Chromone Derivatives Research Articles

Selective Insertion of Alkynes into C-C σ Bonds of Indolin-2-ones: Transition-Metal-Free Ring Expansion Reactions to Seven-Membered-Ring Benzolactams or Chromone Derivatives.

An unprecedented ring expansion reaction of indolin-2-ones with alkynyl ketones under transition-metal-free conditions has been developed. Base-promoted selective cleavage of a C-C σ bond of the amide is the key in this process, which provides a straightforward and efficient way to synthesize seven-membered-ring benzolactams or chromone derivatives. The significant advantages of this method include readily accessible starting materials, wide scope and functional group tolerance, and high atom economy.

Investigation of photophysical behaviours and antimicrobial activity of novel benzo-15-crown-5 substituted coumarin and chromone derivatives

Two different series of crown ether compounds (4-11) were synthesized by the reactions of 4′,5′-bis(bromomethyl)benzo-15-crown-5 (3) and 4′-amino-benzo-15-crown-5 with hydroxycoumarin and chromone derivatives. Coumarin-crown ether compounds (4 and 5) were synthesized by the reactions of 4′,5′-bis(bromomethyl)benzo-15-crown-5 (3) with 4-hydroxycoumarin and 7-hydroxycoumarin. Chromone-crown ether compounds (6-11), were synthesized by the condensation reactions of 4′-amino-benzo-15-crown-5 with 3-formylchromone and 6-methyl-3-formylchromone in different solvent media. Sodium and potassium complexes (4a-11a, 4b-11b) of new coumarin and chromone substituted benzo-15-crown-5 (B15C5) ligands (4-11) were prepared with NaSCN and KSCN, respectively. The syntheses of the novel crown ether compounds (4-11) and complexes (4a-11a, 4b-11b) were elucidated by the elemental analysis, FTIR, 1H NMR, 13C NMR and MS spectral data. The metal selectivities and effects of metal cations (Li+, Na+, K+, Mg2+, Ca2+, Ba2+, Ag+, Al3+, Cu2+, Zn2+, Ni2+, Pb2+, Fe3+, Cr3+) to the new crown ether compounds (4-11) were investigated by the absorption and fluorescence spectra. In addition, all of these substances were examined for antibacterial activity against pathogenic strains Listeria monocytogenes 4b, Staphylococcus aureus, Escherichia coli, Salmonella typhi H, Bacillus cereus, Micrococcus luteus, Shigella dysenteria type 2, Staphylococcus epidermidis, Proteus vulgaris, Klebsiella pneumonia sp., Serratia marcescens sp. and antifungal activity against Candida albicans.

Synthesis of furo[3,2‐g]chromones under microwave irradiation and their antitumor activity evaluation

AbstractA series of furo[3,2‐g]chromone derivatives were synthesized via the reaction of furochromone carbaldehyde 1 with amines 3a‐d and thioglycolic acid to give thiazolidinones 4a‐d. The later react with benzaldehyde/thiourea or hydroxylamine and DMF‐DMA in glacial acetic acid to give thiazolopyrimidines 5a‐d or thiazoloisoxazoles 6a‐d, respectively. Also, the synthesis of α‐aminophosphonates via the one‐pot reaction of 1 and amines 3a,b were trapped by dialkylphosphites 7a‐c afforded the corresponding α‐aminophosphonates 8a‐f. Applying hexaalkyltriamidophosphites 9a,b to 1 gives alkylidenephosphorane ylides 11a,b in an open structure form. In the present investigation, the in vitro inhibition capacity of compounds (4a, 4c, 5b, 5c, 6b‐d, 8a‐f, and 11a) was screened in three human cancer cell lines HCT‐116, MCF‐7, and HepG2. The anticancer activity results revealed that 8b and 8e had more potent cytotoxic inhibition activity against HCT‐116 cell line; however, all the tested compounds had obviously less cytotoxic activity against MCF‐7 cell line, while 5b, 5c, and 6d were potent against HepG2 cell line compared with that of doxorubicin.

A scaffold replacement approach towards new sirtuin 2 inhibitors

Sirtuins (SIRT1–SIRT7) are an evolutionary conserved family of NAD+-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.

Chromone and isocoumarin derivatives from the endophytic fungus Xylomelasma sp. Samif07, and their antibacterial and antioxidant activities

Five chromone derivatives, including 2,6-dimethyl-5-methoxyl-7-hydroxylchromone (1), 6-hydroxymethyleugenin (2), 6-methoxymethyleugenin (3), chaetoquadrin D (4), and isoeugenitol (5), and three isocoumarin congeners, namely diaporthin (6), 8-hydroxy-6-methoxy-3-methylisocoumarin (7), and 6-methoxymellein (8), were isolated from the culture of the endophytic fungus Xylomelasma sp. Samif07 derived from the medicinal plant Salvia miltiorrhiza Bunge. Among them, compound 1 was a new natural product. Their structures were determined by spectroscopic methods and comparison with the literature. The isolated compounds were evaluated for their antibacterial and antioxidant activities. Compound 5 showed notable antitubercular activity against Mycobacterium tuberculosis with MIC value of 10.31 µg/mL, while compounds 1–3, and 5–7 displayed inhibitory activities against the other bacteria with MIC range of 25 ∼ 100 µg/mL. Meanwhile, compound 6 showed potent hydroxyl radical-scavenging activity with EC50 value of 15.1 µg/mL, while compounds 5–7 showed certain ferric reducing ability.

Two New Chromone Derivatives from Cassia leschenaultiana and Their Anti-Tobacco Mosaic Virus Activity

Two new compounds (1 and 2), together with three known chromone derivatives (3–5), were isolated from Cassia leschenaultiana. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1 and 2 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activity. The results showed that compounds 1 and 2 showed potential anti-TMV activities with inhibition rates of 35.6% and 38.7% at the concentration of 20 μM, respectively. These rates are higher than that of the positive control.

Anti-cholinesterase activities of constituents isolated from Lycopodiastrum casuarinoides

Phytochemical investigation of the ethyl acetate extract of Lycopodiastrum casuarinoides (Spring) Holub (Lycopodiaceae) led to the isolation of nine compounds, including two new serratene triterpenoids, serrat-14-en-3α,21α-diol (1), 26-nor-8-oxo-21-one-α-onocerin (6), one new abietane diterpenoid, lycocasuarinone A (7), one new sesquiterpene acid, 7, 9-diene-1,4-epoxy-2-hydroxy-10-carboxylic acid (8) and one new chromone derivative, 5,7-dihydroxy-2-methyl esterchromone (9), together with four known serratene triterpenoids (2–5). Abietane diterpenoid (7) and sesquiterpene acid (8) from Lycopodiastrum casuarinoides are reported for the first time. Their structures and stereochemistry were unambiguously elucidated by spectroscopic analysis and comparison with known ones. All the compounds were tested for acetylcholinesterase (AChE) and butyrocholinesterase (BuChE) inhibitory activities. Bioactivity assays revealed that compound 6 exhibited the most potent AChE inhibitory effect.

Optimization of the chromone scaffold through QSAR and docking studies: Identification of potent inhibitors of ABCG2

The membrane transporter BCRP/ABCG2 has emerged as a privileged biological target for the development of small compounds capable of abolishing multidrug resistance. In this context, the chromone skeleton was found as an excellent scaffold for the design of ABCG2 inhibitors. With the aims of optimizing and developing more potent modulators of the transporter, we herewith propose a multidisciplinary medicinal chemistry approach performed on this promising scaffold. A quantitative structure-activity relationship (QSAR) study on a series of chromone derivatives was first carried out, giving a robust model that was next applied to the design of 13 novel compounds derived from this nucleus. Two of the most active according to the model’s prediction, namely compounds 22 (5-((3,5-dibromobenzyl)oxy)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide) and 31 (5-((2,4-dibromobenzyl)oxy)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide), were synthesized and had their biological potency evaluated by experimental assays, confirming their high inhibitory activity against ABCG2 (experimental EC50 below 0.10 μM). A supplementary docking study was then conducted on the newly designed derivatives, proposing possible binding modes of these novel molecules in the putative ligand-binding site of the transporter and explaining why the two aforementioned compounds exerted the best activity according to biological data. Results from this study are recommended as references for further research in hopes of discovering new potent inhibitors of ABCG2.

Benzophenone and chromone derivatives and their dimers from the scale-insect pathogenic fungus Orbiocrella petchii BCC 51377

A benzophenone derivative, orbiophenone A, and its homodimer, orbiocrellone A, a chromone derivative, orbiochromone A, four benzophenone–chromone heterodimers, orbiocrellones B–E, and a benzophenone–tetrahydroxanthone dimer, ent-secalonic acid I, were isolated from cultures of the scale-insect pathogenic fungus Orbiocrella petchii BCC 51377. Their structures were elucidated by spectroscopic analyses and chemical correlations. Orbiochromone A was isolated for the first time as an optically active natural product, and its absolute configuration was determined by the ECD spectrum combined with TD-DFT calculations. Four of the dimeric compounds, orbiocrellones B–D and ent-secalonic acid I, exhibited antimalarial activity against Plasmodium falciparum K1 with IC50 values of 5.7, 5.6, 14, and 5.5 μM, respectively.

Agarotetrol in agarwood: its use in evaluation of agarwood quality.

Agarwood, which is used as medicine and incense, contains sesquiterpenes and chromones. Agarotetrol is a chromone derivative found in high concentrations in the water-extract fraction of agarwood and thus may be present in pharmaceutical products made from decoctions of agarwood. Agarotetrol has been reported to be present at the early stages of cell death in calli. We therefore examined the presence of agarotetrol in medical- and incense-grade agarwood, in agarwood-source plants lacking resin deposits, and in artificially made agarwood. Agarotetrol appeared as a large peak in the HPLC chromatograms of all samples of medical-grade and artificially made agarwood, and in most incense-grade agarwood samples. In contrast, agarwood samples lacking resin deposits did not contain agarotetrol. These results show that agarotetrol is characteristic of resin formation. Agarotetrol was also detected in decoctions of agarwood. A newly developed TLC method for the detection of agarotetrol in agarwood is described.

A novel chromone derivative as dual probe for selective sensing of Al(III) by fluorescent and Cu(II) by colorimetric methods in aqueous solution

Based on the chromone skeleton, a simple and novel probe that is 6-ethoxychromone-3-carbaldehyde-(furanyl) hydrazone (L) has been synthesized and completely characterized. It exhibited representative turn-on fluorescent properties and obviously colorimetric changes with high selectivity to Al3+ and Cu2+. For Al3+, L displayed a turn on green fluorescence in EtOH/H2O (3/2) aqueous media over other common cations. With Cu2+, L perceived Cu2+ through the naked-eye by the color changed-from colorless to yellow. Moreover, the coordination ratio between L-Al3+and L-Cu2+ was 1:1 which could be verified by the Job’s plot, 1H NMR and high-resolution mass spectrum. Consequentially, L could be used as a solid probe for both Al3+ and Cu2+.

Chromone derivatives, R- and S- taeniolin, from the marine-derived fungus Taeniolella sp. BCC31839

Two unknown enantiomeric compounds, named (R)- and (S)-taeniolin, along with six known compounds, were isolated from the marine-associated fungus Taeniolella sp. BCC31839. Chemical structures were determined by NMR spectroscopic techniques, and the absolute configurations were confirmed by Mosher application together with CD spectral analyses. Both were inactive for antimicrobial activity against multidrug-resistant malaria parasite (Plasmodium falciparum) and bacteria (Mycobacerium tuberculosis and Bacillus cereus) at maximum tested concentration.

Deciphering the interactions of substituted chromones possessing acetylcholinesterase inhibition activity in human serum albumin matrix

A combination of different biophysical techniques is applied in conjunction with molecular docking calculation to explore the binding interaction of two substituted chromone derivatives namely 7-amino-2-methylchromone (AMC) and 3-cyanochromone (CyC), both of which are screened as potential acetylcholinesterase inhibitors, with human serum albumin (HSA). Analysis of intrinsic tryptophan fluorescence quenching reveals the Stern-Volmer constant (KSV) for CyC (~1.2 × 105 M−1) to be one order in magnitude higher than AMC (~3.9 × 104 M−1). Analysis of fluorescence lifetime data indicates static quenching mechanism for AMC; while a significant contribution from the dynamic (collisional) quenching also exits for CyC. The difference in binding thermodynamics of the chromones into the protein binding domain is mainly due to the difference in the primary forces responsible for the binding. The fluorescence titration results are in nice agreement with the complementary circular dichroism (CD) experiments as well as with the results from molecular docking calculation. The results indicate that while CyC binds to Domain IIA (Sudlow's site 1) of HSA with a greater binding affinity of −28.84 kJ/mol, AMC binds at an alternate position, site IB with a lower binding affinity (−27.19 kJ/mol).

Three new 2-(2-phenylethyl)chromone derivatives from agarwood of Aquilaria crassna Pierre ex Lecomte (Thymelaeaceae) in Laos

In our ongoing effort to study the metabolites from agarwood of Aquilaria crassna Pierre ex Lecomte (Thymelaeaceae) produced in Laos, three new 2-(2-phenylethyl)chromone derivatives (1−3) were isolated. Their structures were elucidated by comprehensive spectroscopic analyses, predominantly by 1D and 2D NMR spectroscopic methods, and by comparison with the reported data. Compound 2 exhibited tyrosinase inhibitory activity with IC50 value of 172.6 ± 1.7 μM (kojic acid as the positive control, 46.1 ± 1.3 μM) and its inhibition mode was clarified by molecular modelling study. None of the isolates showed significant cytotoxicity towards tested cancer cell lines.

Chromones and tannins from the fruit of Euscaphis japonica var. wupingensis

Euscaphis japonica var. wupingensis is a variety of E. japonica in the family Staphyleaceae. The biological characteristics of E. japonica var. wupingensis have been well described, but few studies have been conducted on its constituents. After repeated separation using column chromatography and preparative high performance liquid chromatography (HPLC), ten compounds were isolated from the methanol extract of fruit of E. japonica var. wupingensis. The structure of the components was characterized on the basis of spectroscopic data, including nuclear magnetic resonance (NMR), and mass spectra (MS). These compounds included five chromone derivatives: isobiflorin (1), biflorin (2), 2-methyl-5,7-dihydroxy-chromone-7-O-ß-D-glucopyranoside (5), 5,7-dihydroxy-2-methyl-4H-chromen-4-one (6), and quercetin-3-O-D-arabinoside (7), and four tannins: eugeniin (3), ellagic acid (8), 3, 3′-di-O-methylellagic acid 4-(5”-acetyl) -α-L-arabinofuranoside (9), 3,3′-di-O-methylellagic acid (10), and methyl 3,4,5-trihydroxybenzoate (4). The antioxidant activity of the isolated compounds were tested. Ellagic acid (8) exhibited potent 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity with an SC50 value of 4.05 M.

RETRACTED: Two novel chromone derivatives: Crystal structures and anti-lymphoma activity

This article has been retracted, and the online PDF has been watermarked “RETRACTION”. The retraction notice is available at http://doi.org/10.3233/MGC-220954.

New Metabolites From the Co-culture of Marine-Derived Actinomycete Streptomyces rochei MB037 and Fungus Rhinocladiella similis 35

Co-culture of different microbes simulating the natural state of microbial community may produce potentially new compounds because of nutrition or space competition. To mine its metabolic potential in depth, co-culture of Streptomyces rochei MB037 with a gorgonian-derived fungus Rhinocladiella similis 35 was carried out to stimulate the production of new metabolites in this study, using pure cultivation as control. Five metabolites were isolated successfully from co-culture broth, including two new fatty acids with rare nitrile group, borrelidins J and K (1 and 2), one chromone derivative as a new natural product, 7-methoxy-2,3-dimethylchromone-4-one (3), together with two known 18-membered macrolides, borrelidin (4) and borrelidin F (5). The structures of 1–3 were elucidated by using a combination of NMR and MS spectroscopy, ester hydrolysis, and optical rotation methods. Interestingly, 1 and 2 were obtained only in co-culture. Though 3 was gained from either co-culture or single culture, its production was increased significantly by co-culture. Compound 1 exhibited significant antibacterial activity against methicillin-resistant Staphylococcus aureus with a MIC value of 0.195 μg/mL.

Four new guaiane sesquiterpenoids from agarwood of Aquilaria filaria

Six 8,12-epoxyguaiane sesquiterpenes (1–6), together with two known 2-(2-phenylethyl)chromone derivatives (7–8) were isolated from agarwood originating from Aquilaria filaria. Their structures were established by spectroscopic methods including IR, HRESIMS, 1D, and 2D NMR, and comparison with the published data. The absolute configuration of compound 1 was unambiguously determined by quantum chemical calculation of the electronic circular dichroism (ECD) spectrum. All compounds were tested for their α-glucosidase inhibitory activity and cytotoxicity. Compound 5 showed significant α-glucosidase inhibitory activity with IC50 value of 253.2 ± 9.7 μM (Acarbose, 743. 4 ± 3.3 μM). Compounds 2–4 displayed weak cytotoxicity against K562 tumor cell lines.

Synthesis and biological evaluation of novel chromonyl enaminones as α-glucosidase inhibitors

Series of novel chromonyl enaminones 1a–e and 2a–e and 3-alkylated chromones 3a–e were synthesized and evaluated in vitro as α-glucosidase inhibitors as well as antioxidant and antifungal agents. Antifungal activity was tested on strains of Candida albicans. Compounds 2a and 2d–e showed good inhibition of the α-glucosidase enzyme (IC50 = 5.5, 0.9, and 1.5 mM, respectively), their effect being better than that of 1a–e, 3a–e, and acarbose (the standard, IC50 = 7.73 ± 0.9 mM). The structure–activity relationship suggests that the phenyl group at the C-3 position of the chromone ring system and the 4-chlorophenyl group at the enaminone moiety (derivatives 2) increased the inhibition of α-glucosidase. Compounds 2a–e exhibited a slight antioxidant effect, and compounds 3a–e a moderate antifungal activity against C. albicans (IC50 70.5–83.1 µg/mL). Docking studies revealed that compounds 2 interact with the α-glucosidase residues of the binding pocket. Therefore, these chromone derivatives may be considered as potential α-glucosidase inhibitors, as well as antifungal agents against some Candida strains of yeast.

A Schiff-base receptor based chromone derivate: Highly selective fluorescent and colorimetric probe for Al(III).

Upon excitation of the visible light, probes show colorimetric and fluorescent responses to the specific metal ion, which can be easily detected by the naked eye. Owing to the excitation of the visible light at 423 nm, a novel and simple Schiff-base receptor based chromone derivative called 7-methoxychromone-3-carbaldehyde-(indole-3-formyl) hydrazone (MCIH2) had been investigated as a selective and sensitive probe for Al3+ with colorimetric and fluorescent responses. Upon addition of Al3+ to compound MCIH2 solution, compound MCIH2 could respond to Al3+ with a good selective colorimetric signal, which was easily observed from colorless to yellow-green by the naked eye. Furthermore, a remarkable fluorescence emission enhancement with an "OFF-ON" signal by over 700-fold was triggered, but other various metal ions had no such significant effects on the fluorescence emission. In addition, the detection limit of compound MCIH2 for recognizing Al3+ was evaluated to be as low as 1 × 10-7 M level, which was sufficiently low for sensing Al3+ widely distributed in various environmental and biological systems.