Chromone Analogues Research Articles

Synthesis and pharmacological activity evaluation of 2-(2-Phenylethyl)chromone analogues: The principal components in agarwood.

2-(2-Phenylethyl)chromones (PECs), the pivotal constituents responsible for the distinctive aroma and pharmacological potential of agarwood, are primarily obtained through extraction from natural materials. The restricted availability of agarwood has, however, hindered a comprehensive and systematic evaluation of their biological properties. In this study, we have chemically synthesized a total of 38 PEC derivatives, including 23 new compounds that had not been previously isolated from agarwood. These compounds were then evaluated for their inhibitory effects on nitric oxide release, neutrophil superoxide production, as well as their activities against tyrosinase, acetylcholinesterase, and α-glucosidase. The preliminary screening resulted in the identification of promising leads with potential therapeutic activities, and the structure-activity relationship of the synthesized PECs have also been briefly discussed. The results provide a foundation for the synthesis and pharmacological exploration of PECs, which sheds light on the pharmacological potential of agarwood's secondary metabolites.

Antimicrobial and antibiofilm activities of formylchromones against Vibrio parahaemolyticus and Vibrio harveyi.

Gram-negative Vibrio species are major foodborne pathogens often associated with seafood intake that causes gastroenteritis. On food surfaces, biofilm formation by Vibrio species enhances the resistance of bacteria to disinfectants and antimicrobial agents. Hence, an efficient antibacterial and antibiofilm approach is urgently required. This study examined the antibacterial and antivirulence effects of chromones and their 26 derivatives against V. parahaemolyticus and V. harveyi. 6-Bromo-3-formylchromone (6B3FC) and 6-chloro-3-formylchromone (6C3FC) were active antibacterial and antibiofilm compounds. Both 6B3FC and 6C3FC exhibited minimum inhibitory concentrations (MICs) of 20 µg/mL for planktonic cell growth and dose-dependently inhibited biofilm formation. Additionally, they decreased swimming motility, protease activity, fimbrial agglutination, hydrophobicity, and indole production at 20 µg/mL which impaired the growth of the bacteria. Furthermore, the active compounds could completely inhibit the slimy substances and microbial cells on the surface of the squid and shrimp. The most active compound 6B3FC inhibited the gene expression associated in quorum sensing and biofilm formation (luxS, opaR), pathogenicity (tdh), and membrane integrity (vmrA) in V. parahaemolyticus. However, toxicity profiling using seed germination and Caenorhabditis elegans models suggests that 6C3FC may have moderate effect at 50 µg/mL while 6B3FC was toxic to the nematodes 20-100 µg/mL. These findings suggest chromone analogs, particularly two halogenated formylchromones (6B3FC and 6C3FC), were effective antimicrobial and antibiofilm agents against V. parahaemolyticus in the food and pharmaceutical sectors.

Chromone-3-acrylic acid ester analogues: Design, synthesis and biological evaluation as potential pancreatic lipase inhibitors

A novel series of 21 chromone-3-acrylic acid ester analogues (5aa-5cm) were designed, synthesized and evaluated for PL inhibitory activity. The molecular docking study indicate that all the designed chromone analogues have the good binding ability (MolDock score: -115.86 to -160.07 kcal/mol) in the active site of PL enzyme (PDB ID: 1LPB), showing interactions with essential amino acid residues (Phe77, Tyr114, Ser152, Phe215, Arg256). Also, all the analogues were checked for in silico drug likeness property and all were found to have drug like properties, obeying Lipinski rule of 5, with no PAINS alerts. Analogue 5am, with the best docking score, was stable in molecular dynamics simulation for 100 ns (maximum RMSD of 6.4 Å), showing crucial amino acid interactions for more than 60% of the simulation time. The structure of the synthesized analogues were then confirmed by NMR, HRMS and IR spectroscopy. Among the synthesized analogues, 5am and 5ad exhibited potent PL inhibition with IC50 of 5.16 ± 0.287 & 5.82 ± 0.933 µM, respectively, as compared with orlistat (IC50 = 0.86 ± 0.09 µM). The inhibition kinetics and in silico studies confirmed competitive type of inhibition of analogue 5am. The current work highlights the importance of chromone analogues as potential PL inhibitors. Further, the lead optimization may lead to much more potential PL inhibitors.

Retrospective Review of Chromane Analogues as Anti-protozoal Leads: A Decade's Worth of Evolution.

Tropical, vector-borne, and neglected diseases with a limited number of medication therapies include Leishmaniasis, Malaria, Chagas and Human African Trypanosomiasis (HAT). Chromones are a large class of heterocyclic compounds with significant applications. This heterocycle has long aroused the interest of scientists and the general public from biosynthetic and synthetic points of view owing to its interesting pharmacological activities. Chromones and their hybrids and isomeric forms proved to be an exciting scaffold to investigate these diseases. The in vitro activities of Chromone, Chromane, and a panel of other related benzopyran class compounds against Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma cruzi, and numerous Leishmanial and Malarial species were investigated in our previous studies. The current article briefly describes the neglected diseases and the current treatment. This review aims to attempt to find better alternatives by scrutinizing natural and synthetic derivatives for which chromones and their analogues were discovered to be a new and highly effective scaffold for the treatment of neglected diseases, including compounds with dual activity or activity against multiple parasites. Additionally, the efficacy of other new scaffolds was also thoroughly examined. This article also discusses prospects for identifying more unique targets for the disease, focusing on flavonoids as drug molecules that are less cytotoxic and high antiprotozoal potential. It also emphasizes the changes that can be made while searching for potential therapies-comparing existing treatments against protozoal diseases and the advantages of the newer chromone analogues over them. Finally, the structure- activity relationship at each atom of the chromone has also been highlighted.

Synthetic Routes and Biological Activities of Chromone Scaffolds: An Overview

The central backbones of natural assets and therapeutic medications are chromone and flavone. Utilizing such preferred chalcone analogs in drug research has shown a successful blueprint, yielding new hits/leads and fast optimization procedures. Chromone can create novel molecules with pharmacological promise, particularly in neurological, inflammatory, infectious diseases, cancer and diabetes. The current perspective focuses mainly on flavones and flavonoids of biological significance, such as chromon-4-one analogs, both synthetic and natural sources. Furthermore, because drug repurposing is now a popular drug discovery strategy, current chromone-based medication repurposing research is discussed. As well the methods utilized to synthesize chromones and their derivatives are described in detail in this review. Since it’s uses in so many pharmacologically active substances, the stiff bicyclic chalcone fraction has been described as a preferred scaffold in drug development, with few instances as therapeutic agents. Due to their photochemical characteristics, chromone analogs are also utilized as scaffolds for creating bioactive molecules and their application in drug development, such as the production of fluorescent probes.

Four new chromone derivatives from the Arctic fungus Phoma muscivora CPCC 401424 and their antiviral activities.

The crude extract of the Arctic fungus Phoma muscivora CPCC 401424 displayed anti-influenza A virus activities which led us to investigated their secondary metabolites. Four new chromone derivatives, phomarcticones A-D (1-4) and five known chromone analogs (5-9) have been isolated from Arctic fungus Phoma muscivora CPCC 401424. Compounds 3 and 4 possess rare sulfoxide groups in chromone derivatives. Their structures and absolute configurations were elucidated by extensive analysis of spectroscopic data, electronic circular dichroism, and comparison with reported data. Compounds 3, 7, and 9 showed significant anti-influenza A virus activities with the IC50 values of 24.4, 4.2, and 2.7 μM, respectively.

Synthesis, α-glucosidase inhibition and molecular docking studies of natural product 2-(2-phenyethyl)chromone analogues

A series of natural product (2-phenyethyl)chromone analogues (3–34) were designed, synthesized, and screened for their α-glucosidase inhibitory activity. The results indicated that some of the synthesized derivatives displayed inhibitory activities against α-glucosidase with IC50 values ranging from 11.72 ± 0.08 to 85.58 ± 2.30 μM when compared to the standard drug acarbose (IC50 = 832.22 ± 2.00 μM). Among them, compound 4 with a hydroxyl group at the 7-position of chromone and a chloro group at the 4-position of the benzene ring, displayed the most significant inhibitory activity with the IC50 value of 11.72 ± 0.08 μM. The inhibitory mechanism of compound 4 against α-glucosidase was studied by enzyme kinetic, circular dichroism spectra, fluorescence quenching, and molecular docking. Sucrose loading test in vivo further demonstrated that it could decrease blood glucose levels after sucrose administration in normal Kunming mice. In vitro cytotoxicity showed that 4 exhibited low cytotoxicity against normal human cell lines. The ADME study suggested that all compounds are likely to be orally active as they obeyed Lipinski’s rule of five. In summary, our studies showed that these derivatives are a new class of α-glucosidase inhibitors.

Aromatic Polyketides from the Deep-Sea Cold-Seep Mussel Associated Endozoic Fungus Talaromyces minioluteus CS-138.

Five new aromatic polyketides, including a unique benzofuran derivative, talarominine A (1), and four chromone analogs talamins A–D (2–5), along with one known related metabolite, 5-hydroxy-7-methoxy-2,3-dimethylchromone (6), were isolated and identified from the Talaromyces minioluteus CS-138, an endozoic fungus obtained from the deep-sea cold seep mussel Gigantidas platifrons. Their chemical structures were elucidated by detailed analysis of their NMR spectra, HRESIMS and X-ray crystallographic data, and by comparison with literature data as well. The antibacterial and DPPH scavenging activities of compounds 1–6 were evaluated. Compounds 1–3 showed inhibitory activity against some of the tested bacteria whereas compounds 2 and 5 showed potent DPPH radical scavenging activities, which were better than that of the positive control butylated hydroxytoluene (BHT). This work is likely the first report on marine natural products of mussel-derived fungus living in cold seep environments.

Anti-Cancer and Anti-Inflammatory Activities of Three New Chromone Derivatives from the Marine-Derived Penicillium citrinum

Three new and uncommon chromone analogs, epiremisporine F (1), epiremisporine G (2), and epiremisporine H (3), were isolated from marine-origin Penicillium citrinum. Among the isolated compounds, compounds 2–3 remarkably suppressed fMLP-induced superoxide anion generation by human neutrophils, with IC50 values of 31.68 ± 2.53, and 33.52 ± 0.42 μM, respectively. Compound 3 exhibited cytotoxic activities against human colon carcinoma (HT-29) and non-small lung cancer cell (A549) with IC50 values of 21.17 ± 4.89 and 31.43 ± 3.01 μM, respectively, and Western blot assay confirmed that compound 3 obviously induced apoptosis of HT-29 cells, via Bcl-2, Bax, and caspase 3 signaling cascades.

Simultaneous determination of multiple active 2-(2-phenylethyl)chromone analogues in agarwood by HPLC, QAMS, and UPLC-MS.

Chromones are the major constituents of agarwood and are considered to be directly related to its quality. Agarotetrol, a chromone derivative, is a Chinese Pharmacopoeia content detection index. However, comprehensive high-performance liquid chromatography (HPLC), quantitative analysis of multiple components by a single marker (QAMS), and ultra-performance liquid chromatography mass spectrometry (UPLC-MS) analyses of this pharmacopeial plant material have never been performed. Moreover, reports regarding the separation and detection of multiple active 2-(2-phenylethyl)chromone analogues from this plant material are surprisingly scarce. To establish a simple, reliable, and effective HPLC method utilising both diode array and MS detection for the simultaneous determination of multiple active chromone analogues in agarwood. Four 2-(2-phenylethyl)chromones were isolated from methanol extracts of agarwood. After optimising the extraction, separation, and analytical conditions, validation of the developed analytical method indicated good linearity, satisfactory precision, and good recovery. On this basis, a method for the quantitative analysis of multiple components by a single marker was established. The four 2-(2-phenylethyl)chromones were identified by nuclear magnetic resonance spectroscopic analysis and UPLC coupled to electrospray ionisation quadrupole-time-of-flight MS. The behaviour of the chromones characterised by MS fragmentation indicated a loss of molecular CO and the formation of m/z 121 compounds by the cleavage of CH2 -CH2 bonds between the chromone and phenyl moieties. Three detection methods were successfully used in this study for agarwood detection, and this protocol may potentially be used as a tool for the quality control of agarwood.

Reactions of 3-functionalized chromones with triacetic acid lactone

Reaction of 3-formylchromones and triacetic acid lactone proceeds with retention of the chromone skeleton and cyclization into pyrano[3′,4′:5,6]pyrano[2,3-b]chromene system. The crystal structure of the reaction product from unsubstituted 3-formylchromone has been determined from X-ray data. Other chromone analogues bearing CO2H, CO2Me and CN substituents react with triacetic acid lactone affording an o-hydroxychalcone heteroanalogue, pyrano[3,2-c]chromene and chromeno[2,3-b]pyridine derivatives, respectively.

Neuroprotective potential of new chromones isolated from the soil actinomycete Microbispora sp. TBRC6027

Nine new chromone analogs (1–9) were isolated from the soil actinomycete Microbispora sp. TBRC6027. The chemical structures were determined based upon NMR spectroscopic methods. These compounds were evaluated in vitro by using P19-derived neurons for neuroprotective activity against oxidative stress induced by serum deprivation and showed % viability of neurons at the concentration of 1 ng/mL varied from 43.51% to 52.99% without significant neurotoxicity for P19-derived neurons at the same concentration. Moreover, all tested compounds were inactive for antibacterial activity against both Gram-positive and Gram-negative bacteria and for cytotoxicity against MCF-7 (human breast cancer) and Vero cells at maximum tested concentration 50 μg/mL. However, compounds 4, 6, and 7 displayed weak cytotoxicity against NCI-H187 (human small-cell lung cancer) cells with IC50 in a range of 87.99–91.57 μM.

Therapeutic potency of substituted chromones as Alzheimer's drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation.

Introduction: Documentation on the potency of chromones as acetylcholinesterase (AChE) antagonists has paved the way for the design and usage of new chromone analogues as inhibitors of AChE modelled on the hypothesis based on cholinergic pathway of Alzheimer’s disease (AD). Here, 2 minimally substituted chromones, namely 3-cyanochromone (CyC) and 7-amino-3- methylchromone (AMC), were checked for their AChE inhibition efficacies and plasma protein modulation. Methods: Colorimetric enzymatic assay as well as fluorescence measurements were performed for obtaining the experimental results, which were further corroborated by molecular docking and simulation studies. Results: The investigated systems exhibited strong inhibition activities against AChE, with CyC (IC50= 85.12 ± 6.70 nM) acting as better inhibitor than AMC (IC50 = 103.09 ± 11.90 nM) and both having IC50 values in the range of FDA approved cholinergic drug Donepezil (IC50 = 74.13 ± 8.30 nM). Non-competitive inhibition was observed in both the cases with the inhibitors binding near the peripheral anionic site (PAS) of the enzyme. Having one planar nitrile group in CyC as compared to sp3 hybridised substituents in AMC facilitated stacking interactions in the former, accounting for its higher inhibitory efficacy. A significant decrease in the inhibition potency of CyC (~32%) was noted in comparison with AMC (~5%) when the experiments were performed in presence of human serum albumin (HSA) instead of pure aqueous buffer. Conclusion: This comparative study affirms the importance of meticulous substitution in the chromone scaffold to promote maximum inhibition potency, while considering their usage as AD drugs.

The synthesis and anticancer activities of chiral epoxy-substituted chromone analogs

Human DNA topoisomerases (topos) have been recognized as a good target molecule for the development of anticancer drugs because they play an important role in solving DNA topological problems caused by DNA strand separation during replication and transcription. In this study, we designed and synthesized 11 novel chromone backbone compounds possessing epoxy and halohydrin substituents with chirality. In the topos inhibition test, compounds 2, 9, 10, and 11 showed comparable topo I inhibitory activity at concentration of 100 μM compared to camptothecin, and all of the synthesized compounds showed moderate topo IIα inhibitory activity. Among them, compounds 9, 10 and 11 were more potent than the others in both topo I and IIα inhibitory activity. Compound 11 showed the most potent cell antiproliferative activity against all tested cancer cell lines with particularly strong inhibition (an IC50 of 0.04 µM) of K562 myelogenous leukemia cancer cell proliferation. In the brief structure-activity relationship analysis, there was no clear correlation between stereochemistry and topos inhibitory and cytotoxic activity. 5(R),7(S)-bisepoxy-substituted compound 11 was the most potent DNA cross-linker and induced G2/M arrest in a cell cycle assay in a dose- and time-dependent manner. After the treatment time period induced apoptosis in K562 cells without increasing G2/M-phase cells. Overall, compound 11 showed good consistent inhibitory biological activity related to cancer cell proliferation.

Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis.

Monoamine oxidase B (MAO-B) is a validated drug target for Parkinson's disease. Chromone derivatives were identified as novel potent and reversible MAO-B inhibitors, and herewith we report on a crystallographic and biochemical analysis to investigate their inhibition mechanism. The crystal structures of human MAO-B in complex with three chromone analogs bearing different substituents on the exocyclic aromatic ring (determined at 1.6-1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor. These inhibitors form two hydrogen bonds with Tyr435 and Cys172 and perfectly fit the hydrophobic flat active site of human MAO-B. This is reflected in their tight-binding mechanism of inhibition with Ki values of 55, 17, and 31 nM for N-(3',4'-dimethylphenyl)-4-oxo-4 H-chromene-3-carboxamide (1), N-(3'-chlorophenyl)-4-oxo-4 H-chromene-3-carboxamide (2), and N-(3'-fluorophenyl)-4-oxo-4 H-chromene-3-carboxamide (3), respectively. These compounds were also 1000-fold more effective than l-deprenyl in reducing the cellular levels of reactive oxygen species (ROS).

Synthesis and biological effect of chrom-4-one derivatives as functional inhibitors of heat shock protein 27

Heat Shock Protein 27 (HSP27) is a member of small heat shock proteins with a highly-conserved α-crystalline domain. It inhibits aggregation of damaged proteins through a complex structural systems of phosphorylation-dependent oligomerization and self-assembly. It has been demonstrated that HSP27 is involved in a variety of pathophysiological pathways with negative or positive protective activities. In this study, we synthesized six chromone analogs possessing thiiran-2-ylmethoxy or oxyran-2-ylmethoxy substituents and evaluated their biological activities against HSP27 protein. Compounds YK598-2, J4 and J2 induced significant abnormal HSP27 dimer formation in NCI-H460, a human lung cancer cell line. In synergistic anticancer activity test, the compounds effectively producing abnormal HSP27 cross-linking remarkably enhanced the antiproliferative activity of 17-AAG, a HSP90 inhibitor. Target specificity test using the HSP27-silenced cells (shHSP27) showed that compounds YK598-2, J4, and J2 significantly lost their cross-linking activity only under conditions when HSP27 was deprived of. In the evaluation of cancer cell sensitization with cisplatin, cisplatin-induced lung cancer cell growth inhibition was sensitized with statistical significance by J4 and J2 as compared to compound alone treatment. These results suggest that abnormal HSP27 dimerization can be an efficient control point for cancer cell proliferation and chromone compounds might have potential as anticancer agents that modulate abnormal HSP27 dimerization.

2-(2-Phenylethyl)chromones from Endophytic Fungal Strain Botryosphaeria rhodina A13 from Aquilaria sinensis

ObjectiveTo study the characteristic 2-(2-phenylethyl)chromone components of endophytic fungal strain of Aquilaria sinensis by solid culture. MethodsThe compounds were isolated by various chromatographic methods such as silica gel, reverse-phase silica gel, Sephadex-LH20 column chromatography as well as crystallization. ResultsSeven 2-(2-phenylethyl)chromone analogues were isolated from the solid culture of Botryosphaeria rhodina A13. Their structures were established by spectral data as well as physicochemical properties, and identified as 6-hydroxy-7-methoxy-2-(2-phenylethyl)chromone (1), 6,7-dimethoxy-2-(2-phenylethyl) chromone (2), (5S,6R,7S,8R)-2-(2-phenylethyl)-5,6,7,8-tetrahydrchromone (3), 6-hydroxy-2-(2-phenylethyl)chromone (4), 4′-hydroxy-2-(2-phenylethyl)chromone (5), 6-methoxy-2-phenethyl-4H-chromen-4-one (6), and 6-methoxy-2-(4′-methoxy-phenethyl)-4H-chromen-4-one (7). ConclusionAll of the compounds are isolated for the first time from the genus Botryosphaeria. This research opens up a new vista to produce the characteristic components of agarwood by endophytic fungi.

Theoretical Study about the Effect of Halogen Substitution on the Reactivity of Antitumor 3-Formylchromones and Their Free Radicals

The mandatory presence of a chlorine atom on the aromatic ring of 6-hydroxy-3-formyl angular chromones, on the respiration inhibition of mammary carcinoma mouse, is explained through a computational study of these compounds. This study analyzes the reactivity of the neutral molecules and their free radicals, in gas phase and with water solvation, incorporated by the polarizable continuum medium (PCM) approach. Electrophilic reactivities were evaluated using Fukui (f+) and Parr (P+) functions. The stabilities of radical species formed by the abstraction of a hydrogen atom from the O-H bond were evaluated by bond dissociation enthalpy (BDE) and spin density (SD) calculations. This study has potential implications for the design of chromone analogues as anticancer compounds.

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. Because FPRs play an important role in the regulation of inflammatory reactions implicated in disease pathogenesis, FPR antagonists may represent novel therapeutics for modulating innate immunity. Previously, 4H-chromones were reported to be potent and competitive FPR1 antagonists. In the present studies, 96 additional chromone analogs, including related synthetic and natural isoflavones were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited fMLF-induced intracellular Ca2+ mobilization in FPR1-HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-HL60 and FPR1-RBL cells. Compound 10 (6-hexyl-2-methyl-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-chromen-7-yl acetate) was found to be the most potent FPR1-specific antagonist, with binding affinity Ki∼100nM. These chromones inhibited Ca2+ flux and chemotaxis in human neutrophils with nanomolar-micromolar IC50 values. In addition, the most potent novel FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells. These antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, RBL cells transfected with murine Fpr1, or interleukin 8-induced Ca2+ flux in human neutrophils and RBL cells transfected with CXC chemokine receptor 1 (CXCR1). Moreover, pharmacophore modeling showed that the active chromones had a significantly higher degree of similarity with the pharmacophore template as compared to inactive analogs. Thus, the chromone/isoflavone scaffold represents a relevant backbone for development of novel FPR1 antagonists.

Halogenated metabolites isolated from Penicillium citreonigrum.

Three chromone analogs, 1-3, a chlorinated alkaloid sclerotioramine (4), together with two 11-noreremophilane-type sesquiterpenes with a conjugated enolic OH group and a brominated one, 5 and 6, respectively, were isolated from Penicillium citreonigrum (HQ738282). Compounds 1, 5, and 6 were new. Biological tests revealed that 4 exhibited a significant activity (IC50 7.32 μg/ml), and 6 showed a moderate activity (IC50 16.31 μg/ml) in vitro against HepG2 cell line, and 4 also displayed an activity comparable to that of acarbose against α-glucosidase.