Search Results (92)

Coumarin derivatives, whether natural or synthetic, have attracted considerable interest from medicinal chemists due to their versatile biological properties. Their appealing pharmacological activities—such as anticancer, anti-inflammatory, neuroprotective, anticoagulant, and antioxidant effects—combined with the ease of their synthesis and the ability to introduce chemical modifications at multiple positions have made them a widely explored class of compounds. In the scientific literature, there are many examples. On the other hand, dithiocarbamates, originally employed as pesticides and fungicides in agriculture, have recently emerged as potential therapeutic agents for the treatment of serious diseases such as cancer and microbial infections. Moreover, dithiocarbamates bearing diverse organic functionalities have demonstrated significant antifungal properties against resistant phytopathogenic fungi, presenting a promising approach to combat the growing global issue of fungal resistance. Dithiocarbamates linked to coumarin derivatives have been shown to exhibit cytotoxic activity against various human cancer cell lines, including MGC-803 (gastric), MCF-7 (breast), PC-3 (prostate), EC-109 (esophageal), H460 (non-small cell lung), HCCLM-7 (hepatocellular carcinoma), HeLa (cervical carcinoma), MDA-MB-435S (mammary adenocarcinoma), SW480 (colon carcinoma), and Hep-2 (laryngeal carcinoma). Numerous studies have revealed that the inclusion of a dithiocarbamate moiety can provide central nervous system (CNS) activity, particularly through inhibitory potency and selectivity toward acetylcholinesterase (AChE) and monoamine oxidases (MAO-A and MAO-B). Recently, it has been reported that coumarin–dithiocarbamate derivatives exhibit α-glucosidase inhibitory effects and also possess promising antimicrobial activity. This study presents an overview of recent progress in the chemistry of coumarin–dithiocarbamate derivatives, with a focus on their biological activity. Previous review papers focused on coumarin derivatives as multitarget compounds for neurodegenerative diseases and described various types of compounds, with dithiocarbamate derivatives representing only a small part of them. Our work deals exclusively with coumarin dithiocarbamates and their biological activity. Full article

This study focuses on the synthesis, properties, and comparative analysis of new flame-retardant compounds: coumarins and isophosphinolines. These compounds feature a diarylphosphine oxide (DAPO) substituent at the β-position relative to both the carbonyl and the phosphoryl groups. Various derivatives with halogens, phosphorus, and/or aromatics substituents were synthetized and their thermal stability and flammability were evaluated at the microscale by thermogravimetric analysis (TGA) and pyrolysis–combustion flow calorimetry (PCFC) in order to identify the most promising molecules for use as flame-retardant (FR) additives or comonomers. FTIR-coupled PCFC analysis was also carried out to study the combustion profiles of the molecules. Beyond the confirmation of some expected trends, such as the char promotion of phosphorus and flame inhibition of halogens, the study revealed some unexpected findings that warrant further investigation. These include the prominent role of the chlorine substitution position on the aromatic ring, as well as significant differences in FR performance between diastereoisomers. Full article

In this paper, we will present the synthesis of coumarins bearing a phosphonate group in the C-3 position of the coumarin skeleton and phosphacoumarin derivatives. The compounds were synthesized by Knoevenagel condensation. Notably, the synthetic difficulties in preparing phosphacoumarins have limited previous studies. Our approach allows us to efficiently produce these derivatives, opening the way to investigate their biological properties. The resulting compounds were fully characterized using spectroscopic techniques and high-resolution mass spectrometry. We then evaluated the cytotoxicity of the compounds against human colon cancer HT-29 tumor and CCD 841 CoTr normal colon epithelial cells. We compared these results with coumarin activity to assess the effect of the introduction of the phosphonate group on their cytotoxicity. In addition, we performed cell cycle analysis by flow cytometry and examined the antioxidant activity of the compounds by the DPPH and FRAP methods. Furthermore, we conducted ADME analysis to gain more insight into the pharmacokinetic properties of the tested coumarins. Our study is in line with current trends in the search for new compounds with potential anticancer properties. Although there are numerous reports in the scientific literature on the anticancer activity of coumarin derivatives, the cytotoxicity of synthetic derivatives with a phosphonate group has not been investigated to date. Full article

The growing demand for sustainable phytosanitary products has renewed interest in botanical insecticides as viable pest control tools. Amid rising demand for sustainable crop protection, this study screens Cerrado plants traditionally used in medicine to pinpoint bioactive compounds that could replace synthetic pesticides. These products have complex chemical compositions, with compounds acting synergistically through multiple mechanisms, including oral (ingestion of allelochemicals) and topical (contact of allelochemicals on epidermis) toxicity. This study evaluated the oral and topical toxicity of aqueous leaf extracts from Anemopaegma arvense (AEAa), Coussarea hydrangeifolia (AECh), Tapirira guianensis (AETg), and Duguetia furfuracea (AEDf) on Plutella xylostella. In the oral toxicity test, first-instar larvae were fed treated diets until pupation, with biological parameters monitored until adulthood. The extracts caused an average of 45% larval mortality, reduced pupal duration, and lowered egg production. In the topical toxicity test, only the extract from T. guianensis showed significant effect (p = 0.0171), causing 30% mortality in third-instar larvae. The other extracts showed no significant topical toxicity, and AECh showed no lethal or sublethal effects at all. Phytochemical screening was assessed by quantitative spectrophotometric assays, and semi-quantitative classical colorimetric tests. Major compound classes identified were tannins, flavonoids, triterpenoids, coumarins, and alkaloids. These findings highlight the potential of the evaluated plant extracts for pest control, particularly via ingestion, while also underscoring the need for further studies to better understand their efficacy and mechanisms of action. Full article

Antioxidants, such as stilbenes, anthocyanidins, coumarins, tannins and flavonoids, are often based on oxygen-containing redox systems and tend to feature several hydroxyl groups in their chemical structures. From a synthetic perspective, oxygen atoms are prone to bioisosteric replacement with sulfur and, notably, selenium. The main objective of this narrative literature review is to explore if and how bioisosteric substitution of oxygen with sulfur or selenium can enhance the biological activity of natural products. This replacement boosts the biological activity of the resulting molecules considerably as they now combine the redox and antioxidant properties of the original flavonoids and other natural products with the specific redox behavior of sulfur and selenium. Besides sequestering free radicals and peroxides, they may, for instance, also catalyze the removal of oxidative stressors, capture free metal ions and even provide scope for selenium supplementation. Since these molecules resemble their natural counterparts, they also exhibit considerable selectivity inside the body and a good pharmacokinetic profile. Still, the synthesis of such hybrid molecules integrating sulfur and selenium into flavonoids and other natural products is a challenge and requires innovative synthetic strategies and approaches. Full article

In vertebrates, vitamin K is a cofactor for the gamma-glutamyl carboxylase (GGCX) involved in the carboxylation of glutamic acid residues. During the vitamin K cycle, vitamin K is oxidised by GGCX, and then reduced by vitamin K epoxide reductase (VKOR), which is inhibited by the synthetic coumarin warfarin. GGCX and VKOR are present in Drosophila melanogaster, but the existence of a vitamin K cycle remains unproven. Semi-lethal concentrations (LC₅₀) of K₃, menadione sodium bisulfite (MSB), and warfarin to neutralise the negative effect of MSB were selected for the Drosophila cultivation medium. LC-MS analysis was used for vitamin K measurement in flies’ extracts. The EPR method and RT-PCR were used for ROS level measurement and gene transcription assessment, respectively. The LC₅₀ of MSB in the medium resulted in a more than 20-fold increase in endogenous K₂ in flies, demonstrating the mechanism of K₃-to-K₂ conversion. Administration of 1 mM warfarin in the medium with MSB completely neutralised its negative effect on viability. Developed flies had decreased K₂ level, confirming the existence of a vitamin K cycle, and both reduced ROS level and hsp22 gene transcription. The biochemical pathways affected by elevated K₂ concentrations involves both elements of the vitamin K cycle and the adaptive mitochondrial antioxidant system. Full article

Coumarins are natural organic compounds widely found in plants that show promising anticancer properties. This article reviews the current research on the mechanisms of action of coumarins in cancer therapy, including the induction of apoptosis, inhibition of tumor cell proliferation, modulation of oxidative stress, and inhibition of angiogenesis and metastasis. Examples of coumarins with demonstrated anticancer activity, such as scopoletin, umbeliferon, esculetin and their synthetic derivatives, are also presented. The results of preclinical studies, the potential use of coumarins as stand-alone drugs and their role in combination therapy with chemotherapy are discussed. In addition, challenges related to bioavailability, safety and potential interactions with other drugs are highlighted. This review concludes by pointing out future research directions, such as the design of new coumarin analogs and the use of nanotechnology to enhance their efficacy in cancer treatment. Full article

Coumarin represents a privileged structural motif that is quite common in nature-derived and synthetic bioactive molecules. Some of us have recently described the straightforward preparation of complex furo[3,2-c]coumarins through a sequential double coupling protocol. Aiming at finding novel chemical probes for the modulation of key anti-Alzheimer’s targets, a small subset of furo[3,2-c]coumarin prototypes and their non-aromatic synthetic precursors were tested in vitro as inhibitors of ChEs (acetyl- and butyrylcholinesterase, AChE and BChE) and MAOs (monoamine oxidases A and B, MAO A and MAO B). All compounds were low-micromolar AChE inhibitors devoid of toxic effects against SH-SY5Y cells. Lineweaver-Burk plots and docking simulations suggested mixed-type kinetics for inhibitor 3d (IC₅₀ = 4.1 μM toward AChE). Its promising inhibitory profile encompasses additional, highly selective, activity against monoamine oxidase B, with a submicromolar IC₅₀ value (561 nM). Full article

Several new coumarin–isoxazole–pyridine hybrids were synthesized through a 1,3-dipolar cycloaddition reaction of nitrile oxides, prepared in situ from pyridine aldehyde oximes, with propargyloxy- or propargylaminocoumarins in moderate-to-good yields. Synthetic modifications were applied using (diacetoxyiodo)benzene (PIDA) at room temperature, microwave irradiation, or tert-butyl nitrite (TBN) under reflux. Coumarin, isoxazole, and pyridine groups were selected for hybridization in one molecule due to their biological impact to inhibit lipid peroxidation and an enzyme implicated in inflammation. Preliminary in vitro screening tests for lipoxygenase (LOX) inhibition and anti-lipid peroxidation for the new hybrids were performed. A discussion on the structure–activity relationship is presented. Compounds 12b and 13a were found to be potent LOX inhibitors with IC₅₀ 5 μΜ and 10 μΜ, respectively, while 12b presented high (90.4%) anti-lipid peroxidation. Furthermore, hybrids 12b and 13a exhibited moderate-to-low anticancer activities on HeLa, HT-29, and H1437 cancer cells. Full article

Alzheimer’s disease (AD) causes a great socioeconomic burden because of its increasing prevalence and the lack of effective therapies. The multifactorial nature of AD prompts researchers to search for new strategies for discovering disease-modifying therapeutics. To this extent, the multitarget approach holds the potential of synergic or cooperative activities arising from compounds that are properly designed to address two or more pathogenetic mechanisms. As a privileged and nature-friendly scaffold, coumarin has successfully been enrolled as the heterocyclic core in the design of multipotent anti-Alzheimer’s agents. Herein, we comprehensively summarize the most recent literature (2018–2023), covering the rational design and the discovery of coumarin-containing multitarget directed ligands (MTDLs) whose anti-AD profile encompassed at least two different biological activities relevant for disease onset and progression. To enhance the clarity of presentation, synthetic coumarin-based MTDLs are categorized into four clusters based on their substitution pattern and reported bioactivities: (i) mono-, (ii) di-, and (iii) polysubstituted coumarins directed at protein targets, and (iv) coumarins directed at protein targets with additional metal-chelating features. Before discussing multimodal coumarins, the rationale for addressing each biological target is briefly presented. Full article

Recently, 7-diethylamino-4-methylcoumarin (DEAMC) has been identified as a potent antiandrogenic compound in the surface water; however, little is known about the antiandrogenic potentials of other synthetic coumarins and their occurrence in the aquatic ecosystem. In this study, for the first time, we observed that 7-dimethylamino-4-methylcoumarin (DAMC) elicited androgen receptor (AR) antagonistic activity with a 50% inhibitory concentration (IC₅₀) of 1.46 µM, which is 14.3 times more potent than that observed for DEAMC (IC₅₀ = 20.92 µM). We further collected abiotic (water and sediment) and biotic (plant, plankton, and fish) samples (n = 208) from a subtropical freshwater ecosystem, the Dongjiang River basin, in southern China, and determined the concentrations of the two coumarins in these samples. Overall, DAMC was the predominant compound found in the sediment, plant, algae, zooplankton, and fish muscle samples, with median concentrations at 0.189, 0.421, 0.832, 0.798, and 0.335 ng/g dry wt. (DW), respectively, although it was not detected in any surface water sample. For DEAMC, the median concentrations observed in the surface water, sediment, plant, algae, zooplankton, and fish muscle samples were 0.105 ng/L, 0.012, 0.051, 0.009, 0.008, and 0.181 ng/g DW, respectively. The bioaccumulation factor (BAF) values of DAMC and DEAMC in the algae, zooplankton, and fish muscle exceeded 5000 L/kg, suggesting that the two coumarins may have significant bioaccumulation potentials in aquatic biota. Additionally, the mean daily intake (EDI) of coumarins through fish consumption was estimated as 0.19 ng/kg BW/day for male toddlers. This is the first field study to illustrate the antiandrogenic potential of DAMC and document the widespread occurrence of the two synthetic coumarins in aquatic ecosystems. Full article

Polyglutamine (polyQ)-mediated spinocerebellar ataxia (SCA), including SCA1, 2, 3, 6, 7, and 17, are caused by mutant genes with expanded CAG repeats, leading to the intracellular accumulation of aggregated proteins, the production of reactive oxygen species, and cell death. Among SCA, SCA3 is caused by a mutation in the ATXN3 (ataxin-3) gene. In a circumstance of polyQ aggregation, the autophagic pathway is induced to degrade the aggregated proteins, thereby suppressing downstream deleterious effects and promoting neuronal survival. In this study, we tested the effects of synthetic indole (NC009-1, -2, -3, -6) and coumarin (LM-022, -031) derivatives as chemical chaperones to assist mutant ATXN3-Q₇₅ folding, as well as autophagy inducers to clear aggregated protein. Among the tested compounds, NC009-1, -2, and -6 and LM-031 interfered with Escherichia coli-derived ATXN3-Q₇₅ aggregation in thioflavin T binding and filter trap assays. In SH-SY5Y cells expressing GFP-fused ATXN3-Q₇₅, these compounds displayed aggregation-inhibitory and neurite growth-promoting potentials compared to untreated cells. Furthermore, these compounds activated autophagy by increasing the phosphatidylethanolamine-conjugated LC3 (microtubule associated protein 1 light chain 3)-II:cytosolic LC3-I ratio in these cells. A biochemical co-immunoprecipitation assay by using a mixture of HEK 293T cell lysates containing recombinant ATXN3-Q₇₅-Venus-C-terminus (VC) or Venus-N-terminus (VN)-LC3 protein indicated that NC009-1 and -2 and LM-031 served as an autophagosome-tethering compound (ATTEC) to interact with ATXN3-Q₇₅ and LC3, and the interaction was further confirmed by bimolecular fluorescence complementation analysis in cells co-expressing both ATXN3-Q₇₅-VC and VN-LC3 proteins. The study results suggest the potential of NC009-1 and -2 and LM-031 as an ATTEC in treating SCA3 and, probably, other polyQ diseases. Full article

A ligand-free approach for the Suzuki-Miyaura cross coupling reaction using Natural Deep Eutectic Solvents (NaDES) towards coumarin analogs is described. A model reaction between the synthetically prepared 3-(4-acetyloxy-phenyl)-6-bromo-4-methyl-coumarin (3b) and phenylboronic acid was performed in five different NaDES as well as in pure glycerol, using two inorganic bases and palladium catalysts. The reaction proceeded smoothly in Choline Chloride/Glycerol (ChCl/Gly) and Betaine/Glycerol (Bet/Gly) NaDES at 90 °C in 24 h, affording the desired product in high yields up to 95%. The combination of K₂CO₃, Pd(OAc)₂ and ChCl/Gly NaDES provided optimum yields and high purity of the desired compounds, while the solvent was successfully recycled and reused up to two times. The developed methodology is applicable to boronic acids bearing various substituents. The formation of palladium nanoparticles in the reaction mixture was observed, and the size of the nanoparticles was associated with the reaction yield. In addition, in all the glycerol-based NaDES, an effective removal of the acetyl group of the acetyloxy–coumarin analogs was observed; thus, it is noteworthy that the Suzuki–Miyaura coupling and the deacetylation reaction were achieved in one pot. The ten novel coumarin derivatives synthesized were structurally characterized using 1D and 2D NMR spectroscopy and were tested for their cytotoxicity against the A431 squamous cancer cell line, presenting significant activity. Full article

Lamellarins are natural products with a [3,4]-fused pyrrolocoumarin skeleton possessing interesting biological properties. More than 70 members have been isolated from diverse marine organisms, such as sponges, ascidians, mollusks, and tunicates. There is a continuous interest in the synthesis of these compounds. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological properties. Three routes are followed for the synthesis of lamellarins. Initially, pyrrole derivatives are the starting or intermediate compounds, and then they are fused to isoquinoline or a coumarin moiety. Second, isoquinoline is the starting compound fused to an indole moiety. In the last route, coumarins are the starting compounds, which are fused to a pyrrole moiety and an isoquinoline scaffold. The synthesis of isolamellarins, azacoumestans, isoazacoumestans, and analogues is also described. The above synthesis is achieved via metal-catalyzed cross-coupling, [3 + 2] cycloaddition, substitution, and lactonization reactions. The title compounds exhibit cytotoxic, multidrug resistance (MDR), topoisomerase I-targeted antitumor, anti-HIV, antiproliferative, anti-neurodegenerative disease, and anti-inflammatory activities. Full article

This paper presents the efficient reduction of phosphinoylacetic acid esters and 3-phosphorylated coumarin to their corresponding phosphino-boranes using BH₃-THF complexes. Optimized conditions for the reduction of phosphinoylacetic acid esters resulted in high yields of phosphinoborates. The straightforwardness and efficiency of the process were demonstrated for diarylphosphinoylacetic acid ethyl esters, as well as P-stereogenic L-menthyl esters, where the simultaneous reduction of the strong P=O bond and the ester group was exclusively observed for the first time. The study also highlighted the significant influence of steric effects with bulky substituents, such as the menthol group or the 1-naphthyl substituent at phosphorus, on the reduction efficiency. However, the reduction of 3-phosphorylated coumarins produced an unexpected reaction product: a 2,3-dihydrobenzofuran derivative. The present findings provide valuable information on the direct reduction of phosphine oxides and related compounds, demonstrating the versatility of borane complexes in synthetic chemistry, and provide new perspectives for studying the problems of symmetry and asymmetry in the chemistry of such transformations. Full article