Coumarin Core Research Articles

Microwave expedited Cu(I) catalyzed regioselective 1,2,3-triazoles as Mycobacterium Tuberculosis H37Rv inhibitors, in vitro α-amylase and α-glucosidase inhibition, in silico studies

In the present study, an efficient and convenient synthesis of novel 1,2,3-triazoles (8i-t) incorporated quinoline and coumarin cores has been reported. Microwave-assisted Huisgen 1,3-dipolar cycloaddition reaction of azide and alkyne resulted in high yields (88–94 %) of the title compounds. Regioselective single-product formation both under conventional and microwave methods is the foremost supremacy of this work. All the molecules were subjected to in vitro antibacterial assessment wherein the compounds 8i, 8k, 8l, 8n, and 8r demonstrated very good antibacterial activity against other bacterial strains tested. Compounds 8i, 8k, 8l, 8n, 8o, 8q, and 8r demonstrated excellent antitubercular activity with MICs in the range 1.60–6.25 µg/mL in comparison to the standard drugs (Isoniazid-1.60 µg/mL, Ciprofloxacin-3.25 µg/mL, Pyrazinamide-6.25 µg/mL). Compounds 8i, 8n, and 8r also exhibited inhibitory effects against α-amylase and α-glucosidase and thus, also showed anti-diabetic activity. The significantly active compounds were subjected to molecular docking and molecular dynamics simulation studies to study the putative binding pattern as well as the stability of the docked complexes, respectively. In silico ADME profiles of the titled compounds were also predicted to access the drug-likeness properties of the designed compounds. Titled compounds showed potential effectiveness as antibacterial and antidiabetic agents.

Naturally Inspired Coumarin Derivatives in Alzheimer's Disease Drug Discovery: Latest Advances and Current Challenges.

The main feature of neurodegenerative diseases, including Alzheimer's disease, is the network of complex and not fully recognized neuronal pathways and targets involved in their onset and progression. The therapeutic treatment, at present mainly symptomatic, could benefit from a polypharmacological approach based on the development of a single molecular entity designed to simultaneously modulate different validated biological targets. This strategy is principally based on molecular hybridization, obtained by linking or merging different chemical moieties acting with synergistic and/or complementary mechanisms. The coumarin core, widely found in nature, endowed with a recognized broad spectrum of pharmacological activities, large synthetic accessibility and favourable pharmacokinetic properties, appears as a valuable, privileged scaffold to be properly modified in order to obtain compounds able to engage different selected targets. The scientific literature has long been interested in the multifaceted profiles of coumarin derivatives, and in this review, a survey of the most important results of the last four years, on both natural and synthetic coumarin-based compounds, regarding the development of anti-Alzheimer's compounds is reported.

Decarboxylative Iodination of Coumarin‐3‐carboxylic Acids: A Facile Access to 3‐Iodocoumarins

A straightforward protocol for the direct conversion of readily available coumarin‐3‐carboxylic acids to the corresponding 3‐iodocoumarins is described herein. Heating acetonitrile solution of coumarin‐3‐carboxylic acids, molecular iodine and potassium hydrogen phosphate resulted in the decarboxylative iodination of coumarin‐3‐carboxylic acids via radical mechanism. Various electron rich and electron poor coumarin‐3‐carboxylic acids were compatible with the established reaction conditions and consequently afforded the corresponding 3‐iodocoumarins in (46‐93%) reaction yields with minimum purification efforts. The formed products serve as valuable precursors to streamline more complex organic compounds incorporating coumarin core.

Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy

BackgroundBreast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized.MethodsA substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B.ResultsWe synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice.ConclusionsOur findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.

Water-Soluble Small Organic Fluorophores for Oncological Theragnostic Applications: Progress and Development.

Cancer is one of the major noncommunicable diseases, responsible for millions of deaths every year worldwide. Though various cancer detection and treatment modalities are available today, many deaths occur owing to its late-stage detection and metastatic nature. Noninvasive detection using luminescence-based imaging tools is considered one of the promising techniques owing to its low cost, high sensitivity, and brightness. Moreover, these tools are unique and valuable as they can detect even the slightest changes in the cellular microenvironment. To achieve this, a fluorescent probe with strong tumor uptake and high spatial and temporal resolution, especially with highwatersolubility, is highly demanded. Recently, several water-soluble molecules with emission windows in the visible (400-700nm), first near-infrared (NIR-I, 700-1000nm), and second near-infrared (NIR-II, 1000-1700nm) windows have been reported in literature. This review highlights recently reported water-soluble small organic fluorophores/dyes with applications in cancer diagnosis and therapeutics. We systematically highlight and describe the key concepts, structural classes of fluorophores, strategies for imparting water solubility, and applications in cancer therapy and diagnosis, i.e., theragnostics. We discuss examples of water-soluble fluorescent probes based on coumarin, xanthene, boron-dipyrromethene (BODIPY), and cyanine cores. Some other emerging classes of dyes based on carbocyclic and heterocyclic cores are also discussed. Besides, emerging molecular engineering methods to obtain such fluorophores are discussed. Finally, the opportunities and challenges in this research area are also delineated.

Screening drug-induced liver injury through two independent parameters of lipid droplets and peroxynitrite with a π-extended coumarin-based NIR fluorescent probe

Drug-induced liver injury (DILI) or hepatotoxicity is a significant concern for public health. However, relying on a single biomarker for early DILI diagnosis poses a high risk of false positives. In this study, we reported a near-infrared fluorescent probe (BCOU-S), which enables independent visualization of LDs status and ONOO fluctuations. BCOU-S was constructed by combining a π-extended coumarin core as the NIR fluorophore and a methyl thioether group as the ONOO recognition site. BCOU-S could emit 655 nm NIR fluorescence excited at 518 nm, with a low detection limit of 27 nM and a large Stokes shift of 137 nm. The response mechanism to ONOO was confirmed by molecular orbital density function theory (DFT) and time-dependent DFT (TD-DFT) calculations. BCOU-S monitors LDs status through co-localization, oleic acid (OA) incubation, and starvation induction experiments. It sensitively distinguishes subtle changes in ONOO induced by different drugs in DILI cell models. In the acetaminophen (APAP)-induced DILI model, BCOU-S reveals significant LDs accumulation and increase in ONOO levels, establishing a clear time-effect and dose-effect relationship. Simultaneously monitoring ONOO levels and LDs accumulation, BCOU-S proves to be a more sensitive and effective tool for early DILI prevention, effectively avoiding false positives caused by changes in a single parameter. BCOU-S is a useful tool for further monitoring early DILI development.

Terminal methylene biphenyl derived coumarin Schiff base-esters: Synthesis, mesomorphic behaviour and DFT investigations

In the present investigation new unsymmetrical coumarin-methylene biphenyl MBPCE-(2–16) mesogens were designed and synthesized. Methylene biphenyl end group at one end of molecules have been linked to the 7-alkyloxy substituted coumarin core through imine and ester mesogenic connecting units. The structures of new hybrids have been elucidated employing different analytical techniques including FT-IR, 1H NMR, 13C NMR, Mass & CHN elemental analysis. New molecules have been investigated for their mesomorphic behaviour using DSC (Measurement of transition temperature and enthalpy associated) and POM (Texture study) techniques and the existence of mesophase was established by VT-XRD analysis. Compounds with n = 2 (-OC2H5) to n = 7 (-OC7H15) chain length exhibited enantiotropic nematic mesophase with good thermal stability. As the chain length increases, compounds from n = 8 (-OC8H17) and n = 10 (-OC10H21) displayed enantiotropic nematic as well as smectic-A mesophase whereas compound with n = 12 (-OC12H25) showed only interdigitated SmA phase. Next two members of the series failed to show any mesomorphism. The commencement of SmA phase and disappearance of nematic could be attributed to more layer arrangement with increased van der waals interactions. The density functional theory (DFT) calculations were employed to complement the experimental results concerning the mesomorphic behaviour. Development of smectic phase could be due to the augmentation in the area of the intermolecular interaction which increases the degree of molecular packing. Conversely, it was discovered that higher polarizability leads to lower nematic thermal stability because it strengthens parallel intermolecular interactions, which promotes a higher degree of molecular order while reducing the development of lower-order nematic mesophase.

Unsymmetrical coumarin-biphenyl hybrids: Self-assembling behaviour and DFT investigations

A series of new unsymmetrical coumarin-biphenyl hybrid [1,1′-biphenyl]-4-yl (E)-4-(((7-alkyloxy-2-oxo-2H-chromen-3-yl)imino)methyl)benzoates, BPCE-(2–18) self-assembling molecules have been designed and synthesized. Biphenyl end group at one end of molecules have been linked to the substituted coumarin core through imine and ester mesogenic linking units. Initial members of the series exhibited enantiotropic nematic phase, middle members showed nematic as well as smectogenic behaviour (smectic A) whereas the last member showed only smectogenic behaviour with disappearance of nematic mesophase. In addition, a comparative study has been done with structurally similar mesogens. The study incorporated Density Functional Theory calculations to determine the aspect ratio, dipole moment, and polarizability. These factors influence the terminal and lateral interactions of the compounds. Moreover, computation of molecular electrostatic potential was conducted to examine reactivity concerning both nucleophilic and electrophilic attacks. The theoretical findings were then discussed to validate the experimental data and elucidate the mesomorphic behaviour of the compounds. Additionally, calculations for the energy gap of frontier molecular orbitals, global softness, and chemical hardness were performed to assess the potential suitability of the liquid crystalline compounds for various applications.

Natural Coumarin Derivatives Targeting Melanoma.

In general, a cancerous process starts from uncontrolled cell growth, apoptosis, and rapid proliferation of cellular clones, as well as, reactive oxygen species (ROS) and imbalance of ROS-antioxidant production also could be involved in the genesis of the disease. Cancer has accounted for millions of deaths worldwide every year, representing a relevant threat to human lives. In this context, malignant melanoma represents the most aggressive and deadliest type of cancer, leading to increased rates of patient deaths. Natural active compounds have demonstrated their pharmacological benefits in several different studies. Among these compounds, coumarin analogs have demonstrated promising biological profiles, considering their efficacy and low toxicity. In this context, this phytochemical oxygenated core has been broadly investigated since it presents several biological properties of interest in the medicinal field. Herein, we reported a complete compilation of studies focused on natural coumarins against melanoma, as well as, tyrosinase since it is a cooper-catalyzed oxidase that performs an essential role during melanogenesis (Eu-melanins and Pheo-melanins), which is associated with melanoma. Thus, three different subclasses of natural coumarin were described in detail, such as simple coumarin core, furanocoumarins, pyranocoumarins, and pyrone-substituents. Additionally, insights on tyrosinase have been provided, allowing an overview of some structural/functional aspects of its enzyme, such as the presence of a binuclear type 3 cooper coordination at the binding site of this target, acting as cofactors. Posteriorly, several coumarin-based analogs with anti-tyrosinase activity also were reported and discussed. Finally, we believe that unprecedented review can be a valuable source of information, which can be used to design and develop novel coumarin-based analogs targeting melanoma and also tyrosinase enzyme, contributing to the advances in the field of natural products.

Asymmetric 1,2-diaxial synthesis of bi-(hetero)aryl benzofulvene atropisomers via transient directing group-assisted dehydrogenative coupling.

The efficient cross-dehydrogenative coupling of electronically rich and sterically congested benzofulvene with bi-(hetero)aryl moieties to construct an axially chiral benzofulvene core remains a formidable task. In this study, we describe a highly efficient and practical palladium-catalyzed approach for atroposelective bi-(hetero)aryl benzofulvene synthesis, achieving excellent enantioselectivity with moderate yields. This protocol offers a remarkable opportunity for the direct regio- and enantioselective conversion of C-H bonds of benzofulvene to C-C bonds. Furthermore, the protocol permits the incorporation of benzofulvene with a 4-phenyl coumarin core, enabling access to a novel class of axially chiral coumarins.

A simple coumarin-based system for the effective detection of superoxide in bacteria

Superoxide anion is a highly reactive ROS however the sensing of this species is relatively unexplored. The current methods to sense superoxide requires the construction of complex probes which are often hard to synthesize. With this research we report a simple one step high yielding (90%) method to prepare a probe for the detection of O2.- in bacteria using a coumarin core and trifluoromethanesulfonate locking group.

Coumarin Based Fluorescent Probe for Detecting Heavy Metal Ions.

Heavy metals such as Iron, Copper, and Zinc are micro-essential trace metal and involve animportant biological role, but it quickly turns toxic at exceeding the permissible limit, causing gastrointestinal irritation, liver, bone, and kidney damage, as well as disorders including Wilson's, Parkinson's, and Alzheimer's. It is important to detect the metal ions as well as their concentration quickly and affordable cost using organic probes. Among the organic probes,the coumarin fluorescent probe shows a very prominent candidate with heavy metal ions. Therefore, in the present review, we reviewed the very recent literature the identify the heavy metals using modified coumarin fluorescent probes. Readers will get information quickly about the method of preparation of modified coumarin core and their use as fluorescent probes with heavy metals using absorption and emission spectroscopic methods along with the probable mechanistic pathway of detection.

Coumarin derivatives as antifungal agents - A review

Coumarins and pyridines are a promising class of naturally occurring bioactive heterocycles with unique physical and chemical properties. Compounds containing the coumarin framework possess a wide range of pharmacological, biological, and physiological activities, which makes them important for application in medicine, the food industry and agriculture. Among all coumarins' properties, it was found that coumarins may prevent fungal growth, depending on substituents linked to the coumarin core. Therefore, many coumarin derivatives have been investigated as potentially powerful agents in preventing and controlling fungal pathogens. This review summarises the latest research on coumarins and their antifungal activity to provide useful information for further developing more efficient coumarin-based fungicides.

Coumarin functionalized dimeric mesogens for promising anticoagulant activity: Tuning of liquid crystalline property

This paper demonstrates the synthesis of novel bi-substituted coumarin-based symmetrical compounds (A1-A6)via a simple two-step reaction by conversion of coumarin (I) to dicoumarol (II) followed by the alkylation using different alkyl bromides. The chemical proposed structure was confirmed by IR, NMR, Mass, and CHN analysis. These dimeric materials were further investigated for liquid crystalline properties. The thermal behavior and liquid crystalline properties were evaluated using TGA, DSC, POM, and high temperature XRD. The substitution of various alkyl chains on coumarin core presented a broad scope to achieve different types of liquid crystalline properties. These symmetrical dimers of coumarin derivatives exhibited enantiotropic type mesophase with a broad temperature range and wide thermal stability. The compound with a hexadecyloxy tail exhibited mesogenic properties at room temperature. The lower alkoxy side chain substituted materials presented only nematic phase while higher alkoxy side chain substituted materials displayed smectic type mesogenic properties. The present coumarin-based dimeric mesogens were easily fabricated by simple two-step method as compared to other coumarin-based mesogens. In addition, one of the dicoumarol derivatives showed promising anticoagulant activity. Compound A5 at 10.0 mg/5.0 mL of blood concentration revealed good efficacy as an anticoagulant agent to prevent blood clotting.

Biological evaluation of novel amidino substituted coumarin-benzazole hybrids as promising therapeutic agents.

Herein we present the design and the synthesis of novel substituted coumarin-benzimidazole/benzothiazole hybrids bearing a cyclic amidino group on the benzazole core as biologically active agents. All prepared compounds were evaluated for their in vitro antiviral and antioxidative activity as well as for their in vitro antiproliferative activity against a panel of several human cancer cell lines. Coumarin-benzimidazole hybrid 10 (EC50 9.0-43.8 μM) displayed the most promising broad spectrum antiviral activity, while two other coumarin-benzimidazole hybrids 13 and 14 showed the highest antioxidative capacity in the ABTS assay, superior to the reference standard BHT (IC50 0.17 and 0.11 mM, respectively). Computational analysis supported these results and demonstrated that these hybrids benefit from the high C-H hydrogen atom releasing tendency of the cationic amidine unit, and the pronounced ease with which they can liberate an electron, promoted by the electron-donating diethylamine group on the coumarin core. The coumarin ring substitution at position 7 with a N,N-diethylamino group also caused a significant enhancement of the antiproliferative activity, with the most active compounds being derivatives with a 2-imidazolinyl amidine group 13 (IC50 0.3-1.9 μM) and benzothiazole derivative with a hexacyclic amidine group 18 (IC50 1.3-2.0 μM).

Strategies to convert organic fluorophores into red/near-infrared emitting analogues and their utilization in bioimaging probes.

Organic fluorophores aided by current microscopy imaging modalities are essential for studying biological systems. Recently, red/near-infrared emitting fluorophores have attracted great research efforts, as they enable bioimaging applications with reduced autofluorescence interference and light scattering, two significant obstacles for deep-tissue imaging, as well as reduced photodamage and photobleaching. Herein, we analyzed the current strategies to convert key organic fluorophores bearing xanthene, coumarin, and naphthalene cores into longer wavelength-emitting derivatives by focussing on their effectiveness and limitations. Together, we introduced typical examples of how such fluorophores can be used to develop molecular probes for biological analytes, along with key sensing features. Finally, we listed several critical issues to be considered in developing new fluorophores.

Synthesis & Pharmacological Activity of Cytotoxicity Assay of Coumarins SVCM1-SVCM7

The therapeutic properties of natural and synthetic compounds against human illnesses have attracted a lot of interest. The pharmacological and biological effects of coumarins are widely exploited in medicine; they include anti-inflammatory, anticoagulant, antihypertensive, anticonvulsant, antioxidant, antibacterial, and neuroprotective properties. Signaling pathways affecting many cellular functions may also be modulated by coumarin derivates. Whether or not a coumarin has pharmacological, biochemical, or therapeutic characteristics is dependent on the nature of the replacement surrounding the coumarin core structure. The capacity to kill, repel, or otherwise impact the development of Anopheles arabiensis mosquitoes was evaluated using seven synthetic halogenated coumarins (SVCM1-SVCM7). The compounds SVCM1-SVCM7 were evaluated for their bactericidal and fungicidal activities using the disc diffusion method.

Design, Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti-AD Lead Compound.

Coumarins and their derivatives possessed a variety of biological activities and some of coumarin-based drugs have been approved by the US Food and Drug Administration. Alzheimer's disease (AD) has caused great losses to human society. However, due to its complex pathogenesis, the ideal therapeutic approach has not been found yet. Free radical scavenging activity which is one of the main activities of coumarin core structure is closely related to other anti-AD activities. Therefore, in this work coumarins were chosen as privileged lead compounds for the development of anti-AD drugs based on strategy of multi-target directed ligands (MTDLs). Derivatives 1-3 which could modulate multiple targets simultaneously, including ROS, cholinesterase, βamyloid (Aβ) aggregation, and metal dyshomeostasis were designed and for the first time synthesized. Their anti-AD activities were studied both in vitro and in silico. Results showed that 1-3 possessed potent antioxidant activities and 7-OH group did change the electron distribution of the molecule and enhance the antioxidant activities. They also have good inhibition activities on acetylcholinesterase (AChE) and Aβ aggregation and compound 1 had the strongest AChE inhibitory effect among the three compounds (AChE IC50 =11.15 μM). Compound 1-3 could also selectively chelate with Cu2+ and Al3+ to regulate the metal homeostasis. In silico simulations, including molecular docking and prediction of ADMET performance, indicated that 1-3 could interact with target proteins and cross the blood brain barrier. In conclusion, 1-3 could be promising MTDLs applied as anti-AD candidate drugs.

Medicinal chemistry aspects and synthetic strategies of coumarin as aromatase inhibitors: an overview.

Coumarin is a bicyclic oxygen bearing heterocyclic scaffold formed by fusion of benzene with the pyrone ring. Because of its unique physicochemical characteristics and the ease with which it may be transformed into a wide range of functionalized coumarins duringsynthesis, coumarin provides a privileged scaffold for medicinal chemists. As a result, many coumarin derivatives have been developed, synthesized, and evaluated to target a variety of therapeutic domains, thereby making it an attractive template for designing novel anti-breast cancer compounds. The main culprit in estrogen overproduction in the estrogen-dependent breast cancer (EDBC), is the enzyme aromatase (AR), and it is thought to be a significant target for the effective treatment of EDBC. Considering coumarins versatility, this review presents a detailed overview of diverse study of aromatase as a target for coumarins. An overview of structure-activity relationship analysis of coumarin core is also included so as to summarize the desired pharmacophoric features essential for design and development of aromatase inhibitors (AIs) using coumarin core. Identification of key synthesis techniques that could aid researchers in designing and developing novel analogues with significant anti-breast cancer properties along with their mechanism of action have also been covered in the current review.

Evolving a high-performance bio-imaging tool derived from a compact fluorophore as well as creating a reaction-based fluorescent probe for precise determination of Ag+

Commonly, emission of red-region fluorescence is inherently in need of substantial conjugating segments and fused rings, which inescapably burdens fluorescent molecules in their size and molecular weight, impairing their membrane permeability and biocompatibility. Herein, a novel dicyanocoumarin 2-(7-(N,N-diethylamino)-4-(trifluoromethyl)–2H-chromen-2-ylidene)malononitrile (CouMal) has been evolved from traditional coumarin core for the first time. Without enlarged π-conjugation system, the low-molecular-weight CouMal unexpectedly possesses red-region fluorescence both in the solid and solution states with considerable brightness. Based on its compact structure and long-wavelength emission, the CouMal exhibits great cytomembrane penetrability and reduced cytotoxicity, enabling its promising application for intracellular imaging and in vivo imaging. Innovatively, enlightened by the flexible synthetic procedure of CouMal, a reaction-based sensing system named TC-Mal-Et3N, has been freshly designed for the precise detection of silver ion (Ag+). The limit of detection of this sensing system is as low as 60.9 nM. This Ag+-triggered composite probe also exhibits superb selectivity and short reaction time, which has been applied for the accurate quantification of both Ag+ and silver nanoparticles (AgNPs) in real-world representative samples.