Design of new α-glucosidase inhibitors based on the bis-4-hydroxycoumarin skeleton: Synthesis, evaluation, and in silico studies.

In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure-activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.

L-proline H2SO4 catalyzed synthesis of novel coumarin-based spiroindolino-3,4-dihydropyrimidin-2(1H)-ones: in vitro cytotoxic assay and molecular docking study.

Development of environmentally benign catalyst systems, especially those derived from readily available nature's pool, in multicomponent synthesis, consolidates multiple facets of green chemistry. Here, an L-proline derived green acid catalyst in the form of L-proline⋅H2SO4 was developed and employed for multicomponent synthesis of coumarin-based spiroindolino-3,4-dihydropyrimidin-2(1H)-ones from the reaction of 4-hydroxycoumarin, isatin and urea/thiourea. Preliminary cytotoxicity studies showed that a couple of compounds (M5 and M6) have good cytotoxicity (40-50%) against in Dalton's Lymphoma (DL) cells while demonstrating minimal cytotoxicity (10-12%) for normal non-cancerous cell lines. Molecular docking simulations for the least and most cytotoxic compounds, M3 and M6 respectively, against nineteen tumor target proteins were carried out, and seven of them were identified to test against all the sixteen compounds. Based on the estimated docking score and inhibition constants (Ki), the interaction of the compounds with the tumor target protein, beta-hexosaminidase B (PDB ID: 1NOW) matched closely with in vitro cytotoxicity data.

Design, synthesis and bioactivity evaluation of 4-hydroxycoumarin derivatives as potential anti-inflammatory agents against acute lung injury and colitis.

Acute lung injury (ALI) and inflammatory bowel disease (IBD) are common inflammatory illnesses that seriously affect people's health. Herein, a series of 4-hydroxylcoumarin (4-HC) derivatives were designed and synthesized. The inhibitory effects of these compounds on LPS-induced interleukin-6 (IL-6) release from J774A.1 cells were then screened via ELISA assay, compound B8 showed 3 times more active than the lead compound 4-HC. The most active compound B8 had the IC50 values of 4.57 µM and 6.51 µM for IL-6 release on mouse cells J774A.1 and human cells THP-1, respectively. Furthermore, we also found that B8 could act on the MAPK pathway. Based on the target prediction results of computer virtual docking, kinase inhibitory assay was carried out, and it revealed that targeting IRAK1 was a key mechanism for B8 to exert anti-inflammatory activity. Moreover, B8 exerted a good therapeutic effect on the dextran sulfate sodium (DSS)-induced colitis model and liposaccharide (LPS)-induced ALI mouse models. The acute toxicity experiments indicated that high-dose B8 caused no adverse reactions in mice, confirming its safety in vivo. Additionally, the preliminary pharmacokinetic (PK) parameters of B8 in SD rats were also examined, revealing a bioavailability (F) of 28.72 %. In conclusion, B8 is a potential candidate of drug for the treatment of ALI and colitis.

A self-regulated network for dynamically balancing multiple precursors in complex biosynthetic pathways.

Microbial synthesis has emerged as a promising and sustainable alternative to traditional chemical synthesis and plant extraction. However, the competition between synthetic pathways and central metabolic pathways for cellular resources may impair final production efficiency. Moreover, when the synthesis of target product requires multiple precursors from the same node, the conflicts of carbon flux have further negative impacts on yields. In this study, a self-regulated network was developed to relieve the competition of precursors in complex synthetic pathways. Using 4-hydroxycoumarin (4-HC) synthetic pathway as a proof of concept, we employed an intermediate as a trigger to dynamically rewire the metabolic flux of pyruvate and control the expression levels of genes in 4-HC synthetic pathway, achieving self-regulation of multiple precursors and enhanced titer. Transcriptomic analysis results additionally demonstrated that the gene transcriptional levels of both pyruvate kinase PykF and synthetic pathway enzyme SdgA dynamically changed according to the intermediate concentrations. Overall, our work established a self-regulated network to dynamically balance the metabolic flux of two precursors in 4-HC biosynthesis, providing insight into balancing biosynthetic pathways where multiple precursors compete and interfere with each other.

New 5-methyl-4-hydroxycoumarin polyketide derivatives from Gerbera delavayi with anti-inflammatory activity.

Five new 5-methyl-4-hydroxycoumarin polyketide derivatives (MPDs), delavayicoumarins A-E (1-5), were isolated from the whole plants of Gerbera delavayi. Among them, compounds 1-3 are the common monoterpene polyketide coumarins (MPCs), while 4 is a modified MPC with both the lactone ring contracted to a five-membered furan ring and a carboxyl at C-3, and 5 is a pair of unusual phenylpropanoid polyketide coumarin enantiomers (5a and 5b), featuring a phenylpropanoid unit at C-3. The planar structures were elucidated by spectroscopic methods and biosynthetic arguments, and the absolute configurations of 1-3, 5a and 5b were confirmed by calculated electronic circular dichroism (ECD) experiment. Furthermore, compounds 1-3, (+)-5 and (-)-5 were tested for the nitric oxide (NO) inhibitory activity by using lipopolysaccharide (LPS)-induced RAW 264.7 cells in vitro. The results showed that compounds 1-3, (+)-5 and (-)-5 remarkably inhibited NO production at the concentration of 10.0 µM, exhibiting that they have significant anti-inflammatory activity.

SnO2 nanoparticles: A recyclable and heterogeneous catalyst for Pechmann condensation of coumarins and Knoevenagel condensation-Michael addition of biscoumarins.

Recyclable SnO2 nanoparticles catalyze the Pechmann condensation between phenolic alcohols and ß-ketoesters at room temperature in ethanol leading to coumarins. Also, in another study the synthesis of biscoumarins catalyzed by SnO2 nanoparticles in the reaction between 4-hydroxycoumarin and aldehydes under same condition reactions. The corresponding coumarins and biscoumarins were produced efficiently with facility and excellent yields (93-98%). These approaches display the advantages of benign reaction conditions, non-chromatographic purification procedure, appropriate functional group tolerance and valuable process.

Computational tools for exploring peptide-membrane interactions in gram-positive bacteria.

The vital cellular functions in Gram-positive bacteria are controlled by signaling molecules known as quorum sensing peptides (QSPs), considered promising therapeutic interventions for bacterial infections. In the bacterial system QSPs bind to membrane-coupled receptors, which then auto-phosphorylate and activate intracellular response regulators. These response regulators induce target gene expression in bacteria. One of the most reliable trends in drug discovery research for virulence-associated molecular targets is the use of peptide drugs or new functionalities. In this perspective, computational methods act as auxiliary aids for biologists, where methodologies based on machine learning and in silico analysis are developed as suitable tools for target peptide identification. Therefore, the development of quick and reliable computational resources to identify or predict these QSPs along with their receptors and inhibitors is receiving considerable attention. The databases such as Quorumpeps and Quorum Sensing of Human Gut Microbes (QSHGM) provide a detailed overview of the structures and functions of QSPs. The tools and algorithms such as QSPpred, QSPred-FL, iQSP, EnsembleQS and PEPred-Suite have been used for the generic prediction of QSPs and feature representation. The availability of compiled key resources for utilizing peptide features based on amino acid composition, positional preferences, and motifs as well as structural and physicochemical properties, including biofilm inhibitory peptides, can aid in elucidating the QSP and membrane receptor interactions in infectious Gram-positive pathogens. Herein, we present a comprehensive survey of diverse computational approaches that are suitable for detecting QSPs and QS interference molecules. This review highlights the utility of these methods for developing potential biomarkers against infectious Gram-positive pathogens.

Exploring and engineering PAM-diverse Streptococci Cas9 for PAM-directed bifunctional and titratable gene control in bacteria.

The RNA-guided Cas9s serve as powerful tools for programmable gene editing and regulation; their targeting scopes and efficacies, however, are always constrained by the PAM sequence stringency. Most Streptococci Cas9s, including the prototype SpCas9 from S. pyogenes, specifically recognize a canonical NGG PAM via a conserved RxR PAM-binding motif within the PAM-interaction (PI) domain. Here, SpCas9-based mining unveils three distinct and rarely presented PAM-binding motifs (QxxxR, QxQ and RxQ) among Streptococci Cas9 orthologs. With the catalytically-dead QxxxR-containing SedCas9 from S. equinus, we dissect its NAG PAM specificity and elucidate its underlying recognition mechanism via computational prediction and mutagenesis analysis. Replacing the SedCas9 PI domain with alternate PAM-binding motifs rewires its PAM specificity to NGG or NAA. Moreover, a semi-rational design with minimal mutation creates a SedCas9-NQ variant showing robust activity towards expanded NNG and NAA PAMs, based upon which we engineered a compact ω-SedCas9-NQ transcriptional regulator for PAM-directed bifunctional and titratable gene control. The ω-SedCas9-NQ mediated metabolic reprogramming of endogenous genes in Escherichia coli affords a 2.6-fold increase of 4-hydroxycoumarin production. This work reveals new Cas9 scaffolds with distinct PAM-binding motifs for PAM relaxation and creates a new PAM-diverse Cas9 variant for versatile gene control in bacteria.

Chitosan Catalyzed Novel Piperidinium Dicoumarol: Green Synthesis, X-ray Diffraction, Hirshfeld Surface and DFT Studies.

The novel piperidinium dicoumarol has been synthesized by the reaction of 3-formylchromone, 4-hydroxycoumarin, and piperidine under chitosan catalyzed solvent-free green conditions. FT-IR and NMR spectroscopy established the structure of dicoumarol, which was further confirmed by a single X-ray diffraction study. The single diffraction study has revealed the hydrogen bonding interactions, which were further validated by Hirshfeld surface analysis. Geometry optimizations of dicoumarol have been performed at the DFT level of theory by the B3LYP acting along with Gaussian 16, revision B.01 to calculate the geometric and electronic structure parameters.

Magnetic Surface Molecularly Imprinted Polymer for Selective Adsorption of 4-Hydroxycoumarin.

4-hydroxyl coumarin (HC), an important intermediate during the synthesis procedure of rodenticide and anti-cardiovascular drug, shows highly medicinal value and economic value. To achieve the efficient adsorption of HC from natural biological samples, a novel magnetic surface molecularly imprinted polymer (HC/SMIPs) was constructed by employing methacrylic acid (MAA) as functional monomer, organic silane modified magnetic particles as matrix carrier and HC as template molecule. Due to the numerous specific imprinted cavities on the HC/SMIPs, the maximum adsorption capacity of HC/SMIPs for 4-hydroxycoumarin could reach to 22.78 mg g-1 within 20 min. In addition, HC/SMIPs exhibited highly selective adsorption for 4-hydroxycoumarin compared with other active drug molecules (osthole and rutin) and showed excellent regeneration performance. After 8 cycles of adsorption-desorption tests, the adsorption capacity of HC/SMIPs just slightly decreased by 6.64%. The efficient selective removal and easy recycle of 4-hydroxycoumarin from biological samples by HC/SMIPs made a highly promising to advance the application of imprinting polymers in complex practical environments.

Inclusion complexes of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin with 2-hydroxypropyl-(-cyclodextrin: solubility and antimicrobial activity

The aim of the present study is to improve the solubility and antimicrobial activity of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin by formulating its inclusion complexes with 2-hydroxypropyl-ß-cyclodextrin in solution and in solid state. The phase solubility study was used to investigate the interactions between 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin and 2-hydroxypropyl-ß-cyclodextrin and to estimate the molar ratio between them. The structural characterization of binary systems (prepared by physical mixing, kneading and solvent evaporation methods) was analysed using the FTIR-ATM spectroscopy. The antimicrobial activity of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin and inclusion complexes prepared by solvent evaporation method was tested by the diffusion and dilution methods on various strains of microorganisms. The results of phase solubility studies showed that 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin formed the inclusion complexes with 2-hydroxypropyl-ß-cyclodextrin of AP type. The solubility of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin was increased 64.05-fold with 50% w/w of 2-hydroxypropyl-ß-cyclodextrin at 37 oC. The inclusion complexes in solid state, prepared by the solvent evaporation method, showed higher solubility in purified water and in phosphate buffer solutions in comparison with 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin alone. The inclusion complexes prepared by solvent evaporation method showed higher activity on Bacillus subtilis and Staphylococcus aureus compared to uncomplexed 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin due to improved aqueous solubility, thus increasing the amount of available 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin that crosses the bacterial membrane.

Synthesis of Ferulenol by Engineered Escherichia coli: Structural Elucidation by Using the In Silico Tools.

4-Hydroxycoumarin (4HC) has been used as a lead compound for the chemical synthesis of various bioactive substances and drugs. Its prenylated derivatives exhibit potent antibacterial, antitubercular, anticoagulant, and anti-cancer activities. In doing this, E. coli BL21(DE3)pLysS strain was engineered as the in vivo prenylation system to produce the farnesyl derivatives of 4HC by coexpressing the genes encoding Aspergillus terreus aromatic prenyltransferase (AtaPT) and truncated 1-deoxy-D-xylose 5-phosphate synthase of Croton stellatopilosus (CstDXS), where 4HC was the fed precursor. Based on the high-resolution LC-ESI(±)-QTOF-MS/MS with the use of in silico tools (e.g., MetFrag, SIRIUS (version 4.8.2), CSI:FingerID, and CANOPUS), the first major prenylated product (named compound-1) was detected and ultimately elucidated as ferulenol, in which information concerning the correct molecular formula, chemical structure, substructures, and classifications were obtained. The prenylated product (named compound-2) was also detected as the minor product, where this structure proposed to be the isomeric structure of ferulenol formed via the tautomerization. Note that both products were secreted into the culture medium of the recombinant E. coli and could be produced without the external supply of prenyl precursors. The results suggested the potential use of this engineered pathway for synthesizing the farnesylated-4HC derivatives, especially ferulenol.

Development of antisense RNA-mediated quantifiable inhibition for metabolic regulation.

Trans-regulating elements such as noncoding RNAs are crucial in modifying cells, and has shown broad application in synthetic biology, metabolic engineering and RNA therapies. Although effective, titration of the regulatory levels of such elements is less explored. Encouraged by the need of fine-tuning cellular functions, we studied key parameters of the antisense RNA design including oligonucleotide length, targeting region and relative dosage to achieve differentiated inhibition. We determined a 30-nucleotide configuration that renders efficient and robust inhibition. We found that by targeting the core RBS region proportionally, quantifiable inhibition levels can be rationally obtained. A mathematic model was established accordingly with refined energy terms and successfully validated by depicting the inhibition levels for genomic targets. Additionally, we applied this fine-tuning approach for 4-hydroxycoumarin biosynthesis by simultaneous and quantifiable knockdown of multiple targets, resulting in a 3.58-fold increase in titer of the engineered strain comparing to that of the non-regulated. We believe the developed tool is broadly compatible and provides an extra layer of control in modifying living systems.

Reverse Docking for the Identification of Molecular Targets of Anticancer Compounds.

Molecular docking is a useful and powerful computational method for the identification of potential interactions between small molecules and pharmacological targets. In reverse docking, the ability of one or a few compounds to bind a large dataset of proteins is evaluated in silico. This strategy is useful for identifying molecular targets of orphan bioactive compounds, proposing new molecular mechanisms, finding alternative indications of drugs, or predicting drug toxicity. Herein, we describe a detailed reverse docking protocol for the identification of potential targets for 4-hydroxycoumarin (4-HC). Our results showed that RAC1 is a target of 4-HC, which partially explains the biological activities of 4-HC on cancer cells. The strategy reported here can be easily applied to other compounds and protein datasets.

Antiglioma Potential of Coumarins Combined with Sorafenib.

Coumarins, which occur naturally in the plant kingdom, are diverse class of secondary metabolites. With their antiproliferative, chemopreventive and antiangiogenetic properties, they can be used in the treatment of cancer. Their therapeutic potential depends on the type and location of the attachment of substituents to the ring. Therefore, the aim of our study was to investigate the effect of simple coumarins (osthole, umbelliferone, esculin, and 4-hydroxycoumarin) combined with sorafenib (specific inhibitor of Raf (Rapidly Accelerated Fibrosarcoma) kinase) in programmed death induction in human glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells lines. Osthole and umbelliferone were isolated from fruits: Mutellina purpurea L. and Heracleum leskowii L., respectively, while esculin and 4-hydroxycoumarin were purchased from Sigma Aldrich (St. Louis, MO, USA). Apoptosis, autophagy and necrosis were identified microscopically after straining with specific fluorochromes. The level of caspase 3, Beclin 1, PI3K (Phosphoinositide 3-kinase), and Raf kinases were estimated by immunoblotting. Transfection with specific siRNA (small interfering RNA) was used to block Bcl-2 (B-cell lymphoma 2), Raf, and PI3K expression. Cell migration was tested with the wound healing assay. The present study has shown that all the coumarins eliminated the MOGGCCM and T98G tumor cells mainly via apoptosis and, to a lesser extent, via autophagy. Osthole, which has an isoprenyl moiety, was shown to be the most effective compound. Sorafenib did not change the proapoptotic activity of this coumarin; however, it reduced the level of autophagy. At the molecular level, the induction of apoptosis was associated with a decrease in the expression of PI3K and Raf kinases, whereas an increase in the level of Beclin 1 was observed in the case of autophagy. Inhibition of the expression of this protein by specific siRNA eliminated autophagy. Moreover, the blocking of the expression of Bcl-2 and PI3K significantly increased the level of apoptosis. Osthole and sorafenib successfully inhibited the migration of the MOGGCCM and T98G cells.

Meroterpene-Like α-Glucosidase Inhibitors Based on Biomimetic Reactions Starting from ß-Caryophyllene.

BACKGROUND: Natural meroterpenes derived from phloroglucinols and ß-caryophyllene have shown high inhibitory activity against α-glucosidase or cancer cells, however, the chemical diversity of this type of skeletons in Nature is limited. METHODS: To expand the chemical space and explore their inhibitory activities against α-glucosidase (EC 3.2.1.20), we employed ß-caryophyllene and some natural moieties (4-hydroxycoumarins, lawsone or syncarpic acid) to synthesize new types of meroterpene-like skeletons. All the products (including side products) were isolated and characterized by NMR, HR-MS, and ECD. RESULTS: In total, 17 products (representing seven scaffolds) were generated through a one-pot procedure. Most products (12 compounds) showed more potential activity (IC50 < 25 µM) than the positive controls (acarbose and genistein, IC50 58.19, and 54.74 µM, respectively). Compound 7 exhibited the most potent inhibition of α-glucosidase (IC50 3.56 µM) in a mixed-type manner. The CD analysis indicated that compound 7 could bind to α-glucosidase and influence the enzyme's secondary structure. CONCLUSIONS: Compound 7 could serve as a new type of template compound to develop α-glucosidase inhibitors. Full investigation of a biomimic reaction can be used as a concise strategy to explore diverse natural-like skeletons and search for novel lead compounds.

Enzyme inhibition and antibacterial potential of 4-Hydroxycoumarin derivatives

The 4-Hydroxycoumarin derivatives are known to show a broad spectrum of pharmacological applications. In this paper we are reporting the synthesis of a new series of 4-Hydroxycoumarin derivatives synthesized through Knovenegal condensation; they were characterized by using UV-Vis, FT-IR, NMR spectroscopies. The synthesized compounds were evaluated for antibacterial activity against Staphylococcus aureus and Salmonella typhimurium strains. The compounds (2), (3) and (8) showed favorable antibacterial activity with zone of inhibitions 26.5± 0.84, 26.0 ± 0.56 and 26.0 ± 0.26 against Staphylococcus aureus (Gram-positive) respectively. However, the compounds (5) and (9) were found more active with 19.5 ± 0.59 and 19.5 ± 0.32 zone of inhibitions against Salmonella typhimurium (Gram-negative). Whereas, in urease inhibition assay, none of the synthesized derivatives showed significant anti-urease activity; although, in carbonic anhydrase-II inhibition assay, the compound (2) and (6) showed enzyme inhibition activity with IC50 values 263±0.3 and 456±0.1, respectively.

Promiscuous enzyme-catalyzed cascade reaction in water: Synthesis of dicoumarol derivatives.

Lipase RMIM was firstly used as a promiscuous biocatalyst to catalyze the Knoevenagel-Michael cascade reactions of 4-hydroxycoumarin with aromatic, heterocyclic or aliphatic aldehydes to synthesize dicoumarol derivatives in water. Results showed that the adopted methodology could offer many advantages, such as mild reaction conditions, pure aqueous reaction system, wide substrate applicability, recyclable catalyst, excellent yields (81-98%), operational simplicity, and environmentally friendly reactions.

The molecular diversity scope of 4-hydroxycoumarin in the synthesis of heterocyclic compounds via multicomponent reactions.

4-Hydroxycoumarins are some of the most versatile heterocyclic scaffolds and are frequently applied in the synthesis of various organic compounds. 4-Hydroxycoumarin-based compounds are important among heterocyclic structures due to their biological and pharmaceutical activities. In this study, we provide an overview on the recent applications of 4-hydroxycoumarin in multicomponent reactions for the synthesis of various heterocyclic compounds during the time period of 2015-2018.

Grinding Synthesis of Pyrazolyl-Bis Coumarinyl Methanes Using Potassium 2-Oxoimidazolidine-1,3-diide.

AIM AND OBJECTIVE: Potassium 2-oxoimidazolidine-1,3-diide (POImD) as a novel and reusable catalyst was used for the synthesis of pyrazolyl-bis coumarinyl methanes by a nucleophilic addition reaction of synthetized pyrazolecarbaldehyde and two equivalents of 4-hydroxycoumarin under grinding. The catalyst can be reused and recovered several times without loss of activity. This method provides several advantages such as eco-friendliness, simple work-up and shorter reaction time as well as excellent yields. All of the synthesized compounds were characterized by IR, 1H and 13C NMR spectroscopy and elemental analyses. MATERIAL AND METHOD: Synthetized pyrazole carbaldehyde 1a (1 mmol), 4-hydroxycoumarin 2 (2 mmol), 1 mmol of POImD and 10mL of H2O were ground in a mortar by a pestle for 30-90 minutes. After the completion of the reaction, as monitored by TLC on silica gel using ethyl acetate/n-hexane (1:2), the mixture was allowed to cool to room temperature. After completion of the reaction, we extracted the product with CH2Cl2/H2O. This was followed by separation of phases, evaporation of the organic phase and recrystallization of the residue with 50 mL of ethanol/H2O (1:1). The pure product was then obtained in 87 to 96% yield. The aqueous phase was concentrated under reduced pressure to recover the catalyst for subsequent use. RESULTS: To continue our ongoing studies to synthesize heterocyclic and pharmaceutical compounds by mild, facile and efficient protocols, herein we wish to report our experimental results on the synthesis of pyrazolylbis coumarinyl methanes, using various synthetized pyrazole carbaldehydes and 4-hydroxycoumarin in the presence of POImD in aqueous media at room temperature. CONCLUSION: Finally, we developed an efficient, fast and convenient procedure for the three-component synthesis of pyrazolyl-bis coumarinyl methanes through the reaction of pyrazole carbaldehydes and 4- hydroxycoumarin, using POImD as a novel and reusable catalyst. The remarkable advantage offered by this method is that the catalyst is non-toxic, inexpensive, easy to handle and reusable. A short reaction time, simple work-up procedure, high yields of product with better purity and the green aspect by avoiding a hazardous solvent and a toxic catalyst are the other advantages. To the best of our knowledge, this is the first report on the synthesis of pyrazolyl-bis coumarinylmethane derivatives using potassium 2-oxoimidazolidine-1,3-diide (POImD).