Chromone Derivatives Research Articles

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists.

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2AAR were experimentally determined and investigated through a cycle of ligand‐FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X‐ray crystallography of the A2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2AAR, an emerging target in immuno‐oncology.

New Seco-DSP derivatives as potent chemosensitizers

Thirty-four seco-3′R,4′R-disubstituted-2′,2′-dimethyldihydropyrano[2,3-f]chromone (seco-DSP) derivatives were designed, synthesized and evaluated for chemo-reversal activity when combined with paclitaxel or vincristine in P-gp overexpressing A2780/T and KB-VIN drug-resistant cancer cell lines. Most of the compounds displayed moderate to significant MDR reversal activities. Compound 7e showed the most potent chemo-sensitization activity with more than 1471 reversal ratio at a concentration of 10 μM, which was higher than verapamil (VRP) (212-fold). Unexpectedly the newly synthesized compounds did not show chemosensitization activities in a non-P-gp overexpressing cisplatin resistant human ovarian cancer cell line (A2780/CDDP), implying that the MDR reversal effects might be associated with P-gp overexpression. Moreover, the compounds did not exhibit significant anti-proliferative activities against non-tumorigenic cell lines (HUVEC, HOSEC and T29) compared to VRP at the tested concentration and might be safer than VRP. In preliminary pharmacological mechanism studies, the compounds increased accumulation of DOX and promoted P-gp ATPase activity in A2780/T cell lines. Western blot analysis indicated they did not affect the expression level of P-gp in the tested MDR cell lines. Thus, further studies on these seco-DSP derivatives are merited with the goal of developing a desirable chemosensitizer drug candidate.

Potential enzyme inhibitory properties of extracts and fractions from fruit latex of Ficus carica-based on inhibition of α-amylase and α-glucosidase

Ficus L. is one of the widespread genera of the Moraceae family. We aimed to evaluate the inhibiting effect on digestive enzymes linked to diabetes, the antioxidant activity and the phytochemical composition of active extract/fraction of fruit latex of Ficus carica L. subsp. carica (All.) Schinz Et Thel. The inhibition effect of extracts and fractions tested with α-amylase and α-glucosidase methods and the antioxidant effect investigated with ABTS·+ and FRAP tests. The qualitative determination of compounds within the active extract/fraction was carried out by LC–MS/MS. In a result, the highest α-amylase and α-glucosidase activity found in F2 fraction of fruit latex (IC50 = 195.205 ± 0.015 µg/mL and 6.920 ± 0.026 µg/mL, respectively). Moreover, the highest total phenolic (26.816 ± 0.007 mgGAE/gextract) and total flavonoid content (8.615 ± 0.009 mgCA /gextract) was found in S1extract and this extract showed the highest antioxidant activity on FRAP (at a concentration of 1 mg/mL equivalent to 179.802 ± 2.201 mmol Fe2+) and ABTS+· (at a concentration of 1 mg/mL equivalent to 0.296 ± 0.055 µM Trolox) tests. Besides that, a preliminary examination of the mass spectrums of active F2 fraction and S1 extract revealed the presence of one xanthone, one organic acid derivative, one chromone derivative, one fatty acid and one phenolic acid. It is the first report on α-amylase, α-glucosidase and antioxidant activities, and phytochemical analysis of fruit latex of F. carica subsp. carica and these studies could contribute to the advanced pharmacological activity studies of this species.

Current Strategies in Development of New Chromone Derivatives with Diversified Pharmacological Activities: A Review.

Chromone derivatives possess a spectrum of biological activities. Chromone has been recognized as a privileged structure for new drug invention and development. Substitution pattern of chromone scaffold determines different type of biological activities. The type, number and position of substituents connected to the chromone core play a vital role in determining pharmacological activities. In the present review, we have discussed new chromone derivatives as anticancer, anti-diabetic, antimicrobial, anti-inflammatory, antioxidant and as anti-Alzheimer agents. This review deals with the chromone derivatives prepared by combining chromone molecule with various natural and synthetic pharmacophores and pharmacological activities presented by them. The main aim is to highlight the diversified pharmacological activities exhibited by chromone hybrid molecules during the last eight to ten years.

Synthesis of Novel Functionalized Pyrano Annulated/Oxazolone Pendent Chromone Derivatives as Potent Anti-Diabetic Agents

A new series of chromone based annulated coumarin and pendent oxazolone derivatives have been synthesized from 7-hydroxy-8-formyl chromone via one pot Knoevenagel condensation-ring transformation cascade. All the compounds were characterized by FTIR,1H and 13C NMR, mass, and UV spectral analysis. The compounds have been screened for their in vitro α-glucosidase inhibition, and have demonstrated activity also supported by molecular docking. All the newly synthesized compounds exhibit excellent α-glucosidase inhibition activity compared to the reference compound Acarbose. The compound 7d has been characterized by more prominent inhibition activity with IC50 value 34.36 µM which is approximately 24 times more effective in comparison with the reference compound.

Health benefits of chromones: common ingredients of our daily diet

Chromones are naturally occurring phenolic compounds that are universally present in a healthy human diet. To date, thousands of chromone derivatives, including chromone glycosides have been discovered, both from natural and synthetic origin. Many plant genera, including Aloe, Aquilaria, Cassia, Hypericum and Polygonum, are rich sources of chromones. Several genera of fungi, such as Aspergillus, Mycoleptodiscus, Orbiocrella, and Penicillium produce bioactive chromones. This class of compounds is mainly associated with anti-oxidant, antimicrobial, anticancer and anti-inflammatory activities. Various in vitro, in vivo and clinical studies have established the role of chromones in alleviating allergies, reducing oxidative damage, inhibiting cancer, infections and inflammation, and for treating neurological and psychiatric disorders. This review focuses mainly on natural chromones, and elaborates on their nutritional benefits, pharmacological activities, and mechanisms of action. Various scientific databases, including PubMed, Scopus and Google Scholar, were used to find relevant literature on chromones covering all available literature up to, and including the year 2019. This critical analysis of completed research regarding the nutraceutical properties of various chromone derivatives may provide new insight to scientists working in related fields.

In silico fight against novel coronavirus by finding chromone derivatives as inhibitor of coronavirus main proteases enzyme.

Novel coronavirus, 2019-nCoV is a danger to the world and is spreading rapidly. Very little structural information about 2019-nCoV make this situation more difficult for drug designing. Benzylidenechromanones, naturally occurring oxygen heterocyclic compounds, having capability to inhibit various protein and receptors, have been designed here to block mutant variety of coronavirus main protease enzyme (SARC-CoV-2 Mpro) isolated from 2019-nCoV with the assistance of molecular docking, bioinformatics and molecular electrostatic potential. (Z)-3-(4′-chlorobenzylidene)-thiochroman-4-one showed highest binding affinity to the protein. Binding of a compound to this protein actually inhibits the replication and transcription of the virus and, ultimately, stop the virus multiplication. Incorporation of any functional groups to the basic benzylidenechromanones enhances their binding ability. Chloro and bromo substitutions amplify the binding affinity. ADME studies of all these compounds indicate they are lipophilic, high gastro intestine absorbable and blood-brain barrier permeable. The outcome reveals that the investigated benzylidenechromanones can be examined in the case of 2019-nCoV as potent inhibitory drug of SARC-CoV-2 Mpro, for their strong inhibition ability, high reactivity and effective pharmacological properties.Electronic supplementary materialThe online version of this article (10.1007/s11224-020-01537-5) contains supplementary material, which is available to authorized users.

Photoredox Functionalization of 3-Halogenchromones, 3-Formylchromones, and Chromone-3-carboxylic Acids: Routes to 3-Acylchromones.

This work describes a set of new and efficient synthetic routes toward 3-acyl-substituted chromones ranging from readily available chromone precursors, namely 3-halogenchromones, 3-formylchromones, and chromone-3-carboxylic acids by means of visible-light photoredox catalysis. The operationally simple protocols transform a wide variety of chromone derivatives into challenging 3-acyl-substituted chromones in excellent yield. This research also aimed at comparing the developed methodologies by using as the key evaluation criteria the efficiency of the reaction and general availability of the starting materials. The application of all developed methods for the gram-scale preparation of the title chromones was also demonstrated.

Ag doped ZnO nanorods catalyzed photo-triggered synthesis of some novel (1H-tetrazol-5-yl)-coumarin hybrids

Herein, we reported a facile synthetic strategy for the synthesis of 1,5-disubstituted tetrazole (1,5-DST) based chromone derivatives with different through photocatalyzed one-pot multicomponent reactions between aldehyde derivatives 7a-c, sodium azide, chromenocyl bromide in presence of triethylamine using ZnO nanorods (NRs) and Ag-doped ZnO nanocomposites (NCs) as photocatalysts. The reaction optimization was developed under ambient conditions at room temperature in dark and under visible light irradiation which revealed that Ag/ZnO NCs showed efficient catalytic activity towards the synthesis of new 1,5-DST through photocatalytic [3 + 2] cycloaddition reaction. The products 10a-f were afforded in excellent yields (90%–97%). The as-prepared tetrazole derivatives were subjected under cytotoxic evaluation towards MCF-7, HepG2, A549 and Wi38 cancer cell lines. It was revealed that compounds 10e and 10f showed potent anticancer activity.

One-Pot Synthesis of Novel Furochromone and Oxazocine Derivatives as Promising Antitumor Agents with Their Molecular Docking Studies

One-pot efficient synthesis of novel chromone derivatives 4a–h and that of 5a–h were described in a simple method via four-component reaction between furochromone carbaldehyde, amine, isocyanate derivatives, and benzoic acid derivatives or nicotinic acid, respectively. Also, oxazocine derivatives 7a, b were prepared via reaction of visnagine carbaldehyde, ethyl acetoacetate and isocyanate derivatives 2a, b. The obtained derivatives of novel furochromone and oxazocine derivatives were evaluated as promising antitumor agents against panel of two human cell lines, hepatocellular carcinoma (HEPG2) and breast carcinoma (MCF7). The antitumor results suggested that furochromone derivatives 5a–h have activity against MCF7 in comparison with doxorubicin as the standard drug. Furthermore, the molecular docking studies of these novel derivatives of furochromone and oxazocine showed good agreement with the biological results when their binding pattern and affinity towards the active site of EGFR was investigate.

Five new 2-(2-phenylethyl)chromone derivatives from agarwood.

Agarwood has been used as an incense and in traditional medicines as aphrodisiac, sedative, cardiotonic, and carminative. In this study, five new 2-(2-phenylethyl)chromones (2, 13-16) and eleven known compounds (1, 3-12) were isolated from the agarwood. The structures of the new compounds were determined by 1H-, 13C-, and two-dimensional NMR together with electronic circular dichroism (ECD) spectroscopy. All isolated compounds were evaluated for the phosphodiesterase (PDE) 3A and 5A1 inhibitory activity by the fluorescence polarization method. Dimeric 2-(2-phenylehyl)chromones (13, 14, 16) had potent inhibitory activity to PDE 5A1 with IC50 values of micro molar range (13: 4.2μM, 14: 7.9μM, 16: 4.3μM), whereas they had weak activity to PDE 3A. In contrast, compound (15), which has a phenylpropionic acid moiety instead of the 2-(2-phenylethyl)chromone moiety in the dimers, showed moderate inhibition of both PDE 3A (IC50: 42.6μM) and PDE 5A1 (IC50: 15.1μM).

Fusarium solani induces the formation of agarwood in Gyrinops versteegii (Gilg.) Domke branches

Agarwood is a resinous wood produced by some members of plant family Thymelaeaceae under certain conditions. Agarwood is highly prized, but its formation requires a long-time process in nature. Therefore, various induction techniques have been explored to hasten the process. In this study, we induced agarwood in Gyrinops versteegii, one of the most abundant agarwood-producing trees in Indonesia. We used 12 trees and wounded four branches on each tree through an injection process. We used two strains of the endophytic fungi Fusarium solani isolated from Gorontalo and Jambi Provinces. After 3 months, the inoculated wood had an extensive resinous zone, when compared to wounded control wood. Gas chromatographic-mass spectrometric analysis of the inoculated samples revealed the presence of several sesquiterpenes characteristic of agarwood. These included alloaromadendrene, β-eudesmol and β-selinene as well as the chromone derivatives 2-(2-phenylethyl) chromen-4-one, 6-methoxy-2-(2-phenylethyl) chromen-4-one, and 6,7-dimethoxy-2-(2-phenylethyl) chromen-4-one. We conclude that this method successfully induced agarwood to form in a matter of months and could be used to enhance the success of agarwood cultivation.

Synthesis and antiviral activity of some pyrrolonyl substituted heterocycles as additives to enhance inactivated Newcastle disease vaccine

This research reported the design and synthesis of some influential new pyrrolone derivatives bearing a pyrazole scaffold with the evaluation of their antiviral activity against Newcastle disease virus (NDV) in specific pathogen free (SPF) chicken embryos and immune boosting properties of these substances in SPF chicks. The building block synthon was the pyrazolyl acid hydrazide, derived from 2(3H)-furanone, which was reacted with some carbonyl compounds, e.g., salicylaldehyde, furfural, 1,3-diphenylpyrazole-4-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, chromone-3-carbaldehyde, and 3-acetylcoumarin. The results revealed that pyrazole derivative 6, quinoline derivatives 7 and 8 exhibited 100% protection against NDV while the hydroxyphenyl derivative 3 showed 95% protection. In turn, chromone derivative 10 and coumarin derivative 11 exhibited 90% protection. The structures of all products were established on the basis of their elemental analyses and spectroscopic techniques.

Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation.

Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain 1 (BD1)-selective inhibitors 44 (ZL0513) and 45 (ZL0516) have been discovered with high binding affinity (IC50 values of 67-84 nM) and good selectivity over other BRD family proteins and distant BD-containing proteins. Both compounds significantly inhibited the expression of Toll-like receptor-induced inflammatory genes in vitro and airway inflammation in murine models. The cocrystal structure of 45 in complex with human BRD4 BD1 at a high resolution of 2.0 Å has been solved, offering a solid structural basis for its binding validation and further structure-based optimization. These BRD4 BD1 inhibitors demonstrated impressive in vivo efficacy and overall promising pharmacokinetic properties, indicating their therapeutic potential for the treatment of inflammatory diseases.

Recent advances in green synthesis of chromones

This minireview focuses on the recent advances in green synthesis of chromone derivatives which have been published over the last 5–10 years.

A new and green approach for regiospecific synthesis of novel chromeno‐triazolopyrimidin using tungstic acid immobilized MCM‐41 as a reusable catalyst

AbstractA novel, eco‐friendly and fast route has been developed for the synthesis of new and known triazolo[1,5‐a]pyrimidin fused chromone derivatives via a one pot three‐component reaction of 3‐amino‐1,2,4‐triazoles, aromatic aldehydes and 4‐hydroxycoumarin in aqueous medium at room temperature. These reactions are catalyzed by MCM‐41‐HWO4 as a safe and recyclable mesoporous solid acid. It combines successfully the synergistic effect of green chemistry with nanocatalysis. The yields are high and the products were characterized by 1H NMR, 13CNMR spectra and elemental analysis.

Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors.

Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington's disease. Recently, a hit compound 1 with a novel chromone scaffold has shown moderate inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC50 = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t1/2 = 105 min) by using an integrated strategy (molecular modeling, chemical synthesis, bioassay, and cocrystal structure). The cocrystal structural information provides insights into the binding pattern of 3e in the PDE10A catalytic domain to highlight the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693, respectively, thereby resulting in high selectivity against other PDEs. These new observations are of benefit for the rational design of the next generation PDE10 inhibitors for CNS disorders.

Pembentukan Gaharu Gyrinops versteegii oleh Bioinduksi Fusarium solani dengan Teknik Simpori

Agarwood is a non-timber forest product having high economic value. However, its population in nature is getting decrease. An effort to reduce the agarwood hunting in the nature is agarwood cultivation. One of agarwood inoculation methods is simpori as a modification of inoculation method using Fusarium solani and porous nails. The present study aimed to determine the effect of F. solani dosage to the quantity and quality of Gyrinops versteegii agarwood using simpori. The simpori technique used completely randomized design with 3 treatments and 10 replications. The treatments were F. solani at a dosage of 3 mL/porous nail (P0), F. solani at a dosage of 9 mL/porous nail (P1), and F. solani at a dosage of 6 mL/porous nail (P2). The result showed that both dimensions of agarwood formation and the agarwood produced at 7 months after the first inoculation in all treatments were not significant. The highest length and the highest depth of agarwood formation were shown by P1 (5.1 cm) and P0 (7 cm) treatments, respectively. The highest agarwood production was observed in P1 and P2 treatments (0.032%). The visual quality of agarwood based on SNI 7631:2011 equal to kemedangan TG.C. The agarwood quality based on sesquiterpenes and chromone derivatives contents was different in all treatments. P2 treatment showed the highest content of sesquiterpenes and chromone derivatives (17.5%). The difference of F. solani dosages produce agarwood with the same quantity but different in quality when harvest 7 month after the first inoculation. Keywords: agarwood, phenylethyl chromone derivatives, sesquiterpenes, simpori

Design, synthesis and anti-TMV activities of novel chromone derivatives containing dithioacetal moiety

Thirty-five novel chromone derivatives containing dithioacetal moiety were designed, synthesized, and their anti-TMV activities were evaluated through half-leaf method. The results showed compound c23 illustrates highly curative, protective and inactivating activities against TMV at 500 mg/L, with the values of 68.8%, 58.8%, 86.0% respectively, which were superior to that of Ribavirin (42.3%, 49.8%, 68.4%, respectively) and similar to that of Ningnanmycin (59.4%, 52.4%, 88.4%, respectively). The EC50 value of inactivating activities of compound c23 is 9.3 mg/L, which was better than that of Ribavirin (135.2 mg/L), and equivalent to that of Ningnanmycin (8.8 mg/L). Furthermore, compound c23 can destroy the integrity of TMV-CP, resulting in reduced infectivity of TMV. Meanwhile, compound c23 can combine with TMV protein coat and hydrolyze TMV protein coat to impact the process of self-assembling of TMV, with the association constant (Kd) 4.5 mg/L. This finding suggests that chromone derivatives containing dithioacetal moiety can be used as new antiviral agent.

Two New Chromone Derivatives from Cassia nomame and their Anti-Tobacco Mosaic Virus Activity

Two new chromone derivatives, 5-(isobutyryl)-2-(2-oxopropyl)-7-methoxy-4H-chromen-4-one (1) and 5-(isobutyryl)-2-(2-oxopropyl)-6-methoxy-4H-chromen-4-one (2), were isolated from Cassia nomame. 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 28.7% and 31.2%, at the concentration of 20 μM, respectively. These rates are close to that of positive control.