Chalcone Derivatives Research Articles

Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling

The deregulation in the Wnt/β-catenin signaling pathway is associated with many human cancers, particularly colorectal cancer (CRC) and, therefore, represents a promising target for drug development. We have screened over 300 semisynthetic and natural compounds using a Wnt reporter assay and identified a family of novel chalcone derivatives (CXs) that inhibited Wnt signaling and CRC cell proliferation. Among them, we selected CX258 for further in vitro and in vivo study to investigate the molecular mechanisms. We found that CX258 significantly inhibited β-catenin expression and nuclear translocation, inducing cell cycle arrest at the G2/M phase in CRC cells. Additionally, CX258 reduced the expression of DNA Topoisomerase II alpha (TOP2A) in CRC cells. Moreover, knocking down TOP2A by siRNAs inhibited the Wnt/β-catenin signaling pathway, a finding suggesting that CX258 inhibited Wnt/β-catenin signaling and CRC cell proliferation at least partially by modulating TOP2A. Further studies showed that CDK1 that interacts with TOP2A was significantly reduced after TOP2A knockdown. We demonstrated that CX258 significantly inhibited DLD-1 CRC cell xenografts in SCID mice. In summary, we identified CX258 as a promising candidate for colorectal cancer treatment by targeting the TOP2A/Wnt/β-catenin signaling pathway.

Chalcone derivatives as novel, potent and selective inhibitors against human Notum: Structure–activity relationships and biological evaluations

Human Notum (hNotum) inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer. Herein, two series of chalcone derivatives were designed and synthesized aiming to find selective and potent hNotum inhibitors. Structure–activity relationship (SAR) studies showed that 2-methoxyl and 5-bromine substitutions on A-ring significantly enhanced anti-hNotum effect, while 4′-ethoxyl and 3′-alkyl substitutions on B-ring were beneficial for hNotum inhibition. Among all tested chalcones, B11 displayed the most potent anti-Notum effect (IC50 = 3.6 nmol/L), good selectivity, excellent chemical stability and suitable metabolic stability. Further investigations showed that B11 acted as a competitive inhibitor of hNotum, while this agent (5 µmol/L) significantly weaken the migration abilities of colorectal cancer cells. Collectively, this study deciphers the SARs of chalcones as hNotum inhibitors and reports a novel and potent hNotum inhibitor with the anti-migration effect on colorectal cancer cells, which offers a promising lead compound to develop novel anti-cancer agents.

Studying the Inhibitory Effects of Some Chalcone Derivatives on Streptococcus mutans Sortase A to Prevent Dental Caries: An In Silico Approach

Background: Streptococcus mutans is one of the most important microorganisms in tooth decay. Sortase A (SrtA) of S. mutans is responsible for the attachment of bacteria to the host cell and biofilm formation. Therefore, it seems necessary to investigate the inhibitors of this enzyme to prevent dental caries. Chalcones are always of interest in the medical community due to their wide range of biological activities. Many studies have reported that chalcone can help prevent caries. The present study was conducted to identify potential SrtA inhibitors with the chalcone skeleton. Methods: The chalcone derivatives were obtained from the ZINC15, LEA3D, and PubChem databases, and then the selected compounds were optimized by HyperChem software. The affinity of these compounds to SrtA and total binding free energy (ΔGbind) were estimated by the AutoDock 4.0 program. Finally, drug-likeness screening and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the best ligands were obtained using online servers. Results: Compared to chalcone, four of the studied ligands, including compounds 2, 7, 8, and 9 demonstrated high affinity for binding to S. mutans SrtA, with suitable drug-likeness and ADMET properties. Ligand 9 interacted with the key residues in the active site by the most negative ΔGbind (-4.64 kcal/mol). The best conformation of this ligand had the most overlap with the chalcone. Conclusion: By complementary both in vitro and in vivo studies on the inhibitory effects of compounds 2, 7, 8, and 9, the present study can be useful in controlling tooth decay and dental diseases.

Synthesis of Halogen Substituted Chalcone Againts Cervical Cancer (HeLa) Cell Lines using Green Method

Cervical cancer is the second leading cause of death in women. Many cancer treatments currently provide toxic effects on normal cells. Therefore, alternative treatment using chalcone derivatives has potent anticancer properties that can help reduce cancer side effects. Chalcone derivatives with halogen and methoxy groups in ring B can potentially inhibit cancer cells. This research aimed to synthesize halogen-substituted chalcone by a green chemistry approach and determine activity against cervical cancer (HeLa) cell lines. The Claisen-Schmidt reaction was used to synthesize 2'-hydroxy-2-bromo-4,5-dimethoxychalcone using a grinding technique. The purity of the synthesized compound was determined using thin-layer chromatography and melting range. The compounds' structures were characterized using FTIR, MS 1H, and 13C-NMR. The result showed that the synthesized compound was yielded in 53% as a yellow solid. In vitro cytotoxicity of the synthesized chalcone was evaluated by the MTT assay method. The IC50 of the compound was 67,23 μg/mL as a moderate activity inhibiting cervical cancer (HeLa) cell lines. Based on the IC50 value, this compound can be a candidate for anticancer against Cervical cancer (HeLa) cell lines

Design, synthesis and biological activity of chalcone derivatives containing pyridazine

Inspired by the application of fungicide from natural products, a series of chalcone derivatives containing pyridazine were designed, synthesized, and evaluated for their antifungal activities against nine plant fungi and antibacterial activity against three plant bacteria. The antibacterial results revealed that B8 showed the best activity against Xanthomonas campestris pv. citri (Xac) with an EC50 value of 78.89 μg/mL, superior to Bismerthiazol (EC50 = 86.72 μg/mL). The antifungal bioactivity results showed that some of the compounds had good bioactivity against fungi, such as B4 showed the best bioactivity against Botrytis cinerea (BC) with an EC50 value of 8.91 μg/mL, which was better than the azoxystrobin (EC50 = 20.28 μg/mL). Compounds B4, D2 and D3 showed good biological activity against Rhizoctonia solani (RS), with an EC50 value of 18.10, 20.18 and 20.60 μg/mL, comparable to the azoxystrobin. Antifungal mechanism studies of BC by B4 suggest that B4 disrupts the cell membrane of the mycelium and thus inhibits the growth of the fungus. The above indicates that chalcone derivatives containing pyridazine have the potential to become fungicides.

Synthesis, antifungal activity and mechanism of action of novel chalcone derivatives containing 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole.

A series of chalcone derivatives containing 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole was designed and synthesized. Structures of all compounds were characterized by 1H NMR, 13C NMR, 19F NMR, and HRMS. The biological activities of the compounds were determined with the mycelial growth rate method, and further studies showed that some compounds had good antifungal activities at the concentration of 100μg/mL. The EC50 value of compound L31 was 15.9μg/mL against Phomopsis sp., which were better than that of azoxystrobin (EC50 value was 69.4μg/mL). In addition, the mechanism of action of compound L31 shown that compound can affect mycelial growth by disrupting membrane integrity against Phomopsis sp., and that the higher the concentration of the compound is, the greater the disruption of membrane integrity is.

Chalcones and Gastrointestinal Cancers: Experimental Evidence.

Colorectal (CRC) and gastric cancers (GC) are the most common digestive tract cancers with a high incidence rate worldwide. The current treatment including surgery, chemotherapy or radiotherapy has several limitations such as drug toxicity, cancer recurrence or drug resistance and thus it is a great challenge to discover an effective and safe therapy for CRC and GC. In the last decade, numerous phytochemicals and their synthetic analogs have attracted attention due to their anticancer effect and low organ toxicity. Chalcones, plant-derived polyphenols, received marked attention due to their biological activities as well as for relatively easy structural manipulation and synthesis of new chalcone derivatives. In this study, we discuss the mechanisms by which chalcones in both in vitro and in vivo conditions suppress cancer cell proliferation or cancer formation.

An Updated Review on Recent Advancements in the Diverse Biological Applications of Medicinally Privileged Scaffold: Chalcone and its derivatives

Fused heterocyclic compounds rank among the most significant systems in medicinal chemistry because of their wide-ranging biological effects. Among the various class of compounds, chalcones and their derivatives are found to be one of the important classes in the field of synthetic and pharmaceutical chemistry. These derivatives are mainly synthesized by means of Claisen-Schmidt condensation, Crossed Aldol condensation and Knoevenagel condensation reactions, which provides wider applications in the field of medicine. Due to the broader biological applications like antimicrobial, anticancer, antimalarial, antioxidant, anti-inflammatory, antitubercular, antidiabetic, antileishmanial, anti-vitiligo and neuroprotective properties, these derivatives extended their role in coordination chemistry and also act as intermediates for the synthesis of various organic derivatives containing isoxazole, pyrazole, pyrimidine, naphthalene, indole, polyamine and other moieties as hybrid molecules. The present review discusses the biological applications of various chalcone derivatives. Due to their easiest way of synthesis, nowadays, these types of derivatives were tried for various ailments and by means of implementing various greener chemistry approaches, novel and potent derivatives can be synthesized and applied for various applications. Thus, this review will be helpful for the design of potent chalcone derivatives for numerous applications in the future. Keywords: Chalcones, 1,3-diphenyl-2-propene-1-one, microbial properties, anticancer, antioxidant, neuroprotective and biological applications

Synthesis, in vitro cytotoxicity evaluation and mechanism of 5′ monosubstituted chalcone derivatives as antitumor agents

A series of 5′ monosubstituted chalcone derivatives were synthesized to explore their antitumor activity and mechanism of action in vitro. The structures of 5′ monosubstituted chalcone derivatives synthesized by reactions such as Suzuki coupling were confirmed by 1H NMR, 13C NMR and MS, and the target compounds were not reported in the literature. The antitumor activity of the aimed compounds was tested by MTT colorimetric method in vitro. Compound 5c has an IC50 value of 1.97 μM for K562 and a value of 2.23 μM for HepG2. Further investigation of the mechanism of action of compound 5c was found to have effects on K562 cell morphology, proliferation, apoptosis, cell cycle, and wound healing of HepG2 cells. The results showed that compound 5c has research value in antitumor activity and mechanism of action in vitro.

Kinetic and Mechanistic Studies of the Selective Hydrogenation of (E)‐Chalcones in Biomass‐Derived γ‐Valerolactone Catalyzed by Rh−PPh3 Complexes

Abstractγ‐Valerolactone as a renewable, polar aprotic solvent was evaluated in the selective hydrogenation of carbon‐carbon double bond of chalcones from both catalytic and mechanistic aspects. By using triphenylphosphine‐modified cationic rhodium catalyst systems reasonably high activities (TOFinitial∼1200 h−1) were achieved in the selective hydrogenation of (E)‐chalcone (CHL), as a common model substrate for α,β‐unsaturated ketones, to dihydrochalcone (DHC). Various derivatives of CHL, which were substituted on the styryl phenyl groups also showed exclusive selectivity for the hydrogenation of the C=C double bond. The optimal PPh3/Rh ratio was between 2.5 to 3, but higher ratios were advantageously also tolerated, which is beneficial for the process chemistry. The solvent GVL proved to stable enough under the reaction conditions for waste‐free recycling. Kinetic studies and NMR spectra from the analogous deuteration of chalcone by using the cationic Rh‐PPh3 system clearly show the olefin insertion as the rate‐determining step with definite irreversibility. By investigating the substituent effect on the phenyl ring of the styryl moiety of chalcone, a quasi‐linear correlation was found between the electronic parameters of the para‐substituents and the activity with electron donor groups being favorable for the reaction rate. In summary, an environmentally friendly and feasible method is presented for the production of valuable DHC intermediates in view of their pharmaceutical importance.

Synthesis and Characterization of Non-mesogenic Behavior of Chalcone Derivatives

Synthesis and Characterization of Non-mesogenic Behavior of Chalcone Derivatives

Design, synthesis and biological activity of novel chalcone derivatives containing indole

In this study, 24 chalcone derivatives containing indole were designed and synthesized. Some of the target compounds exhibited significant antiviral and antibacterial effects. The results of EC50 test against tobacco mosaic virus showed that the EC50 value of curative activity of D11 was 107.4 μg/mL, which was better than the commercial drug ningnanmycin 311.5 μg/mL, and the EC50 value of protective activity of D16 was 106.6 μg/mL, which was superior to ningnanmycin 205.4 μg/mL, the inactivated activity of D11 was comparable to that of ningnanmycin. Microscale thermophoresis experiments demonstrated D11 (Kd = 0.0030 ± 0.0014 μmol/L) had a stronger binding ability with tobacco mosaic virus capsid protein (TMV-CP), which was much higher than that of ningnanmycin (Kd = 2.6062 ± 1.1767 μmol/L). Molecular docking results showed D11 had a significantly higher affinity with TMV protein than ningnanmycin. In addition, the malondialdehyde (MDA), peroxidase (POD), succinate dehydrogenase content (SDH) assay showed D11 could improve the disease resistance of tobacco. The results of bacterial inhibition activity showed that the EC50 value of D23 against Xoo was 50.3 μg/mL, which was better than the commercial drugs thiodiazole copper (79.8 μg/mL) and bismerthiazol (106.2 μg/mL), the bacterial inhibition activity of D23 was verified by scanning electron microscopy.

Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro

Phytomonas serpens is a trypanosomatid phytoparasite, found in a great variety of species, including tomato plants. It is a significant problem for agriculture, causing high economic loss. In order to reduce the vegetal infections, different strategies have been used. The biological activity of molecules obtained from natural sources has been widely investigated to treat trypanosomatids infections. Among these compounds, chalcones have been shown to have anti-parasitic and anti-inflammatory effects, being described as having a remarkable activity on trypanosomatids, especially in Leishmania species. Here, we evaluated the antiprotozoal activity of the chalcone derivative (NaF) on P. serpens promastigotes, while also assessing its mechanism of action. The results showed that treatment with the derivative NaF for 24 h promotes an important reduction in the parasite proliferation (IC50/24 h = 23.6 ± 4.6 µM). At IC50/24 h concentration, the compound induced an increase in reactive oxygen species (ROS) production and a shortening of the unique flagellum of the parasites. Electron microscopy evaluation reinforced the flagellar phenotype in treated promastigotes, and a dilated flagellar pocket was frequently observed. The treatment also promoted a prominent autophagic phenotype. An increased number of autophagosomes were detected, presenting different levels of cargo degradation, endoplasmic reticulum profiles surrounding different cellular structures, and the presence of concentric membranar structures inside the mitochondrion. Chalcone derivatives may present an opportunity to develop a treatment for the P. serpens infection, as they are easy to synthesize and are low in cost. In order to develop a new product, further studies are still necessary.

Insight into mitigation of corrosion behavior of novel chalcone derivative for AZ91 Mg alloy in saline solution: synthesis, characterization, electrochemical and adsorption studies

Magnesium is the lightest structural metallic element, and exhibited an important developmental potential due to the growing need for lightweight electronics and transportation (aerospace, automobile, etc.). A novel chalcone derivative 4-(3-(4-(4-((4-(4-(3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acryloyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)sulfonyl)phenyl)-5-methyl-1H 1,2,3-triazol-1-yl)-3-oxoprop-1-en-1-yl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (DMPO) was synthesized. The chemical structure of the newly synthesized DMPO was inferred from its spectral data (H1-NMR, C13-NMR, and FT-IR). Its structure was also affirmed by field emission scanning electron microscopy-energy dispersive X-ray (SEM-EDX), and thermal stability was studied by thermal gravimetric analysis (TGA-DTA). Then, its potency as a remarkable corrosion inhibition for AZ91 magnesium alloys in NaCl (3.5 wt%) solution was studied. Hydrogen evolution, potentiodynamic polarization, and electrochemical impedance spectroscopy (EIS) investigations were utilized to assess the impact of the newly synthesized chalcone derivative DMPO on the electrochemical performance of AZ91 Mg alloy in NaCl solution (3.5 wt%). SEM-EDX was used to evaluate the surface and elemental analysis of an AZ91 Mg alloy immersed in NaCl solution (3.5 wt%) with and without DMPO inhibitor. The obtained electrochemical evaluation revealed that DMPO functions as a high-performance, environmentally friendly AZ91 Mg alloy inhibitor in NaCl (3.5%) recording inhibition efficiency 93.7% at 100 ppm. Potentiodynamic polarization experiments revealed that the corrosion was inhibited due to the adsorption of inhibited molecules which follows the Langmuir adsorptive process. The findings also affirmed the development of protective film on Mg alloy surface. In electrochemical tests, it was discovered that DMPO molecules were mixed-type corrosion inhibitors.

Optimization of Spatial Arrangement and Optical Nonlinearity of Chalcone Crystals by Halogen Substituted Donor Groups

Controlling the molecular arrangement by introducing halogen element substituents is a very effective crystal design method. Therefore, four chalcone derivatives, EFDAN, ECDAN, EBDAN, and EIDAN, were synthesized by introducing F, Cl, Br, and I, respectively. The tunable crystals containing Cl and Br elements with appropriate size have a better spatial arrangement, which is conducive to the increase of nonlinearity. Theoretical calculations indicate that electron transfer from the amino group and the adjacent benzene ring to the conjugated bridge is the main contributor to the crystal nonlinearity. Meanwhile, all four crystals have higher transparency, greater thermal stability, and lower dielectric constant. This work realizes the control of crystal structure through the rational replacement of halogen elements and provides a feasible idea for the design of other organic nonlinear materials.

DFT and Molecular Docking Analysis of Newly Synthesized Compound (2E)-3-[3-(Benzyloxy) Phenyl]-1-(4’-Chlorophe-Nyl)- 2-Propen-1-One [Bpclpo

Background: The parent molecule in the skeleton of this chalcone is the benzyloxy phenyl, which is linked to the chlorophenylpropen at C-3. The hydrophobic phenyl groups are naturally resistant to oxidation and reduction. Antiviral, antimalarial, antibacterial, anti-inflammatory, anticancer, antioxidant, antitubercular, and anti-Alzheimer activities are among the many pharmacological properties of chalcone derivatives. As a result, chalcone-based compounds are investigated using molecular docking and molecular modelling calculations to determine their suitability for drug formulation. Aims: To synthesise (2E)-3-[3-(benzyloxy) phenyl]-1-(4’-chlorophenyl)-2-propen-1-one [BPClPO] and perform DFT and molecular docking analysis of the synthesized compound to better understand its medicinal properties. Objective: The characterization of BPClPO is investigated in this study using various approaches, including wavefunction analysis and spectral analysis, which are associated with quantum chemical calculations to investigate its medicinal properties. Methods: The Gaussian 09W programme was used to perform computational chemistry calculations. The BPClPO's molecular structure was optimised, and the vibrational frequencies, Natural Bond Orbital (NBO), Fukui function, electronic properties and Nuclear Magnetic Resonance (NMR) chemical shifts were calculated using the B3LYP/6-311G (d, p) as the basis set. The VMD user interface and Multiwfn (3.4.1) software were used to conduct topological analyses of the Electron Localization Function (ELF), Localized Orbital Locator (LOL) and Reduced Density Gradient (RDG). The binding sites of active cancer proteins were calculated using the auto dock and auto grid. Results: Theoretical reaction path investigation was done for BPClPO to detect reactions from the parent chemical to the synthesized compound. Theoretical bond lengths and bond angles are compared with XRD values. Theoretical values of vibrations caused by electron-rich and electrondeficient centres were investigated. The electronic spectra of λmax were examined under UV-Vis light and the electron absorbance spectrum was absorbance wavelength and oscillator strength compared to theoretical values. The electron-rich carbon atoms are de-shielded in NMR, resulting in stronger fields and chemical shifts. The Harmonic Oscillator Model of Aromaticity (HOMA)and the retain ability of aromaticity in the addition and removal of electrons are examined in the Nucleus Independent Chemical Shift (NICS) study. The stability of the compound was investigated using Thermo- Gravimetric analysis and Differential Scanning Calorimeter (TG/DSC) analysis. Four cancer proteins with the reactive site were studied in docking simulations. Conclusions: The NBO analysis determined the intramolecular charge transfer within the molecule of high stabilization transition from C34-C37 donor to C35-C39 acceptor of (22.31 Kcal/mol) (π→π*) due to phenyl transition belonging to Cl atom in the ring. In the solvent phase, UV-visible spectra reveal a prominent peak at 300 λmax, with an absorbance range of intensity of 0.6983. (a.u.). According to TG/DSC experiments, the molecule begins to break around 290-370°C, and total decomposition occurs at 300°C. The molecule was found to have a higher bioactivity than and was employed related more to medicinal properties mechanism(s) of action in drug docking investigations.

Antitumor Effect of Chalcone Derivatives against Human Prostate (LNCaP and PC-3), Cervix HPV-Positive (HeLa) and Lymphocyte (Jurkat) Cell Lines and Their Effect on Macrophage Functions

Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, the effect of chalcones 1-18 against the metabolic viability of cervical (HeLa) and prostate (PC-3 and LNCaP) tumor cell lines was tested, to compare the activity against solid and liquid tumor cells. Their effect was also evaluated on the Jurkat cell line. Chalcone 16 showed the highest inhibitory effect on the metabolic viability of the tested tumor cells and was selected for further studies. Recent antitumor therapies include compounds with the ability to influence immune cells on the tumor microenvironment, with immunotherapy being one actual goal in cancer treatment. Therefore, the effect of chalcone 16 on the expression of mTOR, HIF-1α, IL-1β, TNF-α, IL-10, and TGF-β, after THP-1 macrophage stimulation (none, LPS or IL-4), was evaluated. Chalcone 16 significantly increased the expression of mTORC1, IL-1β, TNF-α, and IL-10 of IL-4 stimulated macrophages (that induces an M2 phenotype). HIF-1α and TGF-β were not significantly affected. Chalcone 16 also decreased nitric oxide production by the RAW 264.7 murine macrophage cell line, this effect probably being due to an inhibition of iNOS expression. These results suggest that chalcone 16 may influence macrophage polarization, inducing the pro-tumoral M2 macrophages (IL-4 stimulated) to adopt a profile closer to the antitumor M1 profile.

Microwave assisted reaction, photophysical studies and antibacterial activities of simple sugar chalcone derivatives

Aldol condensation is adopted for the synthesis of sugar chalcone derivatives from b-C-glycosidic ketones with various aromatic aldehydes under basic condition with both conventional as well as microwave condition. Microwave assisted reaction gave an excellent yield. Products obtained were characterized using (1H, 13C) and elemental analysis. Sugar chalcone derivatives exhibited an excellent antibacterial activity.S

Synthesis, in-vitro antitubercular, antifungal activities and in silico molecular docking study of Chalcone derivatives from 1-(2'-Hydroxyphenyl)-3-(substituted-phenyl)-2-propenone.

Synthesis, in-vitro antitubercular, antifungal activities and in silico molecular docking study of Chalcone derivatives from 1-(2'-Hydroxyphenyl)-3-(substituted-phenyl)-2-propenone.

Ir(III)-Catalyzed Dual C-H Activation of 2-Aryl Phthalazinediones and 3-Aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxides for the Construction of Spiro-Fused Cyclic Frameworks.

An Ir(III)-catalyzed double C-H activation strategy has been developed for the synthesis of highly rigid spiro frameworks by means of ortho-functionalization of 2-aryl phthalazinediones and 2,3-diphenylcycloprop-2-en-1-ones using the Ir(III)/AgSbF6 catalytic system. Similarly, 3-aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxides undergo smooth cyclization with 2,3-diphenylcycloprop-2-en-1-ones to afford a diverse range of spiro compounds in good yields with excellent selectivity. Additionally, 2-arylindazoles provide the corresponding chalcone derivatives under similar reaction conditions.