Chalcone Analogues Research Articles

Novel chalcone analogs derived from 4-(benzyloxy)benzaldehyde

Abstract Eight chalcone analogs were prepared through an aldol condensation starting from 4-(benzyloxy)benzaldehyde and either less common acetophenones or a few selected heteroaryl methyl ketones. The reaction has been performed through the classical approach that employs an alkali as catalyst for five chalcone analogs, while a variant that uses piperidine as basic catalyst was employed for the other three chalcone analogs. The structure of the resulting enones has been established by NMR spectroscopy. Photoinduced dimerization of a selected benzyloxy-substituted chalcone analog under irradiation with UV light for periods of time ranging from 30 minutes to 24 h has also been monitored using NMR spectroscopy. Analysis of the results demonstrated the presence of the E isomer of the chalcone analog along with three regioisomeric cyclobutanes in the irradiated sample.

Synthesis and Characterization of 1-(1-naphthyl)-5-phenyl-2,4-pentadien-1-one from trans-cinnamaldehyde and 1-acetonaphthone

Chalcone analogues (1-(1-naphthyl)-5-phenyl-2,4-pentadiene-1-one) have been synthesized through an aldol condensation reaction between cinnamaldehyde and 1-acetylnaphthalene. The method used in this study is the stirrer method, with the reaction conducted at room temperature for 24 hours using a NaOH catalyst in H2O/ethanol (50%, v/v). The purity of the product was analyzed using thin-layer chromatography on silica gel plates with n-hexane: ethyl acetate (9:1) employed as the solvent. The resulting product obtained was 0.88 g with a yield of 61.97%. Structure Analysis and elucidation of the synthesized compounds were performed by measuring the vibrations of the functional groups using FTIR, LCMSMS analysis, and determining the 1H and 13C atoms by HNMR and CNMR analysis. The FTIR, LCMSMS, 1H, and 13C NMR analysis identified that the synthesized product as chalcone analogues, specifically 1-(1-naphthyl)-5-phenyl-2,4-pentadiene-1-one.

Fluoroindole chalcone analogues targeting the colchicine binding site of tubulin for colorectal oncotherapy

Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract with high morbidity and mortality. Our previous studies have demonstrated that indole-chalcone-based compounds targeting tubulin displayed potential cytotoxicity to CRC cells. Herein, three new series of derivatives were systematically designed and synthesized to explore their structure-activity relationship (SAR) against CRC based on prior research. Among them, a representative fluorine-containing analog (FC116) exerted superior efficacy on HCT116 (IC50 = 4.52 nM) and CT26 (IC50 = 18.69 nM) cell lines, and HCT116-xenograft mice with tumor growth inhibition rate of 65.96% (3 mg/kg). Of note, FC116 could also suppress the growth of organoid models (IC50 = 1.8–2.5 nM) and showed adenoma number inhibition rate of 76.25% at the dose of 3 mg/kg in APCmin/+ mice. In terms of mechanism, FC116 could induce endoplasmic reticulum (ER) stress to produce excess reactive oxygen species (ROS), leading to mitochondrial damage to promote the apoptosis of CRC cells by targeting microtubules. Our results support that indole-chalcone compounds are promising tubulin inhibitors and highlight the potential of FC116 to combat CRC.

Chalcone and pyrazoline derivatives of dehydroacetic acid as digestive enzyme effectors and In silico studies

In the present work, chalcone and pyrazoline derivatives of dehydroacetic acid have been synthesized using methanol as solvent. All the synthesized compounds were characterized by 1HNMR , IR and melting point. The DHA-derivatives were evaluated for their potential towards digestive enzymes. Interactions between the synthesized compounds and the active sites of gastric enzymes like amylase, lipase, trypsin and pepsin have also been studied by using Autodock Vina. In vitro evaluation of the activity of the title compounds for the digestive enzymes were also carried out. We found that the chalcone analogs activate lipase and amylase whereas the pyrazolines inhibit the enzymes. For trypsin also, chalcones and pyrazolines showed acted differently. Chalcones and pyrazolines, both exhibited anti-pepsin activities. Furthermore, the binding affinities for reference systems (amylase, lipase, trypsin, and pepsin) were found to be 6.1, 6.5, 8.1, and 9.5 respectively. Similar results were also collected for interactions of enzymes with the synthesized compounds 3 and 4 with binding affinities ranging from 6.1 to 7.4, 6.5 to 10.9, 6.4 to 8.1, and 7.3 to 9.5, respectively. Keeping in mind the necessary metabolization of the synthesized drug candidates, the safety profile was checked, using the online tool Vnn- ADMET.

Structural basis for fluorine substitution on a new naphthalene–chalcone analog

AbstractFluorinated chalcones are organic compounds with diverse biological activities and are of interest for drug development due to their improved properties, such as lipophilicity, bioavailability, and metabolic stability. Therefore, the correlation between structure and properties is fundamental to discover the potential use on pharmaceutical and technological applications. In this sense, we synthesized and characterized a novel fluorinated chalcone (E)-1-(4-fluorophenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (FCH), and compared its supramolecular arrangement and topological analysis with a chalcone (E)-1-(4-hydroxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (HCH). The molecular electrostatic potential, QTAIM, and frontier molecular orbitals of both chalcones were investigated using the M06-2X/6-311++G(d,p) level of theory. Our findings show that the FCH exhibits a herringbone packing with intermolecular interactions of C–H⋯F and C–H⋯π, while the HCH assumes a staircase packing coordinated by O–H⋯O and π⋯π intermolecular interactions. Furthermore, the electrostatic potential analysis shows that FCH is susceptible to electrophilic attack, while HCH is susceptible to nucleophilic attack. Finally, the structural basis analysis for both chalcones indicated that FCH has a higher lipophilicity than HCH due to the stronger hydrogen bond of HCH with water.

(E)-2-Benzylidenecyclanones: Part XVIII Study the Possible Link between Glutathione Reactivity and Cancer Cell Cytotoxic Effects of Some Cyclic Chalcone Analogs A Comparison of the Reactivity of the Open-Chain and the Seven-Membered Homologs.

Non-enzymatic thiol addition into the α,β-unsaturated carbonyl system is associated with several biological effects. In vivo, the reactions can form small-molecule thiol (e.g., glutathione) or protein thiol adducts. The reaction of two synthetic (4'-methyl- and 4'-methoxy substituted) cyclic chalcone analogs with reduced glutathione (GSH) and N-acetylcysteine (NAC) was studied by (high-pressure liquid chromatography-ultraviolet spectroscopy) HPLC-UV method. The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The structure of the formed adducts was confirmed by (high-pressure liquid chromatography-mass spectrometry) HPLC-MS. The incubations were performed under three different pH conditions (pH 3.2/3.7, 6.3/6.8, and 8.0/7.4). The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended on the substitution and the pH. The frontier molecular orbitals and the Fukui function were carried out to investigate the effects on open-chain and seven-membered cyclic analogs. Furthermore, machine learning protocols were used to provide more insights into physicochemical properties and to support the different thiol-reactivity. HPLC analysis indicated diastereoselectivity of the reactions. The observed reactivities do not directly relate to the different in vitro cancer cell cytotoxicity of the compounds.

Structure-Activity Relationship of Chalcones Against Influenza H1N1: Quantum Chemical Chemiometric Evaluation

It is well known that the influenza virus causes annual epidemics provoking thousands of deaths annually. Although there is already a vaccine for influenza, the virus mutates and acquires seasonal resistance to medicines. Therefore, due to the urgent need for new compounds with the inhibitory potential of the virus, many studies have presented several substances to avoid inhibitory activity to the enzyme responsible for the release of the virus into the respiratory tract. Here, a demonstrative calculation of theoretical and chemometric was performed studies of a set of eight chalcones with potential inhibition of the neuraminidase enzyme. It was performed calculations of electronic structure to determine the geometric and electronic parameters using the theory of density functional at M06-2X/6-311++G(d,p) level calculation. The relationship between the structure of the compounds and their activity against the H1N1 influenza virus was accessed by principal component analysis and hierarchical cluster analysis. We hope that our results can help to explain the activities of chalcone analogs to model new compounds with influenza virus activity.

An ongoing journey of chalcone analogues as single and multi-target ligands in the field of Alzheimer's disease: A review with structural aspects.

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder with progressive dementia and cognitive impairment. AD poses severe health challenge in elderly people and become one of the leading causes of death worldwide. It possesses complex pathophysiology with several hypotheses (cholinergic hypothesis, amyloid hypothesis, tau hypothesis, oxidative stress, mitochondrial dysfunction etc.). Several attempts have been made for the management of multifactorial AD. Acetylcholinesterase is the only target has been widely explored in the management of AD to the date. The current review set forth the chalcone based natural, semi-synthetic and synthetic compounds in the search of potential anti-Alzheimer's agents. The main highlights of current review emphasizes on chalcone target different enzymes and pathways like Acetylcholinesterase, β-secretase (BACE1), tau proteins, MAO, free radicals, Advanced glycation end Products (AGEs) etc. and their structure activity relationships contributing in the inhibition of above mentioned various targets of AD.

Signal transduction of the insulin secretion induced by the chalcone analogue, (E)-3-(phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, and its role in glucose and lipid metabolism

A chalcone analogue, (E)-3-(phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (DMU 101), was synthesized using classic base catalysis and Claisen-Schmidt condensation, and then screened for its antidiabetic properties. The compound's effects on glucose and lipid metabolism were assayed in rats that were treated acutely and for a short time to elucidate its mechanism of action, evaluating glucose tolerance and lactate dehydrogenase activity in response to chalcone analogue administration. The chalcone's in vitro and ex vivo effects on glycogen, glucose, lipid and lipolysis were also investigated, as well as the mechanism by which it induces 45Ca2+ influx-mediated insulin secretion. The analogue (10 mg/kg) diminished glycemia, without inducing acute cell damage, increased glycogen content in the skeletal muscle and reduced serum triacylglycerol and total cholesterol, but did not alter high-density lipoprotein or low-density lipoprotein. Chalcone (10 μM) stimulated glucose uptake in the soleus muscle and did not modulate in vitro or ex vivo lipolysis. This analogue also increased insulin secretion by triggering calcium influx and blocking ATP-sensitive K+ channels and voltage-dependent calcium channels. However, it also modulated stored calcium via sarco/endoplasmic reticulum calcium ATPase (SERCA) and ryanodine receptor (RYR) activity. These findings indicate that this chalcone may induce cellular repolarization via a mechanism mediated by calcium-dependent potassium channels.

Novel Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis.

Chalcones are interesting anticancer drug candidates which have attracted much interest due to their unique structure and their extensive biological activity. Various functional modifications in chalcones have been reported, along with their pharmacological properties. In the current study, novel chalcone derivatives with the chemical base of tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-arylprop-2-en-1-one were synthesized, and the structure of their molecules was confirmed through NMR spectroscopy. The antitumor activity of these newly synthesized chalcone derivatives was tested on mouse (Luc-4T1) and human (MDA-MB-231) breast cancer cell lines. The antiproliferative effect was evaluated through SRB screening and the MTT assay after 48 h of treatment at different concentrations. Interestingly, among the tested chalcone derivatives, chalcone analogues with a methoxy group were found to have significant anticancer activity and displayed gradient-dependent inhibition against breast cancer cell proliferation. The anticancer properties of these unique analogues were examined further by cytometric analysis of the cell cycle, quantitative PCR, and the caspases-Glo 3/7 assay. Chalcone methoxy derivatives showed the capability of cell cycle arrest and increased Bax/Bcl2 mRNA ratios as well as caspases 3/7 activity. The molecular docking analysis suggests that these chalcone methoxy derivatives may inhibit anti-apoptotic proteins, particularly cIAP1, BCL2, and EGFRK proteins. In conclusion, our findings confirm that chalcone methoxy derivatives could be considered to be potent drug candidates against breast cancer.

Synthesis, biological evaluation and molecular docking study of oxindole based chalcone analogues as potent anti-Alzheimer agents

With the goal of developing potential cholinesterase pharmaco-therapeutics, a new class of thirty analogs oxindole-based chalcone were synthesized by reacting nitro substituted oxindole with various substituted benzaldehyde in the presence of a base in ethanol under reflux conditions. All the synthesized analogs were characterized through different spectroscopic and spectrometric techniques such as 1H NMR, 13C NMR, HREI-MS and tested for their ability to inhibit acetylcholinesterase and butyrylcholinesterase that exhibited a variable degree of inhibitory potential with IC50 values ranging from 0.20 ± 0.010 to 11.20 ± 0.30 µM for acetylcholinesterase and 0.30 ± 0.010 μM to 13.20 ± 0.30 µM for butyrylcholinesterase as compared to the standard drug donepezil (IC50 value 2.16 ± 0.12 and 4.5 ± 0.11 µM respectively). Analog 22 is the most potent among the series having an IC50 value 0.10 ± 0.010 µM for acetylcholinesterase and 0.30 ± 0.010 µM for butyrylcholinesterase. Structure-activity relationship of this series has been established which is mainly based on the position and nature of the substituent on the phenyl ring. Molecular docking study was also carried out to discover the binding affinity of active derivatives with enzymes.

Solvent‐free, microwave‐assisted, solid‐catalyzed synthesis and α‐Glucosidase inhibition of chalcones

AbstractA series of chalcone analogues were synthesized using Claisen‐Schmidt condensation and assayed for in vitro inhibitory activity against α‐glucosidase. The synthesis involved in solvent‐free reaction conditions including NaOH‐catalyzed grinding or microwave irradiation in the presence of a clay‐based catalyst. Hydroxychalcones and 2′‐hydroxychalcones were not isolated when using grinding method, while the microwave‐assisted, clay‐catalyzed synthesis gave these desired products. In addition, flavanones, cyclization products from 2′‐hydroxychalcones were formed in both methods. Flavanones 3g and 3s were the most active toward α‐glucosidase. Compound 3g exhibited an effect (IC50 = 10.4±0.2 μM) close to genistein (IC50 = 7.8±0.3 μM), a known α‐glucosidase inhibitor. Structure‐activity relationship analysis indicated that the 4‐hydroxy substituted motif in ring B of chalcones seems to be an important factor on the α‐glucosidase inhibitory activity. Furthermore, the 3,4‐difluorinated chalcones also exhibited activities as compared to mono‐fluorinated derivatives, suggesting that the more fluorination in ring B may be crucial for the inhibitory activity.

Synthesis and cytotoxic activity of novel chalcone analogues with pyridine-2,4(1<i>H</i>,3<i>H</i>)-dione fragment

New heterocyclic chalcone analogues with pyridine-2,4(1 Н ,3 Н )-dione fragment were synthesized by the condensation reaction of 3-acetylpyridine-2,4(1 H ,3 H )-diones with different aromatic aldehydes in pyridine in the presence of a catalytic amount of piperidine and acetic acid. Structures of the synthesized compounds were confirmed by of IR, 1H, 13C NMR spectroscopy methods and two-dimensional NMR spectroscopy methods and elemental analysis data. Cytotoxic activity of the series of obtained compounds was investigated in vitro against human cell lines of breast cancer (MCF-7) and liver cancer (Hep G2).

Synthesis and Cytotoxic Activity of Novel Chalcone Analogues with Pyridine-2,4(1Н,3Н)-dione Fragment

Synthesis and Cytotoxic Activity of Novel Chalcone Analogues with Pyridine-2,4(1Н,3Н)-dione Fragment

Synthesis and biological evaluation of benzamide-chalcone hybrids as potential c-Metkinase and COX-2 inhibitors.

c-Met kinase and cyclooxygenase 2 (COX-2) enzymes are two significant targets in tumor progression. Chalcone and benzamide moieties were combined using molecular hybridization to assess their potential as c-Met kinase and COX-2 inhibitors. 4-Methylbenzamide and 4-chlorobenzamide chalcone analogs were synthesized, characterized, and evaluated for antiproliferative activity on Michigan Cancer Foundation-7 (MCF-7), HT-29, MDA-MB-231, COLO-205, and A549 cell lines by sulforhodamine-B stain (SRB) assay. Following the SRB assay, compounds were evaluated for their c-Met kinase and COX-2 inhibitory potential. All compounds inhibited COX-2 with half-maximal inhibitory concentration (IC50 ) <10 µM. Compounds 7h, 7i, 7j, 8f, and 8j inhibited c-Met with IC50 <10 µM. Compound 7h was evaluated for its long-term antiproliferative and anti-migratory effects by colony formation and wound healing assay. It exerted these effects in a concentration-dependent manner. Compounds 7j and 8j were further evaluated for in vitro antiangiogenic effects. Compound 7j exhibited moderate antiangiogenic effect while compound 8j exhibited strong effect. Compounds 7h, 7i, 7j, 8f, and 8j were evaluated for the serum protein binding, using the in vitro bovine serum albumin binding assay. The results indicated that the tested compounds bind to bovine serum albumin (BSA) and can be further explored by other studies.

Homotaurine and Curcumin Analogues as Potential Anti-Amyloidogenic Agents

Currently, there is neither a cure for Alzheimer’s disease (AD) nor a way to stop the progressive death of neuronal cells associated with this devastating aliment. To date, there are only medications that temporarily slow its progression, and do not interfere with its pathogenesis. One of the hallmarks of AD is the presence of amyloid-beta plaques derived from the metabolism of the amyloid precursor protein, via the cleavage by beta followed by gamma secretase. Homotaurine, a naturally occurring small molecule found in some seaweeds, and curcumin, a phenolic antioxidant found in Curcuma longa, have been extensively studied as potential compounds to prevent/reverse plaque formation. In this study, libraries of chalcones and extended chalcones based on curcumin, as well as aminopropylsulfonamides inspired by homotaurine, were synthesized. Using fluorescence spectroscopic analysis with Thioflavin T, the anti-aggregation effect on Aβ42 was determined. A select number of newly synthesized chalcones and extended chalcone analogs were revealed to be potential anti-amyloidogenic agents. These were further evaluated with regard to their neurotoxicity/neuroprotection. The extended chalcone analogs that displayed the most anti-aggregation effect on Aβ42 were further analyzed in an MTT assay. Although none of the compounds alone displayed any neurotoxicity, none were able to provide neuroprotection against Aβ42.

Design, synthesis, and enzyme inhibition evaluation of some novel Mono- and Di-O-β-D-Glycopyranosyl Chalcone analogues with molecular docking studies.

In this study, some novel mono- and di-O-β-D-glycopyranosyl chalcone analogs were designed, synthesized, and characterized. The chalcone derivatives were synthesized with good yields by base-catalyzed Claisen-Schmidt condensation in EtOH solution. Then these chalcones were reacted with TAGBr (2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide) in dry acetone under the anhydrous condition at 0-5 °C. Deacylated was carried out by the Zemplen's method with NaOCH3 in dry methanol results in substituted chalcone-O-glycosides (mono- and di-O-β-D-glycopyranosyl chalcone analogs). The chemical structures of all synthesized compounds were elucidated based on IR, NMR spectral data, and mass spectrometry. Further, the compounds (7a-c, 8a-c, 12a-c, 16a-c, and 17a-c) were tested for their enzyme inhibition activity against α-glycosidase, tyrosinase, and AChE with in vitro and in silico analysis. Amongst them, compounds 12a-c, 16a-c, and 17a-c displayed moderate or less enzyme inhibition activity against α-glycosidase while other compounds 7a-c and 8a-c) were not active. Remarkably interesting enzyme inhibition effects, with IC50 values below 30.59 ± 0.30 μM were recorded with 7c (IC50=11.07 ± 0.55 μM) against tyrosinase.

Synthesis of novel pyrazolic analogues of chalcones as potential antibacterial and antifungal agents

The present includes the synthesis of pyrazoline derivatives using chalcones and phenyl hydrazine in the presence of ethanol. It also reveals that 2-pyrazoline complexes are physiologically active and may be used in a variety of therapeutic functions. FT-IR, 1H-NMR, 13C-NMR, LC-MS, and elemental analyses were used to characterise newly synthesised phenyl-pyrazoline derivatives. The antimicrobial activity of the synthesised compounds was assessed using the agar well diffusion assay and the Minimum Inhibition Concentration (MIC). Compounds 4b, 4f, and 4h have exhibited remarkable antibiotic action against bacterial strains such as Staphylococcus aureus, Bacillus subtilis, Salmonella. Typhi, and Shigella sp. On the other hand, compound 4h had significant antifungal activity against Candida albicans and Aspergillus fusarium and was a highly promising agent when compared to standard nystatin.

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.

Synthesis of selenophene-based chalcone analogs and assessment of their biological activity as anticancer agents.

Selenium is an essential micronutrient that is beneficial to human health. Selenium-containing drugs have been developed as antioxidants, anti-inflammatory, and anticancer agents. However, the synthesis of selenium-containing chalcones has not been fully explored. Therefore, we report the synthesis of novel selenophene-based chalcone analogs and reveal their biological activities as anticancer agents. Among the seven synthesized molecules, compounds 6, 8, and 10 exhibited anticancer activity with IC50 values of 19.98 ± 3.38, 38.23 ± 3.30, and 46.95 ± 5.68 μM, respectively, against human colorectal adenocarcinoma (HT-29) cells. Clonogenic assays and Western blot analysis tests further confirmed that compound 6 effectively induced apoptosis in HT-29 cells through mitochondrial- and caspase-3-dependent pathways.