Synthesis of 6-alkoxy and 6-hydroxy-alkyl amine derivatives of braylin as vasorelaxing agents.

Braylin (10b) is a 8,8-dimethyl chromenocoumarin present in the plants of the family Rutaceae and Meliaceae and possesses vasorelaxing and anti-inflammatory activities. In this study, six 6-alkoxy (10b, 15-19), and twelve 6-hydroxy-alkyl amine (20a-20l) derivatives of braylin (11 and 12) were synthesized to delineate its structural requirement for vasorelaxing activity. The synthesized compounds were evaluated for vasorelaxation response in preconstricted intact rat Main Mesenteric Artery (MMA). The compounds showed l-type VDCC channel blockade depended and endothelium-independent vasorelaxation within the range of Emax < 50.00-96.70 % at 30 µM. Amongst all, 6-alkoxy derivatives were more active than 6-hydroxy-alkyl amine derivatives. The structural refinements about braylin showed that deletion of its methoxy group or homologation beyond ethoxy group presented deleterious effect on vasorelaxation response of braylin. Interestingly, substituting the ethoxy group in 10b presented the best activity and selectivity towards l-type VDCC channel blockade, a specific target cardiovascular function.

Synthesis, computational study and cytotoxicity of 4-hydroxycoumarin-derived imines/enamines.

In this study, we applied a direct condensation between 3-acetyl-4-hydroxy-2H-chromen-2-one and different amines (anilines and benzyl amines) in order to synthesize some coumarin-based imines/enamines (3a-o) as cytotoxic agents. All the compounds were characterized by means of FT-IR, NMR, mass spectroscopy and elemental analyses. Since the title compounds can exist as different forms including (s-cis)-imine and (s-trans)-imine or (E and Z)-enamines, their conformational and geometrical aspects were investigated computationally by DFT method. The optimized geometry parameters, ΔE, ΔG, ΔH, Mulliken atomic charge, HOMO and LUMO energy, and NBO analysis suggested that these compounds can exist predominantly in (E)-enamine form. All the synthesized compounds (3a-o) were evaluated in vitro for their cytotoxic activities against cancer cell lines (MCF-7 and A549) and normal cell line (BEAS-2B) using the MTT assay. The 4-hydroxybenzyl derivative 3k was found to be the most potent cytotoxic agent with no selectivity, similar to doxorubicin. However, the 4-chlorobenzyl analog 3o could be considered as an equipotent compound respect to doxorubicin with higher selectivity.

Asymmetric organocatalyzed synthesis of coumarin derivatives.

Coumarin derivatives are essential scaffolds in medicinal and synthetic chemistry. Compounds of this class have shown important activities, such as anticancer and antiparasitic, besides the commercially available drugs. These properties led to the development of efficient and greener synthetic methods to achieve the 2H-chromen-2-one core. In this context, the advances in asymmetric organocatalyzed synthesis of coumarin derivatives are discussed in this review, according to the mode of activation of the catalyst.

Synthesis and evaluation of substituted 8,8-dimethyl-8H-pyrano[2,3-f]chromen-2-one derivatives as vasorelaxing agents.

A series of substituted 8,8-dimethyl-8H-pyrano[2,3-f]chromen-2-ones (chromeno-coumarin hybrids) was synthesized from scopoletin (11) as vasorelaxing agents. The synthesized compounds 21a-f, 22, 23a-e and scopoletin (11) were evaluated for vasorelaxation in endothelium intact rat main mesenteric artery (MMA). Compounds 11, 21a, 21c-f and 22 showed significant vasorelaxation in precontracted MMA within the range of EC50 value 1.58-5.02 µM. These derivatives presented 29.40-70.89 fold increased sensitivity for experimental tissue compared to scopoletin (11), the parent molecule. Among others, 22 was found to be the most active compound which had EC50 1.58 µM with 70.89 fold increased sensitivity. The mechanistic evaluation of 22 showed that it exerted vasorelaxation through Ca2+-activated K+ (BKca) channel and the effect was endothelium-independent.

Sulfonylhydrazones: Design, synthesis and investigation of ectonucleotidase (ALP & e5'NT) inhibition activities.

Medicinal importance of the sulfonylhydrazones is well-evident owing to their binding ability with zinc containing metalloenzymes. In the present study, we have synthesized different series of sulfonylhydrazones by using facile synthetic methods in good to excellent yield. All the successfully prepared sulfonylhydrazones were screened for ectonucleotidase (ALP & e5'NT) inhibitory activity. Among the chromen-2-one scaffold based sulfonylhydrazones, the compounds 7 was found to be most potent inhibitor for h-TNAP (human tissue non-specific alkaline phosphatase) and h-IAP (human intestinal alkaline phosphatase) with IC50 values of 1.02 ± 0.13 and 0.32 ± 0.0 3 µM respectively, compared with levamisole (IC50 = 25.2 ± 1.90 µM for h-TNAP) and l-phenylalanine (IC50 = 100 ± 3.00 µM for h-IAP) as standards. Further, the chromen-2-one based molecule 5a showed excellent activity against h-ecto 5'-NT (human ecto-5'-nucleotidase) with IC50 value of 0.29 ± 0.004 µM compared to standard, sulfamic acid (IC50 = 42.1 ± 7.8 µM). However, among the series of phenyl ring based sulfonylhydrazones, compound 9d was found to be most potent against h-TNAP and h-IAP with IC50 values of 0.85 ± 0.08 and 0.52 ± 0.03 µM, respectively. Moreover, in silico studies were also carried to demonstrate their putative binding with the target enzymes. The potent compounds 5a, 7, and 9d against different ectonucleotidases (h-ecto 5'-NT, h-TNAP, h-IAP) could potentially serve as lead for the development of new therapeutic agents.

Synthesis, biological evaluation and molecular docking of 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs containing the piperazine moiety.

Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 21, 23, and 24) exhibited potent antagonistic potency against AR (inhibition >50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) versus PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 23 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals' force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.

Click chemistry based regioselective one-pot synthesis of coumarin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones as newer potent antitubercular agents.

Coumarin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones (8k-z) were synthesized via copper(I)-catalyzed azide-alkyne cycloaddition click chemistry. The synthesized hybrid molecules were characterized by spectral studies. Compounds 8k-z were screened for their in vitro anti-TB activity by using the Microplate Alamar Blue assay and for cytotoxicity using the MTT assay. Some of the compounds were found to be most potent against the tested Mycobacterium tuberculosis H37Rv strain with a MIC of 1.60 µg/ml. Further, docking the compounds into the InhA binding pocket showed strong binding interactions and effective overall docking scores were recorded. The drug-likeness and toxicity studies were computed using Molinspiration and Protox, respectively.

Design, synthesis, biological evaluation and molecular docking studies of novel 3-aryl-4-anilino-2H-chromen-2-one derivatives targeting ERα as anti-breast cancer agents.

The estrogen receptor (ER) has played an important role in breast cancer development and progression and is a central target for anticancer drug discovery. In order to develop novel selective ERα modulators (SERMs), we designed and synthesized 18 novel 3-aryl-4-anilino-2H-chromen-2-one derivatives based on previously reported lead compounds. The biological results indicated that most of the compounds presented potent ERα binding affinity and possessed better anti-proliferative activities against MCF-7 and Ishikawa cell lines than the positive control tamoxifen. The piperidyl substituted compounds such as 16d and 18d demonstrated strong ERα binding affinities and excellent anti-proliferative activities respectively. Compound 18d displayed the most potent ERα binding affinity with RBA value of 2.83%, while 16d exhibited the best anti-proliferative activity against MCF-7 cells with IC50 value of 4.52±2.47µM. Further molecular docking studies were also carried out to investigate binding pattern of the newly synthesized compounds with ERα. All these results together with the structure-activity relationships (SARs) indicated that these 3-aryl-4-anilino-2H-chromen-2-one derivatives with basic side chain could serve as promising leads for further optimization as novel SERMs.

One pot Click chemistry: A three component reaction for the synthesis of 2-mercaptobenzimidazole linked coumarinyl triazoles as anti-tubercular agents.

2-Propargylthiobenzimidazole 1, 4-bromomethyl coumarins/1-aza-coumarins 2/3 and sodium azide have been reacted in one pot under Click chemistry conditions to give exclusively 1,4-disubstituted triazoles 5a-n. Anti-tubercular assays against M. tuberculosis (H37Rv) coupled with in silico molecular docking studies indicated that dimethyl substituents 5c and 5d showed promising activity with higher C-score values.

Isotopic splitting patterns in the (13) C NMR spectra of some partially deuterated 1-aryl-2-(phenyldiazenyl)butane-1,3-dione and 4-hydroxy-3-(phenyldiazenyl)-2H-chromen-2-one: evidence for elucidation of tautomeric forms.

Nuclear magnetic resonance spectra of synthesized azo dyes derived from aniline derivatives in reaction with benzoylacetone and 4-hydroxycoumarin were studied in both CDCl3 and (CD3 )2 SO (two drops of D2 O were added into solutions of dyes). All dyes showed intramolecular hydrogen bonding. Dyes derived from o-nitro aniline in the reaction with benzoylacetone, and 4-hydroxycoumarin showed bifurcated intramolecular hydrogen bonds. The solvent-substrate proton exchange of dyes derived from benzoylacetone and 4-hydroxycoumarin was examined in the presence of two drops of D2 O. Among ten dye samples, two dyes derived from benzoylacetone did not show deuteration, three dyes showed partial deuteration and five dyes showed full deuteration under similar conditions. For the partially deuterated dyes the ß-isotope effect in (13) C splitting was investigated and was used for the determination of the predominant tautomeric form.

Asymmetric Aldol Reaction of 3-Acetyl-2H-chromen-2-ones and Isatins Catalyzed by a Bifunctional Quinidine Urea Catalyst.

The asymmetric aldol reaction of 3-acetyl-2H-chromen-2-ones and isatins has been realized by using a bifunctional quinidine-derived urea as the catalyst. The corresponding 3-hydroxyoxindole derivatives containing a 2H-chromen-2-one moiety were obtained in good yields and high enantioselectivities. When (Z)-ethyl 2-benzylideneacetoacetate was used as the substrate, a mixture of two diastereomers (both Z and E) was obtained due to the isomerization of the double bond under the reaction conditions.

Design and synthesis of novel 2H-chromen-2-one derivatives bearing 1,2,3-triazole moiety as lead antimicrobials.

A series of novel 2H-chromen-2-one derivatives decorated with 1,2,3-triazole moiety were designed and synthesized using the click reaction of azidoalkyloxy-2H-chromen-2-ones with different propargylamines. Propargylamines were obtained by alkylation of various heterocyclic amines with propargyl bromide. Newly synthesized compounds and intermediates were evaluated for their antifungal activity against four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus and Candida albicans). Antibacterial studies were also carried out against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis and Staphylococcus epidermis) and four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Klebsiella pneumoniae). In vitro, bioassay results showed that all the synthesized compounds exhibited excellent activity against fungal strains Aspergillus fumigatus, Aspergillus flavus and Candida albicans. Interestingly, all the compounds have shown even superior activity than the reference drug miconazole against Aspergillus fumigatus. Morpholine and N-acetyl piperazine containing compounds 10c and 10e have shown promising activity against various bacterial strains. Compound 10e was found to be most active against Pseudomonas aeruginosa. Based on, in silico pharmacokinetic studies, compounds 10a-e were identified as lead compounds for future investigation due to their lower toxicity, high drug score values and good oral bioavailability as per OECD guidelines.

Crystal structure of (Z)-3-{3-(4-chloro-phen-yl)-2-[(4-chloro-phen-yl)imino]-2,3-di-hydro-thia-zol-4-yl}-2H-chromen-2-one.

In the title compound, C24H14Cl2N2O2S, the 2H-chromene ring system is approximately planar, with a maximum deviation of 0.025 (2) Å. The thia-zole ring is almost planar, with an r.m.s. deviation of 0.0022 Å, and makes a dihedral angle of 58.52 (7)° with the chromene ring system. The chromene ring system is inclined at angles of 58.3 (1) and 55.39 (9)° with respect to the two chloro-phenyl rings. The two chloro-phenyl rings show significant deviation from coplanarity, with a dihedral angle between them of 47.69 (8)°. The crystal structure features C-H⋯Cl inter-actions extending in (100) and propagating along the a-axis direction and weak π-π inter-actions [centroid-centroid separation = 3.867 (2) Å].

Ethyl 2-[(2-oxo-2H-chromen-6-yl)-oxy]acetate.

Ethyl 2-[(2-oxo-2H-chromen-6-yl)-oxy]acetate, C13H12O5, a member of the pharmacologically important class of coumarins, crystallizes in the monoclinic C2/c space group in the form of sheets, within which mol-ecules are related by inversion centers and 21 axes. Multiple C-H⋯O weak hydrogen-bonding inter-actions reinforce this pattern. The planes of these sheets are oriented in the approximate direction of the ac face diagonal. Inter-sheet inter-actions are a combination of coumarin system π-π stacking and additional C-H⋯O weak hydrogen bonds between ethyl acet-oxy groups.

Heteroaromatization of Coumarin Part I: Design, Synthesis, Reactions, Antitumor Activities of Novel Pyridine and Naphthyridine Derivatives.

INTRODUCTION: A novel series of chromen-3-yl-pyridine moieties were synthesized. IR, NMR, and MS spectroscopy were used to confirm the structure of these novel compounds and study antitumor activity of these compounds. The structure-activity relationship investigation demonstrated that 2,4-diamino- 5-(3-methoxyphenyl)-7-(2-oxo-2H-chromen-3-yl)-1,8-naphthyridine-3-carbonitrile (16), naphthyridine- 3-carbonitrile derivatives 17, 18 and pyrido[2,3-d]pyrimidine derivative 12 were found to be more effective, while compounds 5a,b, 9c, 11, 13 and 14 showed moderate activity for antitumor activities. OBJECTIVES: The objective was to design a series of new chromen-3-yl-pyridine and pyrido[2,3-d]pyrimidine derivatives and study the antitumor of these compounds. MATERIALS AND METHODS: The condensation reaction of 3-acetyl-2H-chromen-2-one with 3-methoxy benzaldehyde and malononitrile or ethyl cyanoacetate in the presence of ammonium acetate and acetic acid under reflux to give the corresponding chromen-3-yl pyridine-3-carbonitrile derivatives. RESULTS: In this study, the antitumor activity of the synthesized compounds chromen-3-yl-pyridine derivatives has been determined for the broad spectrum of cytotoxic activity toward the investigated three cell lines and 5-Fluorouracil, as reference drugs. CONCLUSION: A series of new chromen-3-yl-pyridine and pyrido[2,3-d]pyrimidine derivatives were synthesized in this work. All compounds were evaluated for cytotoxic activity.

Effect of further substitutions at 5-, 6-, 7-, or 8-position of 3-[3-(4-methoxyphenyl)-1-hydroxyprop-2-yl]coumarin on phytotoxicity.

Derivatives of the coumarin ring in (R)-3-[3-(4-methoxyphenyl)-1-hydroxyprop-2-yl]coumarin 2, which is a lignan structure, were synthesized to clarify their structure-phytotoxicity relationships. The growth-inhibitory activity of the 8-OCH3 derivative 8 (IC50=228 µM) was more potent against the roots of lettuce seedlings than the compound without substituents 2. As for the roots of Italian ryegrass seedlings, the presence of the methoxy group at the 7- or 8-position was extremely effective for inhibiting growth (7-OCH3 7: IC50=121 µM, 8-OCH3 8: 56.7 µM). Methyl derivatives at the 5- or 8-position showed activity levels similar to those of the compound without substituents 2 (5-CH3 13: IC50=214 µM, 8-CH3 16: IC50=225 µM). The activities of OH- and F-derivatives were not observed or were lower.

Development of potent isoflavone-based formyl peptide receptor 1 (FPR1) antagonists and their effects in gastric cancer cell models.

Formyl peptide receptor-1 (FPR1) is a G protein-coupled chemoattractant receptor that plays a crucial role in the trafficking of leukocytes into the sites of bacterial infection and inflammation. Recently, FPR1 was shown to be expressed in different types of tumor cells and could play a significant role in tumor growth and invasiveness. Starting from the previously reported FPR1 antagonist 4, we have designed a new series of 4H-chromen-2-one derivatives that exhibited a substantial increase in FPR1 antagonist potency. Docking studies identified the key interactions for antagonist activity. The most potent compounds in this series (24a and 25b) were selected to study the effects of the pharmacological blockade of FPR1 in NCl-N87 and AGS gastric cancer cells. Both compounds potently inhibited cell growth through a combined effect on cell proliferation and apoptosis and reduced cell migration, while inducing an increase in angiogenesis, thus suggesting that FPR1 could play a dual role as oncogene and onco-suppressor.

Plant Growth Suppressive Activity of (R)-3-(7'-Aryl-9'-hydroxyprop-8'-yl)coumarin, Structural Isomer of Z-2-Hydroxybenzylidene-γ-butyrolactone-type Lignan.

3-(7'-Aryl-9'-hydroxyprop-8'-yl)coumarin, which is a structural isomer of a Z-2-hydroxybenzylidene-γ-butyrolactone-type lignan, was stereoselectively synthesized and subjected to plant growth regulation examination. (R)-4'-Methoxyphenyl derivative 3 showed stereospecific plant growth suppressive activity. The significance of the presence of hydroxy group at the 9'-position for the activity was clarified. The effect of the substituent at the 7'-aryl group was also shown. The 3'-methoxy, 4'-methoxy, and 4'-trifluoromethyl derivatives 10, 3, and 22 led to the most significant growth suppression of Italian ryegrass roots. The 2'-methoxy derivative 9 and 4'-methoxy derivative 3 provided the most growth suppressive activity against lettuce shoots and roots, respectively.

A Mini-Review: Recent Advances in Coumarin-Metal Complexes With Biological Properties.

The coumarin nucleus is a recurring motif in both natural and synthetic compounds that exhibit a broad spectrum of biological properties including anticoagulant, anti-inflammatory, antioxidant, antiviral, antimicrobial and anticancer agents as well as enzyme inhibitors. On the other hand, it has been reported that the incorporation of a metal ion into coumarin derivatives can increase the activity of such complexes compared to coumarin-based ligands. Accordingly, some of them have been found to display promising antioxidant, antitumor or antibacterial activities. This mini-review briefly summarizes the recent development of coumarin-metal complexes with proven biological properties. The attention is also paid to agents for which practical applications in the detection of biologically important species may be found.

Design, Synthesis, and Biological Evaluation of 4-amino Substituted 2Hchromen- 2-one Derivatives as an NEDD8 Activating Enzyme Inhibitor in Pancreatic Cancer Cells.

BACKGROUND: NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in carcinomas. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment. OBJECTIVE: In this article, we decided to study the synthesis and screening of 4-amino substituted 2H-chromen-2-one derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3. METHODS: After synthesis of twenty targeted compounds, we evaluated their anti-proliferative activity against six cancer cell lines, cytotoxicity against three normal cell lines through MTT assay, and hemolysis to screen out the candidate compound, which was further conducted drug-like physical property measurement, target confirmation by enzyme-based experiment, cell apoptosis, and synergistic effect research. RESULTS: Starting from intermediates 4 and 5, several new 4-amino substituted 2H-chromen-2-one derivatives (9-28) were synthesized and evaluated for their cell activities using six cancer cell lines. We performed tests of cytotoxicity, hemolysis, ATP-dependent NAE inhibition in the enzyme- based system, apoptosis, and synergistic effect in BxPC-3 cells against the best candidate compound 21. CONCLUSION: Based on these results, we found that compound 21 inhibited NAE activity in an ATP-dependent manner in the enzyme-based system, induced apoptosis in BxPC-3 cells, and synergized with bortezomib on BxPC-3 cell growth inhibition. Additionally, it had low toxicity with reasonable Log P-value and water solubility.