Heterocyclic Chalcone Research Articles

How methoxy groups change nature of the thiophene based heterocyclic chalcones from p-channel to ambipolar transport semiconducting materials

Chalcone derivatives gained significant consideration from scientific community due to their potential applications ranging from better biological activity to the efficient semiconducting properties. Present investigation deals with the in-depth study of three chalcone derivatives (2E)-1-(2,5-Dimethyl-3-thienyl)-3-(2-methoxyphenyl)prop-2-en-1-one (1), (2E)-3-(3,4-Dimethoxyphenyl)-1-(2,5-dimethylthiophen-3-yl)prop-2-en-1-one (2), and (E)-1-(2,5-Dimethyl-3-thienyl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one (3) highlighting their optoelectronic, charge transport (CT) and nonlinear optical (NLO) response. The ground and excited state geometries are optimized by applying density functional theory (DFT) and time dependent DFT, respectively. The effect of electron donating groups on the frontier molecular orbitals, absorption and emission wavelengths are investigated and discussed thoroughly using the quantum chemical calculations. The comprehensive intra-molecular charge transfer (ICT) is perceived from the occupied orbitals to the unoccupied molecular orbitals. A novel structure-property relationship is established on the basis of their calculated electronic structures, frontier orbitals and density of states. The electro-optical and nonlinear optical (NLO) properties are finely tuned in the chalcone derivatives comprising of di- and tri-methoxy groups at peripheral. The nature of the p-type and ambipolar charge transport behavior of the compounds 1–3 is limelighted on the basis of their ionization potentials, electron affinities, reorganization energies, transfer integrals and intrinsic mobility. The mono- and di-substituted methoxy chalcone derivatives show the ambipolar performance owing to the better transfer integral and intrinsic mobility values for hole and electron. Whilst tri-methoxy at peripheral would lead the p-channel characteristics due to the balanced reorganization energy (hole and electron) and superior hole transfer integrals leads to higher hole intrinsic mobility.

First principles study of the n-channel thiophene based heterocyclic chalcones

In present investigation, we limelight the key electro-optical properties including electronic structure, optical, charge transport and nonlinear optical properties of two novel chalcone derivatives ((E)-1-(2,5-Dimethyl-3-Thienyl)-3-(2-hydroxyphenyl)prop-2-en-1-one (chalc1) and (2E)-3-[4-(Dimethylamino)phenyl]-1-(2,5-dimethyl-3-Thienyl)prop-2-en-1-one (chalc2). The ground (S0) and excited state (S1) geometries are optimized using B3LYP/6-31G** and TD-B3LYP/6-31G** levels of theory, respectively, which show reasonably good agreement to the available experimental data of respective crystal structures. A comprehensive electronic structure-property relationship is elucidated through the prism of frontier molecular orbitals (FMOs), orbital energy gap (Eg) analysis, density of states (DOS), as well as molecular electrostatic potential (MEP) plots. The effect of electron donating groups (-OH and −N(CH3)2) is investigated on the absorption and emission wavelengths, ionization potentials (IP), electron affinities (EA), reorganization energies. Finally, the n-channel charge transport nature of these compounds is considered on the bases of our calculated transfer integrals and intrinsic mobilities.

Temperature dependence of the Raman spectrum of 1-(4-chlorophenyl)-3-(2-thienyl)prop-2-en-1-one

The heterocyclic chalcone containing thiophene ring 1-(4-chlorophenyl)-3-(2-thienyl)prop-2-en-1-one, C13H9ClOS was synthesized and investigated using experimental techniques such as nuclear magnetic resonance (1H and 13C NMR), Fourier transform infrared spectroscopy (FTIR) at room temperature, differential scanning calorimeter (DSC) from room temperature to 500K and Raman scattering at the temperature range 10–413K in order to study its structure and vibrational properties as well as stability and possible phase transition. Density functional theory (DFT) calculations were performed to determine the vibrational spectrum viewing to improve the knowledge of the material properties. A reasonable agreement was observed between theoretical and experimental Raman spectrum taken at 10K since anharmonic effects of the molecular motion is reduced at low temperatures, leading to a more comprehensive assignment of the vibrational modes. Increasing the temperature up to 393K, was observed the typical phonon anharmonicity behavior associated to changes in the Raman line intensities, line-widths and red-shift, in special in the external mode region, whereas the internal modes region remains almost unchanged due its strong chemical bonds. Furthermore, C13H9ClOS goes to melting phase transition in the temperature range 393–403K and then sublimates in the temperature range 403–413K. This is denounced by the disappearance of the external modes and the absence of internal modes in the Raman spectra, in accordance with DSC curve. The enthalpy (ΔH) obtained from the integration of the endothermic peak in DSC curve centered at 397K is founded to be 121.5J/g.

Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines

The structure of alpha-napthoflavone (ANF), a potent inhibitor of CYP1A1 and CYP1B1, mimics the structure of chalcones. Two potent CYP1B1 inhibitors 7k (DMU2105) and 6j (DMU2139) have been identified from two series of synthetic pyridylchalcones. They inhibit human CYP1B1 enzyme bound to yeast-derived microsomes (Sacchrosomes™) with IC50 values of 10 and 9 nM, respectively, and show a very high level of selectivity towards CYP1B1 with respect to the IC50 values obtained with CYP1A1, CYP1A2, CYP3A4, CYP2D6, CYP2C9 and CYP2C19 Sacchrosomes™. Both compounds also potently inhibit CYP1B1 expressed within ‘live’ recombinant yeast and human HEK293 kidney cells with IC50 values of 63, 65, and 4, 4 nM, respectively. Furthermore, the synthesized pyridylchalcones possess better solubility and lipophilicity values than ANF. Both compounds overcome cisplatin–resistance in HEK293 and A2780 cells which results from CYP1B1 overexpression. These potent cell-permeable and water-soluble CYP1B1 inhibitors are likely to have useful roles in the treatment of cancer, glaucoma, ischemia and obesity.

Hirshfeld Surfaces and Nonlinear Optics on Two Conformers of a Heterocyclic Chalcone

Heterocyclic chalcones have been prominent in the scientific community due to various biological activities reported for these compounds. The structural knowledge of heterocyclic chalcones can help in the understanding of their mechanism of action. The Hirshfeld surfaces were used to study the supramolecular arrangement of two conformers present into asymmetric unit of the heterocyclic chalcone (2E)-3-(4-methylphenyl)-1-(pyridin-3-yl)-prop-2-en-1-one on crystalline state. In addition, the linear polarizability (α), the first hyperpolarizability (β||z), and the second hyperpolarizability (γ) of the conformers were calculated to get a better insight on the linear and nonlinear optical behaviors of these structures in presence of solvent medium, as well as their band-gap energies. The Hirshfeld surfaces confirmed the presence of C−H···N, C−H···O and C−H···C interactions in packaging stabilization. Finally, the 2D fingeprint plot was used to the quantification of contacts and indicated that there are both π···π and C−H···π interactions present in the compound.

Nrf2 exerts cell-autonomous antifibrotic effects: compromised function in systemic sclerosis and therapeutic rescue with a novel heterocyclic chalcone derivative

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) governs antioxidant, innate immune and cytoprotective responses and its deregulation is prominent in chronic inflammatory conditions. To examine the hypothesis that Nrf2 might be implicated in systemic sclerosis (SSc), we investigated its expression, activity, and mechanism of action in SSc patient samples and mouse models of fibrosis and evaluated the effects of a novel pharmacologic Nrf2 agonist. We found that both expression and activity of Nrf2 were significantly reduced in SSc patient skin biopsies and showed negative correlation with inflammatory gene expression. In skin fibroblasts, Nrf2 mitigated fibrotic responses by blocking canonical transforming growth factor-β (TGF-β)-Smad signaling, whereas silencing Nrf2 resulted in constitutively elevated collagen synthesis, spontaneous myofibroblast differentiation, and enhanced TGF-ß responses. Bleomycin treatment of Nrf2-null mice resulted in exaggerated fibrosis. In wild-type mice, treatment with a novel pharmacologic Nrf2 agonist 2-trifluoromethyl-2'-methoxychalcone prevented dermal fibrosis induced by TGF-β. These findings are the first to identify Nrf2 as a cell-intrinsic antifibrotic factor with key roles in maintaining extracellular matrix homeostasis and a pathogenic role in SSc. Pharmacologic reactivation of Nrf2, therefore, represents a novel therapeutic strategy toward effective treatment of fibrosis in SSc.

Synthesis, characterization, POM analysis and antifungal activity of novel heterocyclic chalcone derivatives containing acylated pyrazole

A series of heterocyclic chalcone derivatives (4a–h) were synthesized and characterized by IR, 1H and 13C NMR as well as MS. All the synthesized compounds were evaluated for their antifungal activity on Candida albicans and Aspergillus niger. The assay revealed that compounds 3d and 4f showed significant activity against both tested fungal strains. POM analyses showed that the compounds are highly lipophyllic but present a potential bioactivity. Moreover, they have no NH–O or N–HO intramoleculcular interaction which is a crucial parameter controlling solubility of compounds possessing these encouraging pharmaceutical properties. This series gives us an important lesson in drug design: We should take the balance of hydrosolubility/lipophilicity into consideration. POM analyses were in agreement with the idea of coexistence of two combined antifungal N,O and O,S-pharmacophore sites for series 4a–h. On the other hand, two coexistents and identical N,Cl-pharmacophore sites have been identified for Fluconazole.

2-Heteroarylidene-1-indanone derivatives as inhibitors of monoamine oxidase

In the present study a series of fifteen 2-heteroarylidene-1-indanone derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. These compounds are structurally related to series of heterocyclic chalcone derivatives which have previously been shown to act as MAO-B specific inhibitors. The results document that the 2-heteroarylidene-1-indanones are in vitro inhibitors of MAO-B, displaying IC50 values of 0.0044–1.53μM. Although with lower potencies, the derivatives also inhibit the MAO-A isoform with IC50 values as low as 0.061μM. An analysis of the structure-activity relationships for MAO-B inhibition indicates that substitution with the methoxy group on the A-ring leads to a significant enhancement in MAO-B inhibition compared to the unsubstituted homologues while the effect of the heteroaromatic substituent on activity, in decreasing order is: 5-bromo-2-furan>5-methyl-2-furan>2-pyridine≈2-thiophene>cyclohexyl>3-pyridine≈2-furan. It may therefore be concluded that 2-heteroarylidene-1-indanone derivatives are promising leads for the design of MAO inhibitors for the treatment of Parkinson’s disease and possibly other neurodegenerative disorders.

Synthesis, characterization, and cytotoxic activities of heterocyclic chalcones containing furan, and crystal structure of 1-(4-iodophenyl)-3-(5-methylfuran-2-yl)prop-2-en-1-one

ABSTRACTA series of heterocyclic chalcone (3a–e, 5, 7) were synthesized and characterized by Infrared, 1H and 13C nuclear magnetic resonance, and mass spectra. Crystal structure of 1-(4-iodophenyl)-3-(5-methylfuran-2-yl)prop-2-en-1-one was determined using single crystal X-ray diffraction. All the synthesized compounds were evaluated for their cytotoxic activities on MDA MB 231 and CHO cell by using MTT assay. Compound 3c showed good cytotoxic effect on MDA MB 231 with IC50 values of 9.8 µg/mL.

Synthesis and Selective Cytotoxic Activities on Rhabdomyosarcoma and Noncancerous Cells of Some Heterocyclic Chalcones.

Chemically diverse heterocyclic chalcones were prepared and evaluated for cytotoxicity, aiming to push forward potency and selectivity. They were tested against rhabdomyosarcoma (RMS) and noncancerous cell line (LLC-PK1). The influence of heteroaryl patterns on rings A and B was studied. Heterocycle functionalities on both rings, such as phenothiazine, thiophene, furan and pyridine were evaluated. Notably, the introduction of three methoxy groups at positions 3, 4, 5 on ring B appears to be critical for cytotoxicity. The best compound, with potent and selective cytotoxicity (IC50 = 12.51 μM in comparison with the value 10.84 μM of paclitaxel), contains a phenothiazine moiety on ring A and a thiophene heterocycle on ring B. Most of the potential compounds only show weak cytoxicity on the noncancerous cell line LLC-PK1.

Synthesis and Regioselective Reaction of Some Unsymmetrical Heterocyclic Chalcone Derivatives and Spiro Heterocyclic Compounds as Antibacterial Agents.

A number of novel heterocyclic chalcone derivatives can be synthesized by thermal and microwave tools. Treatment of 4-(4-Acetylamino- and/or 4-bromo-phenyl)-4-oxobut-2-enoic acids with hydrogen peroxide in alkaline medium were afforded oxirane derivatives 2. Reaction of the epoxide 2 with 2-amino-5-aryl-1,3,4-thiadiazole derivatives yielded chalcone of imidazo[2,1-b]thiadiazole derivative 4 via two thermal routes. In one pot reaction of 4-bromoacetophenone, diethyloxalate, and 2-amino-5-aryl-1,3,4-thiadiazole derivatives in MW irradiation (W 250 and T 150 °C) under eco-friendly conditions afforded an unsuitable yield of the desired chalcone 4d. The chalcone derivatives 4 were used as a key starting material to synthesize some new spiroheterocyclic compounds via Michael and aza-Michael adducts. The chalcone 4f was similar to the aryl-oxo-vinylamide derivatives for the inhibition of tyrosine kinase and cancer cell growth. The electron-withdrawing substituents, such as halogens, and 2-amino-1,3,4-thiadiazole moeity decreasing the electron density, thereby decreasing the energy of HOMO, and the presence of imidazothiadiazole moiety should improve the antibacterial activity. Thus, the newly synthesized compounds were evaluated for their anti-bacterial activity against (ATCC 25923), (ATCC 10987), (ATCC 274,) and (SM514). The structure of the newly synthesized compounds was confirmed by elemental analysis and spectroscopic data.

SYNTHESIS AND CHARACTERIZATION OF HETEROCYCLIC CHALCONES CONTAINING HALOGENATED THIOPHENES

Heterocyclic chalcones containing halogenated thiophenes were synthesized. The first step was to synthesize 3-acetyl-2,5-dichlorothiophene and 2-acetyl-5-chlorothiophene as heterocyclic ketones by using Friedel-Crafts acylation. The ketones were then used to synthesize thiophene chalcones through Claisen-Schmidt reaction with the respective heterocyclic aldehydes such as 5-bromothiophene-2-carbaldehyde, 3-methyl-2-thiophene carboxaldehyde and 2-thiophene carboxaldehyde with 3-acetyl-2,5-dichlorothiophene or 2-acetyl-5-chlorothiophene in presence of basic medium, sodium hydroxide to form the corresponding chalcones. Structures of the synthetic compounds were confirmed by IR, MS, 1H and 13C NMR spectral data.

Monoamine oxidase inhibitory activities of heterocyclic chalcones.

Studies have shown that natural and synthetic chalcones (1,3-diphenyl-2-propen-1-ones) possess monoamine oxidase (MAO) inhibition activities. Of particular importance to the present study is a report that a series of furanochalcones acts as MAO-B selective inhibitors. Since the effect of heterocyclic substitution, other than furan (and more recently thiophene, piperidine and quinoline) on the MAO inhibitory properties of the chalcone scaffold remains unexplored, the aim of this study was to synthesise and evaluate further heterocyclic chalcone analogues as inhibitors of the human MAOs. For this purpose, heterocyclic chalcone analogues that incorporate pyrrole, 5-methylthiophene, 5-chlorothiophene and 6-methoxypyridine substitution were examined. Seven of the nine synthesised compounds exhibited IC50 values <1 μM for the inhibition of MAO-B, with all compounds exhibiting higher affinities for MAO-B compared to the MAO-A isoform. The most potent MAO-B inhibitor (4h) displays an IC50 value of 0.067 μM while the most potent MAO-A inhibitor (4e) exhibits an IC50 value of 3.81 μM. It was further established that selected heterocyclic chalcones are reversible and competitive MAO inhibitors. 4h, however, may exhibit tight-binding to MAO-B, a property linked to its thiophene moiety. We conclude that high potency chalcones such as 4h represent suitable leads for the development of MAO-B inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders.

Heterocyclic chalcone activators of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) with improved in vivo efficacy

Nrf2 activators represent a good drug target for designing agents to treat diseases associated with oxidative stress. Building upon previous work, we designed and prepared a series of heterocyclic chalcone-based Nrf2 activators with reduced lipophilicity and, in some cases, greater in vitro potency compared to the respective carbocyclic scaffold. These changes resulted in enhanced oral bioavailability and a superior pharmacodynamic effect in vivo.

Groove binding mediated structural modulation and DNA cleavage by quinoline appended chalcone derivative

The present study embodies the detail DNA binding interaction of a potential bioactive quinoline appended chalcone derivative (E)-3-(anthracen-10-yl)-1-(6,8-dibromo-2-methylquinolin-3-yl)prop-2-en-1-one (ADMQ) with calf thymus DNA (ctDNA) and its consequences by UV–Vis absorption, steady state fluorescence spectroscopy, fluorescence anisotropy, circular dichromism, helix melting, agarose gel electrophoresis, molecular docking, Induced Fit Docking (IFD) and molecular dynamics (MD) simulation. The UV–Vis absorption and fluorescence study reveal that the molecule undergoes considerable interaction with the nucleic acid. The control KI quenching experiment shows the lesser accessibility of ADMQ molecule to the ionic quencher (I−) in presence of ctDNA as compared to the bulk aqueous phase. Insignificant change in helix melting temperature as well as in circular dichromism (CD) spectra points toward non-covalent groove binding interaction. The moderate rotational confinement of this chalcone derivative (anisotropy=0.106) trapped in the nucleic acid environment, the comparative displacement assay with well-known minor groove binder Hoechst 33258 and intercalator Ethidium Bromide establishes the minor groove binding interactions of the probe molecule. Molecular docking, IFD and MD simulation reveal that the DNA undergoes prominent morphological changes in terms of helix unwinding and bending to accommodate ADMQ in a crescent shape at an angle of 110° in a sequence specific manner. During interaction, ADMQ rigidifies and bends the sugar phosphate backbone of the nucleic acid and thereby shortens its overall length by 3.02Å. Agarose gel electrophoresis experiment with plasmid pBR 322 reveals that the groove binded ADMQ result in a concentration dependent cleavage of plasmid DNA into its supercoiled and nicked circular form. The consolidated spectroscopic research described herein provides quantitative insight into the interaction of a heterocyclic chalcone derivative with relevant target nucleic acid, which may be useful for the future research on chalcone based therapeutic agents.

Synthesis and Molecular Docking studies of Heterocyclic Chalcone Derivatives as BRCA1 inhibitors

According to Claisen-Schmidt condensation a series of novel substituted Indolyl Chalcone derivatives were synthesized and evaluated Docking study. The synthesized compounds have been characterized by TLC, elemental analysis, IR and 1 H and 13 C NMR spectroscopy.

Synthetic and Mechanistic Studies on the Solvent-Dependent Copper-Catalyzed Formation of Indolizines and Chalcones

Copper nanoparticles supported on activated carbon have been found to catalyze the multicomponent synthesis of indolizines from pyridine-2-carbaldehyde derivatives, secondary amines, and terminal alkynes in dichloromethane; in the absence of solvent, however, heterocyclic chalcones are formed. We provide compelling evidence that both processes take place through aldehyde–amine–alkyne coupling intermediates. In contrast to other well-known mechanisms for chalcone formation from aldehydes and alkynes, a new reaction pathway involving propargyl amines as intermediates that do not undergo rearrangement is presented. The formation of indolizines or chalcones is driven by inductive and solvent effects, with a wide array of both being reported. In both reactions, the nanoparticulate catalyst has been shown to be superior to some commercially available copper catalysts, and it could be recycled in the case of the chalcone synthesis.

Antihypertensive activity of a quinoline appended chalcone derivative and its site specific binding interaction with a relevant target carrier protein

The usefulness of heterocyclic chalcone derivative as a therapeutic target in controlling hypertension and its site specific binding interaction with model transport protein to get a clear picture about its delivery mechanism.

Synthesis, Characterisation and biological activities of some Heterocyclic Chalcone Derivatives

According to Claisen-Schmidt condensation a series of novel substituted Indolyl chalcone derivatives were synthesized and evaluated for their antibacterial and antifungal activity against three different bacterial strain such as Moraxella, Enterobacter and Pseudomonas aeruginosa and three fungal strain against Candida albicans, A.niger and Trichophyton. The synthesized compounds have been characterised by TLC, elemental analysis, IR and 1H and 13C NMR spectroscopy.

Synthesis and in vitro biological evaluation of new pyrazole chalcones and heterocyclic diamides as potential anticancer agents

Synthesis and characterization of new heterocyclic pyrazole chalcones (4a–e) and diamide (6a–e) derivatives are described. Pyrazole chalcones were synthesized by the reaction of pyrazole aldehydes and suitable aromatic ketones. Diamides were synthesized by the reaction of phthalic acid and amines. Newly synthesized compounds were characterized by spectral studies and their biological activity was assessed in vitro using MCF-7 (human breast adenocarcinoma) and HeLa (human cervical tumor cells) cell lines. Few of the synthesized molecules inhibited the growth of the human breast cancer cell lines and human cervical tumor cell lines at low micromolar to nanomolar concentrations.