Heterocyclic Chalcone Research Articles

Synthesis and Antiproliferative Effect of 3,4,5-Trimethoxylated Chalcones on Colorectal and Prostatic Cancer Cells.

In the context of designing innovative anticancer agents, the synthesis of a series of chalcones bearing a 3,4,5-trimethoxylated A ring and a variety of B rings, including phenols and original heterocycles such as chromones, was conducted. For this end, Claisen-Schmidt condensation was performed in basic or acidic conditions between the common starting material 3,4,5-trimethoxyacetophenone and appropriate aldehydes; this allowed the recovery of fifteen chalcones in moderate-good yields. The synthesized compounds were screened for their antiproliferative activity against colorectal and prostatic cancer cells, using a colorimetric MTT assay. Among the new chromonyl series, chalcone 13 demonstrates an interesting antiproliferative effect, with IC50 values in the range of 2.6-5.1 µM at 48 h. Then, our study evidenced that indolyl chalcone 10 exhibits excellent activity towards the selected cell lines (with IC50 less than 50 nM). This compound has already been described and has been shown to be a potent anticancer agent against other cancer cell lines. Our investigations highlighted apoptosis induction, through several pro-apoptotic markers, of these two heterocyclic chalcones. Considering phenolic chalcones, compounds 2 and 8 were found to be the most active against cell proliferation, exerting their effect by inducing the depolymerization of cell microtubules. The most promising compounds in this series will be selected for application in a strategy of vectorization by either active or passive targeting.

DFT and Molecular Docking Studies of Two Heterocyclic Chalcone Derivatives

AbstractThe newly synthesized heterocyclic chalcone derivatives 3‐(5‐methyl furan‐2‐yl)‐1‐phenyl prop‐2‐en‐1‐one (MFPP) and 1‐(4‐chlorophenyl)‐3‐(5‐methylfuran‐2‐yl) prop‐2‐en‐1‐one (CPMFP) are recently being recognized for their cytotoxicity and anti‐plant pathogenic fungi activities. The quantum chemical calculations for the above‐mentioned compounds have been performed using B3LYP/6‐311++G (d,p) level of theory to get perceptive information about the molecules. After verifying the drug‐likeness of the title compounds, chemical reactivity has been analyzed through frontier molecular orbital analysis. The quantitative and qualitative description of activity at various sites has been investigated through conceptual DFT approach and molecular electrostatic potential surface analyses, respectively. In‐silico bioactivity studies of these compounds with the main protease (6LU7) present in SARS‐CoV‐2 causing COVID‐19, human breast cancer cell line (6VJ3), plant pathogenic fungi R. Solani (4G9N), and G. Zeae (2L2F) have exposed a reasonable binding affinity and inhibition constant with all these targets.

Synthesis of Novel Heterocyclic Ferrocenyl Chalcones and Their Biological Evaluation.

Breast cancer is currently the most commonly diagnosed cancer, with 287,850 new cases estimated for 2022 as reported by the American Cancer Society. Therefore, finding an effective treatment for this disease is imperative. Chalcones are α,β-unsaturated systems found in nature. These compounds have shown a wide array of biological activities, making them popular synthetic targets. Chalcones consist of two aromatic substituents connected by an enone bridge; this arrangement allows for a large number of derivatives. Given the biological relevance of these compounds, novel ferrocene-heterocycle-containing chalcones were synthesized and characterized based on a hybrid drug design approach. These heterocycles included thiophene, pyrimidine, thiazolyl, and indole groups. Fourteen novel heterocyclic ferrocenyl chalcones were synthesized and characterized. Herein, we also report their cytotoxicity against triple-negative breast cancer cell lines MDA-MB-231 and 4T1 and the noncancer lung cell line MRC-5. System 3 ferrocenyl chalcones displayed superior anticancer properties compared to their system 1 analogues. System 3 chalcones bearing five-membered heterocyclic substituents (thiophene, pyrazole, pyrrole, and pyrimidine) were the most active toward the MDA-MB-231 cancer cell line with IC50 values from 6.59 to 12.51 μM. Cytotoxicity of the evaluated compounds in the 4T1 cell line exhibited IC50 values from 13.23 to 213.7 μM. System 3 pyrazole chalcone had consistent toxicity toward both cell lines (IC50 ∼ 13 μM) as well as promising selectivity relative to the noncancer MRC-5 control. Antioxidant activity was also evaluated, where, contrary to anticancer capabilities, system 1 ferrocenyl chalcones were superior to their system 3 analogues. Antioxidant activity comparable to that of ascorbic acid was observed for thiophene-bearing ferrocenyl chalcone with EC50 = 31 μM.

Heterocyclic chalcone (E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-3-(thiophen-2-yl) prop-2-en-1-one derived from a natural product with antinociceptive, anti-inflammatory, and hypoglycemic effect in adult zebrafish.

The online version contains supplementary material available at 10.1007/s13205-023-03696-8.

Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives.

This study involved the design and synthesis of 21 new nitrogen-containing heterocyclic chalcone derivatives utilizing the active substructure splicing principle, with glycyrrhiza chalcone serving as the lead compound. The targets of these derivatives were VEGFR-2 and P-gp, and their efficacy against cervical cancer was evaluated. Following preliminary conformational analysis, compound 6f ((E)-1-(2-hydroxy-5-((4-hydroxypiperidin-1-yl)methyl)-4-methoxyphenyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)prop-2-en-1-one) exhibited significant antiproliferative activity against human cervical cancer cells (HeLa and SiHa) with IC50 values of 6.52 ± 0.42 and 7.88 ± 0.52 μM, respectively, when compared to other compounds and positive control drugs. Additionally, this compound demonstrated lower toxicity towards human normal cervical epithelial cells (H8). Subsequent investigations have demonstrated that 6f exerts an inhibitory impact on VEGFR-2, as evidenced by its ability to impede the phosphorylation of p-VEGFR-2, p-PI3K, and p-Akt proteins in HeLa cells. This, in turn, results in the suppression of cell proliferation and the induction of both early and late apoptosis in a concentration-dependent manner. Furthermore, 6f significantly curtails the invasion and migration of HeLa cells. In addition, 6f had an IC50 of 7.74 ± 0.36 μM against human cervical cancer cisplatin-resistant HeLa/DDP cells and a resistance index (RI) of 1.19, compared to 7.36 for cisplatin HeLa cells. The combination of 6f and cisplatin resulted in a significant reduction in cisplatin resistance in HeLa/DDP cells. Molecular docking analyses revealed that 6f exhibited binding free energies of -9.074 and -9.823 kcal·mol-1 to VEGFR-2 and P-gp targets, respectively, and formed hydrogen bonding forces. These findings suggest that 6f has potential as an anti-cervical cancer agent and may reverse cisplatin-resistant activity in cervical cancer. The introduction of the 4-hydroxy piperidine and 4-methyl piperidine rings may contribute to its efficacy, and its mechanism of action may involve dual inhibition of VEGFR-2 and P-gp targets.

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).

Heterocyclic chalcone derivatives with D-π-A framing modulated electronic, linear and nonlinear optical properties as effective candidates for nonlinear optical applications

Polarizability and hyperpolarizability values from the theoretical studies provided evidence that the material can be employed as an efficient nonlinear optical (NLO) material. The z-scan analysis reveals a good value for third order susceptibilities (χ3) in order of 10−6 esu and the optical limiting behavior shows a low optical limiting threshold, indicating suitability for nonlinear optical applications. Quantum chemical calculations give additional information on molecular structures, frontier orbitals, and global reactivity indices, allowing for a deeper understanding of the chalcone's electronic structure and properties. NBO computation revealed that extended hyperconjugation and strong intermolecular interactions are important for their structural stability as well as their contribution to NLO responses. Large dipole moment values, small HOMO-LUMO gap and Molecular Electrostatic Potential (MEP) surface analysis are evidence of intermolecular charge transfer (ICT) occurring within the molecules. Based on our experimental and theoretical results, we can conclude that the compounds under consideration have potential in NLO applications such as optical limiting devices.

SUBSTITUTED HETEROCYCLIC CHALCONES: ELECTROCHEMICAL, SPECTROSCOPIC AND THEORETICAL STUDY

We have studied the electronic and electrochemical properties of seven substituted heterocyclic chalcones (CHL 1-6) wich are functionalized with 2-thienyl groups. The phenyl ring of the chalcone scaffold has been substituted in orto or para position with electron donnor and acceptor groups (-F, -NO2, -CH3O). The electrochemical features were analyzed by cyclic voltammetry; irreversible processes were observed and attributed to the oxidation and reduction of the 2-thienyl group and the carbonyl group of the chalcone, respectively. DFT calculations were made to gain more in-depth understanding of their electronic properties. Relatively high HOMO level and low LUMO values were calculated, Eg values computed varies between 3.0-3.29 eV. These values enable us to postulate that these type of compounds are suitable building blocks to fabricate optoelectronic devices.

Synthesis, Biological Activity and Molecular Docking Studies of Heterocyclic Chalcones.

Nineteen heterocyclic chalcones were synthesized from 4-acetyl-5-methylquinolylpyrazole and heteroaryl (imidazole, pyrazole, thiophene, indole and triazole) aldehydes and were screened in vitro using four tumor cell lines for their cytotoxic capability and for antimicrobial activity. The chalcone 5b exhibited the highest activity with IC50 values 2.14 μM against colon (HCT-116) and 5.0 μM, against prostate (PC-3) cancer cell lines and also displayed good activity against fungal strain (A. niger) with MIC value 9.1 μM. The chalcones 5q and 5p displayed good activity against bacterial strains (S. aureus) having MIC value 2.6 μM and fungal strain (C. albicans) having MIC value 5.4 μM, respectively. The molecular docking outcome revealed that the synthesized heterocyclic chalcones demonstrated hydrogen bond, hydrophobic and electrostatic interactions with their respective biochemical targets.

Synthesis and Characterization of Novel Heterocyclic Chalcones from 1-Phenyl-1H-pyrazol-3-ol.

An efficient synthetic route to construct diverse pyrazole-based chalcones from 1-phenyl-1H-pyrazol-3-ols bearing a formyl or acetyl group on the C4 position of pyrazole ring, employing a base-catalysed Claisen–Schmidt condensation reaction, is described. Isomeric chalcones were further reacted with N-hydroxy-4-toluenesulfonamide and regioselective formation of 3,5-disubstituted 1,2-oxazoles was established. The novel pyrazole-chalcones and 1,2-oxazoles were characterized by an in-depth analysis of NMR spectral data, which were obtained through a combination of standard and advanced NMR spectroscopy techniques.

Nonlinear Optical Behavior Due to Charge Transfer within Selected Heterocyclic Anthracenyl Chalcones under Continuous Wave Laser Excitation

Three new heterocyclic-chalcone (HC) derivatives consisting of the π-conjugated system attached to anthracene moiety were proposed for nonlinear optical properties and optical limiting application. The NLO behavior is confirmed through obtained χ3 by Z-scan method. The closed aperture z-scan showed the HC possesses a self-defocusing effect with a negative nonlinear refractive index, n 2 ∼ 10−8 cm/W, with a magnitude of real part of the third-order nonlinear optical susceptibilities, Re χ( 3 ) of the order of 10−7 esu. Open Z-scan results showed that the HC samples demonstrate a reverse saturable absorption (RSA), β ∼ 10−4 cm/W, corresponding to large imaginary parts, Im χ( 3 ) in the order of 10−6 esu. Overall, the Z-scan analysis unveils an excellent value of χ3 in order of 10−6 which indicates good nonlinear material under 532 nm continuous wave laser. The optical limiting study reveals that AC exhibit a strong limiting behavior with action beginning from 0.8 KW/cm2, and seems to be promising optical limiting candidates for future optoelectronic applications. Through B3LYP/6-311G++d,p level of theory Density Functional Theory (DFT), Global Reactivity, Natural Bond Orbital (NBO), and Natural Population were calculated and investigated. Delocalization and hyperconjugation interactions, intramolecular charge transfers, and stabilization energies were discovered using NBO and NPA. The comprehensive studies of Hirshfeld surface (HS) and fingerprint plots (FP) calculations were done in order to evaluate the nature of intermolecular interactions in the compounds. The inclusion of a strong donor and the π-conjugated system improved charge transfer, chemical stability, and optoelectronic properties of the anthracene-heterocyclic chalcone derivatives. As a result, the present work realizes the potential of designed derivatives that can be used in NLO applications.

Design, Synthesis and Molecular Docking Study of N-Heterocyclic Chalcone Derivatives as an Anti-cancer Agents

The Claisen-Schmidt condensation of 4-(aryl)-aminobenzaldehyde and 2-hydroxyacetophenone resulted in a new series of heterocyclic chalcone (4a-4g) derivatives. Nucleophilic aromatic substitution (SNAr) of 4-fluorobenzaldehyde with heterocycle amines by ultrasonication in the presence of a base and polar aprotic solvent yielde 4-(aryl)-aminobenzaldehydes. Spectral investigations were used to establish the structures of synthesized compounds. The in vitro anti-cancer activity of the synthesized derivative was evaluated against MCF-7 (breast cancer) cells by SRB assay. Compounds 4c, 4b, and 4c have a high affinity for the ER receptor binding site, whereas compounds 4c and 4g have a moderate affinity for the VEGER-2 receptor. The GI50 value of 4c ((E)-1-(2-hydroxyphenyl)-3-(4-(4-methylpiperazin-1-yl)-phenyl) prop-2-en-1-one) was 44.6 uM, while the GI50 value of all other derivatives was greater than 80 uM. These findings lay the groundwork for additional research into the combination's potential uses in cancer therapy.

Synthesis of Heterocyclic Pyridine-Based Chalcones with Dimeric Structure

Three new heterocyclic chalcones containing pyridine moiety were synthesized and their chemical structures were determined via IR, 1H NMR and 13C NMR spectroscopy. General name of these compounds are α,ω-bis{3-(pyridin-3-yl)-1-(phenyl-4-oxy)prop-2-en-1-one}alkanes. The chalcones are dimers having a symmetrical structure and they can be differed by the alkyl spacer length (CnH2n, where n = 8, 10 or 12). Differential scanning calorimetry (DSC) technique was employed to study their phase transition behaviors. DSC thermograms displayed direct isotropization and recrystallization during heating and cooling processes, respectively. The crystal phase turned into isotropic phase without exhibiting any mesophase. Influence of structure-liquid crystalline property relationships of the symmetrical dimers was examined in order to explain the reasons for the non-liquid crystalline properties in the current chalcones.

Microwave‐Assisted Synthesis, Antimicrobial Activities and Molecular Docking of Methoxycarboxylated Chalcone Derived Pyrazoline and Pyrazole Derivatives

AbstractThe synthesis of effective antimicrobial therapeutics has become a challenge due to the occurrence of genetic mutations in microbes that reduced the efficiency of drugs. A new series of heterocyclic chalcone derivatives (1 a‐g, 2 a‐g, 3 a‐g, 4 a‐g) were designed with 52.64‐93.69 % yield under microwave and scrutinized for their antimicrobial activities on Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) via turbidimetric and disc diffusion method. Carboxylated pyrazoline derivatives (3 a‐g) gave strong interaction potency with the zone inhibition of 12–16 mm compared to the reference drug of ampicillin (11 mm). Among all synthesized compounds, phenyl carboxyl pyrazoline (3 d) gave the highest antimicrobial activity with inhibition zone 16 mm compared to other carboxylated chalcone derivatives (1 a‐g) (6‐11 mm) and phenyl carboxylated pyrazole derivatives (4 a‐g) (8‐13 mm) against S. aureus bacteria. The molecular docking analysis of compounds (1 d), (3 d), and (4 e) exhibited the binding affinity −7.4 kcal/mol, −7.7 kcal/mol, −7.6 kcal/mol respectively, which significantly conclude the pyrazoline derivatives have better antimicrobial activity than chalcone and pyrazole derivatives. This research on effective and safe drug designing is beneficial for the medicinal field and pharmaceutical industry.

Multi-Step Synthesis, Photophysical and Physicochemical Properties of Novel Push- π -Pull AADC Chromophores

Coumarin based heterocyclic chalcone (E)-3-(3-(1-allyl-1H-indol-3-yl) acryloyl)-7-(diethylamino)-2H-chromen-2-one (AADC) was synthesized by the multi-steps synthesis. The structure of the AADC was established by the spectroscopic technics and purity of the AADC was confirmed by the elemental analysis. Physicochemical parameters of the AADC in ten different solvents such as molar absorption coefficient, transition dipole moments, stokes shift, oscillator strength and fluorescence quantum yield were calculated. Interaction of the AADC chromophore with cationic CATB and anionic SDS surfactants were determined by using the fluorescence spectroscopy techniques. It was observed that band fluorescence spectrum intensity increases with increasing the concentration of the surfactants. This suggests that strong interaction occurs between AADC with surfactants and this interaction arise from electrostatic forces. So, AADC chromophore could be used as analysis to define the CMC of the surfactants.

Synthesis, biological activities of chalcones and novel 4-acetylpyridine oximes, molecular docking of the synthesized products as acetylcholinesterase ligands

Heterocyclic chalcones were synthesized by reaction of 4-acetylpyridine with the corresponding aromatic aldehydes under Claisen Schmidt conditions. These chalcones were used as starting material for the synthesis of oximes in the presence of hydroxylamine hydrochloride. The structures of the synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and ESI-MS, HRMS spectral analyses. All the synthesized compounds were evaluated for their antioxidant activity by DPPH• method and their in vitro antimicrobial activity by disk diffusion method against two Gram-negative bacteria, one Gram-positive bacteria and two fungal strains (C. albicans and A. niger). The results showed that the synthesized compounds did not display significant antioxidant activity. However, compounds 3b, 3d, 3f, 3h, 3i showed excellent antibacterial activity better than the standard drug against the bacterial strain S. aureus (ATCC 25923). The two compounds 3c, 3d proved very active against the fungal strain A. niger (MIC= 7.81 µg/ mL, 15.62 µg/mL respectively) while the antifungal drug used as reference (Fluconazole) was inactive. Molecular docking and molecular dynamics results revealed that the synthesized compounds, 4e, 4c, and 5j, were involved in a large number of favorable interactions with the active site residues of the acetylcholinesterase protein, which can stabilize the ligands in the active site and increase their affinities.

Multi-step Synthesis, Characterization and Photophysical Investigation of Novel Biologically Active Heterocyclic Chalcone (AECO).

Novel alkylated heterocyclic chalcone (E)-1-(2-(allyloxy)phenyl)-3-(9-ethyl-9H-carbazol-3-yl)prop-2-en-1-one (AECO) with extended π-bond was prepared by the multi-steps synthesis. The structure of the AECO was established by the spectroscopic technics and purity of the compound was confirmed by the elemental analysis. Physicochemical parameters of the AECO such as molar absorption coefficient, transition dipole moments, stokes shift, oscillator strength and fluorescence quantum yield were calculated in ten various solvents on the basis of polarity of the solvents to see the effect of the solvent with AECO. Interaction of the AECO chromophore with cationic CTAB and anionic SDS surfactants were determined by using the fluorescence spectroscopy techniques. The intensity of the florescence spectrum increase with increasing the concentrations of surfactants. This suggests that strong interaction occurs between AECO with surfactants and this interaction arise from electrostatic forces. So, AECO chromophore could be used as analysis to define the Critical Micelle Concentration (CMC) of the surfactants. In addition the in-vitro antibacterial active of novel heterocyclic chalcone agents four bacteria's strain were evaluated and result showed AECO is beater antibacterial agent against Gram-Negative Bacteria (E. coli and S. flexneri) as compare to the Gram Negative Bacteria with respected to the standard drug Tetracycline.

Synthesis of Heterocyclic Chalcones as Novel Antileishmanial Agents

Severe skin disfigurement, scarring of the mouth and nose, and internal organ failure afflict an estimated 1.3 million people annually due to the flesh-eating parasite which causes the disease known as leishmaniasis. It the second largest parasitic killer behind malaria. There are no vaccines and current drug treatments are highly toxic. Even after treatment, the parasite is not eradicated, it remains dormant in the body to potentially strike again. The World Health Organization classifies leishmaniasis as a Neglected Tropical Disease (NTD) which means it occurs in tropical or sub-tropical regions of the Earth. The most affected areas are Northern Africa, the Middle East, Southern Europe, parts of Asia, and Central America; plaguing those that live in poverty the hardest. These people typically do not have the access, finances, or ability to obtain treatments which need intravenous delivery over multiple sessions, thus creating an unfortunate health disparity. The skin lesions and disfiguration caused by the cutaneous and mucosal forms may result in becoming outcasts from their communities and cause a significant reduction in quality of life. The visceral form, also known as kala-azar, is potentially fatal. The areas affected are growing due to vector habitat increase from the warming global climate. The parasite is transmitted via the bite of the phlebotomine sandfly. With more than 1 billion people in approximately 90 countries at risk of infection due to living in areas where leishmaniasis is endemic, the discovery of new effective medications is imperative to improve the lives of millions worldwide. Recent reports of a privileged class of natural products known as chalcones show promise as new antileishmanial agents for all three forms of the disease; cutaneous, mucosal, and visceral. This study will showcase our efforts to discover new targets of opportunity that may lead to better treatments for cutaneous leishmaniasis caused by the protozoan parasite Leishmania major via the synthesis of novel chalcones containing heterocyclic functionalities to impart a dual pharmacophore effect.

Multi-Step Synthesis, Physicochemical investigation and optical properties of pyrazoline derivative: A Donor-π-Acceptor chromophore

The new extended π-bond pyrazoline derivative (ENTD) was prepared from heterocyclic chalcone with 2-hydrazinylbenzo[d] thiazole. The spectroscopic methods established the structure of the ENTD, and the elemental analysis established the purity of the ENTD. In ten different solvents, physicochemical ENTD parameters such as the molar absorption coefficient, transition dipole moments, Stokes shift, oscillator intensity and fluorescence quantum yield were determined to see the effect of the solvent with pyrazoline derivative (ENTD) on the basis of different polarity. In addition, the interaction of ENTD chromophore with the cationic and anionic surfactants have been studied. The intensity of fluorescence spectrum of the ENTD was found to increase with an increase in the surfactant concentration. This indicates that there is a strong interaction between ENTD and surfactants. The ENTD chromophore can therefore be used as a probe to define the surfactants' CMC.

A transition metal-free cascade reaction using heterogeneous tin(IV)oxide catalyzed and iodine promoted synthesis of 3-aroylimidazo[1,2-a]pyridines

The cascade synthesis of 3-aroylimidazo[1,2-a]pyridines using chalcones and 2-aminopyridine was achieved over the SnO2/I2 catalytic system in toluene at ambient air atmosphere. The catalyst shows high activity towards the broad substrate scope of the various aromatic and heterocyclic chalcones with 2-aminopyridine, 4-methyl 2-aminopyridine, and 5-methyl 2-aminopyridine in good yields during the synthesis of 3-aroylimidazo[1,2-a]pyridines. The methodology was further extended for the one-pot three-component synthesis of 3-aroylimidazo[1,2-a]pyridines using acetophenone, benzaldehyde, and 2-aminopyridine derivatives. The present protocol describes the easy purification methodology in the synthesis of 3-aroylimidazo[1,2-a]pyridines.