential new avenues for targeting both Gram positive and negative bacteria and could be useful as chemical probes for understanding these pathogens in an effort to overcome drug resistance.

Synthesis, Spectrometric Characterization, X-Ray Crystallography and Quantum Chemical Calculations of 2-oxo-2H-chromen-7-yl Propionate

The title compound, (I), has been solved by direct methods and refined to a final R value of 0.038 for 1835 independent reflections. In the structure, the planar [r.m.s deviation = 0.014 Å] chromen-2-one ring and the 7-propionate side chain are inclined to one another at an acute angle of 65.34(9)°. The molecules form R₄⁴ (30) tetrameric units via C—H···O interactions which extend into layers approximately parallel to the <i>ab</i> plane. Furthermore, the crystal structure is supported by π–π stacking interactions between neighbouring benzene and pyrone or coumarin rings [centroid–centroid distances in the range 3.6097(8)–3.6475(9)Å], as well as C–H···π interactions [H···centroid distances in the range 2.95–3.00Å]. The molecular geometry of (I) was also optimized using density functional theory (DFT/RB3LYP), RMP2 and RHF methods with the 6-311⁺⁺G(<i>d</i>, <i>p</i>) basis set in ground state. The theoretical data resulting from these quantum chemical calculations are in good agreement with the observed structure, although the observed C—O—C—C torsion angle between the coumarin ring system and the 7-propionate side chain (121.49 (16)°) is somewhat lower than the DFT/RB3LYP calculated value (132.32°) and larger than the RMP2 (114.65°) and the RHF (69.19°) values. Hirshfeld surface analysis has been used to confirm and quantify the supramolecular interactions.

Microwave assisted synthesis of coumarin-purine derivatives: An approach to in vitro anti-oxidant, DNA cleavage, crystal structure, DFT studies and Hirshfeld surface analysis

An easy and efficient microwave-assisted protocol has been developed for the synthesis of coumarin-purine hybrids (3a-3j). The newly constructed 1,3-dimethyl-7-((substituted)-2-oxo-2H-chromen-4-yl)methyl)-1H-purine-2,6(3H,7H)-dione derivatives were evaluated for their in vitro antioxidant activity by DPPH free radical-scavenging ability assay and DNA cleavage by using calf thymus. The compound 3i, shows the most excellent DPPH scavenging activity with a –OH substitution at C7 of coumarin ring. In addition, the structure of compound 3f, has been elucidated using single crystal X-ray diffraction technique. Theoretical calculations (DFT) were carried out using Gaussian09 program package and B3LYP correlation function. Full geometry optimization were carried out using 6-311G++(d, p) basis set and the frontier orbital energy were presented. Hirshfeld surface analysis was used for the intermolecular interactions in the crystal structure. The experimental result of the compound 3f has been compared with the theoretical results and it was found that the experimental data are in a good agreement with the calculated values.

Domino Bischler–Napieralski – Michael Reaction and Oxidation – New Route to Coumarin‐Pyrrole‐Isoquinoline Fused Pentacycles

Lamellarin scaffold is synthesized by a metal free convergent route involving domino Bischler–Napieralski reaction – Michael reaction – oxidation sequence. Six lamellarin analogues were synthesised having substituent on aryl as well as coumarin ring A.

Structural investigation of Cu(II) complexes with dibromo 7-hydroxycoumarin derivatives using methodology based on XAS

Two new copper(II) complexes based on 6/8-acetyl-3,8/6-dibromo-7-hydroxy-4-methylcoumarin have been synthesized and structurally characterized. The electrochemical synthesis has been applied to enforce the complexation reaction. Characterization of non-crystalline product have been performed using methodology based on X-ray absorption spectroscopy. Both compounds have square planar geometry with four oxygen atoms in the nearest distance to the copper(II) ion. The hydroxycoumarin ligands coordinate to the cooper(II) either in bidentate or monodentate manner depending on the acetyl group position in the coumarin ring. The complexes have been evaluated from microbiological and cytotoxic point of view, but no significant activity has been found.

Photophysical insights and guidelines for blue “turn‐on” fluorescent probes for the direct detection of nitric oxide (NO•) in biological systems

AbstractSynthesis and photophysical properties of a family of five blue fluorescent “turn‐on” probes for the direct detection of nitric oxide (NO•) is reported. The probes CB1‐5 feature a substituted 7‐hydroxy coumarin chromophore coupled to 2‐methyl‐8‐aminoquinoline, which act as tridentate ligand for Cu(II) and active site for monitoring NO• using a replacement strategy. The UV/vis absorption and fluorescence emission characteristics of the probes are significantly influenced by the substitution pattern on the coumarin ring, as well as by solvent polarity and pH. Time‐dependent density functional theory (TD‐DFT) calculations for CB4 and CB5 showed that the absorptions are due to π‐π* transitions localised on coumarin, with a small charge transfer contribution from the quinoline system at higher pH where the 7‐hydroxy coumarin moiety is deprotonated, which leads to a bathochromic shift of the absorption. Complexation of the probes with Cu(II) quenches the fluorescence, which is turned back on upon reaction with NO•, allowing selective detection of this important signalling molecule in μM concentrations. Preliminary experiments revealed that CB4 and CB5 enable to monitor endogenously produced NO• in living bacterial cells in multi‐dye imaging experiments.

Synthesis and Characterisation of Some New Hybrid Molecules Containing Thiophene, Triazole and Coumarin Rings under Microwave Conditions

In this work, a new series of N‘-{[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-2-oxo-2H-1-benzopyran-3-carbohydrazides (thiophene–triazole–coumarin hybrid molecules) was synthesised from the reaction of 2-[4-amino-5-oxo-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetohydrazide and 3-(1H-benzotriazol-1-ylcarbonyl)-2H-chromen-2-ones by using microwave irradiation and conventional heating procedures and their results were compared. The reaction was performed using a very small amount of organic solvent and without using a catalyst.

Synthesis and in vitro Evaluation of 1,2,3-triazole-4-chloromethylcoumarins with Antioxidant Activity

Background: Coumarins are secondary plant metabolites typically found in the species of Asteraceae, Rutaceae and Umbeliferae families which demonstrate several pharmacological properties, including antioxidant activity. As antioxidants, coumarins are known to influence the formation and uptake of Reactive Oxygen Species (ROS), to reduce the oxidative damage caused by free radicals and to prevent eicosanoid formation, being of interest for drug design. In this context, we designed the synthesis of 4-chloromethylcoumarins via Pechmann condensation with different substituents at the position 6 of the coumarin ring through Click chemistry reactions, aiming to improve their antioxidant activities. Methods: The synthesis of the envisioned compounds started with Pechmann condensation using hydroquinone and ethyl 4-chloroaceacetate followed by functionalization of the phenolic hydroxyl with propargyl bromide via Williamsom ether synthesis. Subsequently, Click chemistry reactions were performed under microwave irradiation using previously synthesized organic azides, then yielding five 6-substituted-4-chloromethylcoumarin analogues. These compounds had their intrinsic toxicities estimated via cell viability assays using the NIH 3T3 Cell Line (mouse embryonic fibroblasts) by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. The antioxidant activities were then assayed using the DCFH-DA (2’,7’-diihydrochlorofluorescin diacetate) assay. Result and Conclusion: Five novel coumarins were synthesized with low to moderate yields (11-61%), while four of these compounds displayed some degree of toxicity in the cell viability assay. However, the remaining coumarin, LaSOM 322, was nearly atoxic in all the assayed conditions and displayed the most relevant antioxidant properties, being a promising lead for subsequent optimization. Keywords: Coumarins, antioxidants, reactive oxygen species, free radical scavenging, Click chemistry, Pechmann condensation.