Series Of Chalcones Research Articles

Synthesis, biological evaluation and molecular docking of novel chalcone–coumarin hybrids as anticancer and antimalarial agents

A new series of chalcone–coumarin derivatives (9–19) linked by the 1,2,3-triazole ring were synthesized through the azide/alkyne dipolar cycloaddition. Hybrid molecules were evaluated for their cytotoxic activity against four cancer cell lines (e.g., HuCCA-1, HepG2, A549 and MOLT-3) and antimalarial activity toward Plasmodium falciparum. Most of the synthesized hybrids, except for analogs 10 and 16, displayed cytotoxicity against MOLT-3 cell line without affecting normal cells. Analogs (10, 11, 16 and 18) exhibited higher inhibitory efficacy than the control drug, etoposide, in HepG2 cells. Significantly, the high cytotoxic potency of the hybrid 11 was shown to be non-toxic to normal cells. Interestingly, the chalcone–coumarin 18 was the most potent antimalarial compound affording IC50 value of 1.60 μM. Molecular docking suggested that the cytotoxicity of reported hybrids could be possibly due to their dual inhibition of α- and β-tubulins at GTP and colchicine binding sites, respectively. Furthermore, falcipain-2 was identified to be a plausible target site of the hybrids given their antimalarial potency.

Methylenedioxy flavonoids: Assessment of cytotoxic and anti-cancer potential in human leukemia cells

A new series of chalcones, flavanones and flavones with methylenedioxy group at the 3ʹ,4ʹ position in chalcone, 7,8 position in flavanones and flavones with mono-, di- and trimethoxy groups in the benzaldehyde ring have been assessed for their effect on proliferation, cytotoxic potential and apoptosis in human leukemia cells. Among the tested compounds, the chalcone series showed the best activity and chalcone 3 (mono methoxy group at the ortho position in A-ring) showed a significant effect on down-regulation of cancer cell proliferation and viability in three different leukemia cell lines (K562, Jurkat, U937). The executioner caspase cleavage analyses indicated that the cytotoxic effect mediated by chalcone 3 is due to induction of apoptotic cell death. Interestingly, the cytotoxic effect was cell type-specific and targeted preferentially cancer cells as peripheral blood mononuclear cells (PBMCs) from healthy donors were less affected by the treatment compared to K562, Jurkat and U937 leukemia cells. Altogether our results indicate a potential drug candidate with interesting differential toxicity obeying Lipinski's rule of five.

Synthesis and Biological Evaluation of Flavonoids as Antiacetyl- cholinesterase Agent

A series of chalcones, a flavone and one flavanone were synthesized and elucidated structurally by IR and 1H NMR spectroscopies. The synthetic compounds were then screened for acetylcholinesterase inhibitory activity using thin layer chromatography (TLC) and microplate assays. In the TLC assay, only 2′-hydroxy-4-methoxychalcone and 2′-hydroxy-4′-O-prenyl-2,6-dichlorochalcone were found to show moderate and weak activity respectively against acetylcholinesterase (AchE) at 0.1 mM concentration compared to the control galanthamine. 4′-Hydroxy-2,6-dichlorochalcone, 2′-hydroxy-4-nitrochalcone, 2′-hydroxy-4-(dimethyl)aminochalcone and 2′-hydroxy-4-methoxychalcone showed moderate AchE inhibitory activity with percentage inhibition of 54.24, 46.14 and 49.32 % respectively in the microplate assay.

Quinoxaline-substituted chalcones as new inhibitors of breast cancer resistance protein ABCG2: polyspecificity at B-ring position.

A series of chalcones substituted by a quinoxaline unit at the B-ring were synthesized and tested as inhibitors of breast cancer resistance protein-mediated mitoxantrone efflux. These compounds appeared more efficient than analogs containing other B-ring substituents such as 2-naphthyl or 3,4-methylenedioxyphenyl while an intermediate inhibitory activity was obtained with a 1-naphthyl group. In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition. Molecular modeling indicated both electrostatic and steric positive contributions. A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition.

ChemInform Abstract: Synthesis and anti‐Parasitic Activity of a Novel Quinolinone—Chalcone Series.

AbstractA series of novel quinolinone‐chalcone hybrids (III) (14 examples) and pyrazole analogues such as (V) are designed, synthesized and evaluated for their antiparasitic activity.

Antimicrobial Activities of Some Synthetic Flavonoids

In an attempt to study the biological activities of flavonoids, a flavone, flavanone and series of chalcones were synthesized and characterized by IR and 1 H NMR and elemental analysis. All the targeted compounds were screened for their antibacterial activity against Bacillus cereus, Enterococcus faecalis, Kleibsiella pneumonia and Pseudomonas aeroginosa and antifungal activity against Aspergillus fumigatus and Candida glabrata. Only 2'-hydroxy-4-chlorochalcone (3) and 2'-hydroxy-4-nitrochalcone (4) showed moderate antimicrobial activity against the Gram-positive bacteria with MIC 125 µg/ml and a very weak antifungal activity with MIC 250 µg/ml. All other compounds displayed very weak activities against all the tested microorganisms. I. Introduction Antimicrobial is a general term for natural or synthetic compounds which at certain concentrations inhibit the growth of or kill microorganisms completely. The term antimicrobials are collective for antiviral, antibacterial, antifungal and antiprotozoal. Due to the rapid development of microorganism's resistance to antimicrobial agents, it is necessary to discover compounds both naturally and synthetic of the new antimicrobial agents to help in the battle against pathogenic microorganisms. Much research has been carried out with the aim to discover the therapeutic values of flavonoid derivatives. Flavonoids are poly-phenolic compounds that are ubiquitous in nature and have been reported to possess various biological activities some of which include; antimicrobial, antioxidant, antimalarial, cytotoxic, antidepressant, anti-inflammatory, anti HIV and anticancer (1-7). Scientific studies involving pharmaceutical drug potencies of flavonoids are extensively examined in the past several years and are increasing (8). Chalcones been the precursors of various biologically important heterocyclic compounds have a reactive α,β-unsaturated carbonyl group which was found to be responsible for their antimicrobial activities. The antimicrobial activities may be altered depending on the type and position of the substituent(s) on the aromatic rings (9). Despite the successful report on the targeted compounds, their effect on the antibacterial and antifungal activities against the tested microorganisms has not been reported. However, this study focuses on the synthesis and biological evaluation of the compounds as antibacterial and antifungal agents and also the effect of the substituents on aromatic rings against the tested microorganisms.

Design, synthesis and anticancer activity of benzofuran derivatives targeting VEGFR-2 tyrosine kinase

Two series of chalcone and thiopyrimidine benzofuran derivatives were designed, synthesized and evaluated in vitro for their vascular endothelial growth factor receptor (VEGFR-2) inhibitory activity, their cytotoxicity on seventeen human cancer cell lines and their in vivo antiprostate cancer activity. The highest anti-VEGFR-2 activity was demonstrated by 1-(6-hydroxy-4-methoxybenzofuran-5-yl)-3-(4-nitrophenyl)prop-2-en-1-one (6d) exhibiting an IC50 value (1.00 × 10−3 μM) higher than the reference drug Sorafenib (IC50 = 2.00 × 10−3 μM). On the other hand, most of the synthesized compounds showed potent cytotoxicity against most of the tested cell lines and were more potent than the reference drugs, in particular, bromovisnagin (4) exhibited the best activity on the majority of the cell lines with IC50 values ranging from 3.67 × 10−13 to 7.65 × 10−7 μM. Moreover, the synthesized compounds showed significant in vivo antiprostate cancer activity. The docking experiments were performed using the GOLD program on (VEGFR-2) kinase which introduced new information about the enzyme–inhibitor interaction and the potential therapeutic application of the benzofuran scaffold.

An Antibacterial, Antifungal and Anthelmintic Evaluations of Some Synthesized Chalcone Derived Benzimidazoles

The Chalcone nucleus based natural plant products have various biological activities due to their highly reactive a, b unsaturated carbonyl group. If these medicinal plants not traceable in nature we must go through new synthetic drugs as a source of chalcone analogues. So we synthesized a series of chalcone derived benzimidazoles by condensation of 2-acetyl benzimidazole in alkali with various aromatic aldehydes. The synthesized chalcones were screened for their in-vitro antimicrobial activity using disc diffusion and broth micro-dilution assays. The synthesized chalcones shows good activity against the tested fungal species. They have better activity against gram positive bacteria but shows poor activity against gram negative bacteria. The In-vitro anthelmintic screening of all chalcones exhibited significant potency when compared to standard drug albendazole.

Synthesis and evaluation of new chalcones, derived pyrazoline and cyclohexenone derivatives as potent antimicrobial, antitubercular and antileishmanial agents

A series of chalcones (1–8) were prepared by Claisen–Schmidt condensation of 3-nitroacetophenone with various aldehydes. These chalcones on cyclization with hydrazine hydrate in the presence of glacial acetic acid, hydrazine hydrate in absolute ethanol and ethyl acetoacetate in the presence of barium hydroxide gave corresponding N-acetyl pyrazolines (9–16), N-unsubstituted pyrazolines (17–19) and cyclohexenone derivatives (20–22). All the synthesized compounds were evaluated for their in vitro antibacterial and antifungal activity by using broth microdilution method, and many compounds showed promising activity against various tested bacteria and fungi. Among various tested compounds, 16 and 19 exhibited strongest activities against Streptococcus pyogenes and Pseudomonas aeruginosa; both have MIC value of 25 μg/mL, which is fourfold greater than the standard drug. Many compounds showed good activity against Candida albican. Analogs 11, 12, 15–17 and 19 displayed two- to fivefold greater activity against C. albican as compared to the standard drug. Results of antitubercular evaluation revealed that compounds 4 and 19 displayed strong antimycobacterial activity against H37Rv having MIC of 25 and 62.5 μg/mL, respectively. All analogs were found to be inactive against Leishmania braziliensis except analogs 4 and 5 which exhibited strong leishmanicidal activity against Leishmania promastigotes with IC50 values of 9.3 and 8.9 μg/mL, respectively.

Synthesis and anti-parasitic activity of a novel quinolinone–chalcone series

A series of novel quinolinone–chalcone hybrids and analogues were designed, synthesized and their biological activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum evaluated. Promising molecular scaffolds with significant microbicidal activity and low cytotoxicity were identified. Quinolinone–chalcone 10 exhibited anti-parasitic properties against both organisms, being the most potent anti-L. infantum agent of the entire series (IC50 value of 1.3±0.1μM). Compounds 4 and 11 showed potency toward the intracellular, amastigote stage of L. infantum (IC50 values of 2.1±0.6 and 3.1±1.05μM, respectively). Promising trypanocidal compounds include 5 and 10 (IC50 values of 2.6±0.1 and 3.3±0.1μM, respectively) as well as 6 and 9 (both having IC50 values of <5μM). Chemical modifications on the quinolinone–chalcone scaffold were performed on selected compounds in order to investigate the influence of these structural features on antiparasitic activity.

Synthesis and anticonvulsant activity of some 2-pyrazolines derived from chalcones

Synthesis of chalcones (1,3-diarylprop-2-en-1-ones) and 2-pyrazoline derivatives has been an active field of research due to their established pharmacological effects. In this study, a series of chalcones were prepared with methyl aryl ketones and substituted aldehydes in the presence of sodium hydroxide and methanol through Claisen-Schmidt condensation. 3,5-Disubstituted-4,5-dihydro-1H-pyrazole-1-carbothioamides were synthesized by refluxing selected chalcones and thiosemicarbazide in alkaline medium. Similarly N-3,5-trisubstituted-4,5-dihydro-1H-pyrazole-1-carboxamides were synthesized by refluxing selected chalcones with N-(4-chlorophenyl)semicarbazide in alkaline medium. Structures of the synthesized compounds were confirmed by elemental analysis and spectral (UV, IR, 1H NMR, 13C NMR, and mass) data, which were in line with the proposed structures.All compounds were tested for their anticonvulsant activity using pentylenetetrazole induced seizure (PTZ) and maximal electroshock seizure (MES) tests in mice at a dose level of 50mg/kg. Among the 2-pyrazoline-1-carbothioamide derivatives, 5-(2,6-dichlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (2e) reduced grade-5 seizure activity and also increased survival rate in PTZ test. In MES test, 5-(4-methoxyphenyl)-3-[4-(methylsulphonyl)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide(2g) has not only decreased seizure severity, but also increased survival rate. Among the 2-pyrazoline-1-carboxamide derivatives, 3-(5-bromothiophen-2-yl)-N-(4-chlorophenyl)-5-(2,6-dichlorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (3d) having 5-bromothiophen and 2,6-dichlorophenyl moieties and N-(4-chlorophenyl)-5-(2,6-dichlorophenyl)-3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboxamide (3e) having 5-chlorothiophen and 2,6-dichlorophenyl moieties showed remarkable activities in PTZ test. Among all tested derivatives, compound 3d was found to be the most active one and reduced grade-5 seizure severity and also increased survival rate.

Synthesis, Characterization, and Biological Activity of 4-(2-Hydroxy-5-(aryl-diazenyl)phenyl)-6-(aryl)pyrimidin-2-ols Derivatives

With the aim of synthesizing new heterocyclic compounds and exploring biological potency, new series of chalcones, that is, 3-(2-hydroxy-5-(aryl-diazenyl)phenyl)-1-(aryl)prop-2-en-1-one and their pyrimidine derivatives, that is, 4-(2-hydroxy-5-(aryl-diazenyl)phenyl)-6-(aryl)pyrimidin-2-ols were synthesized using different aromatic amines and salicylaldehyde as starting moieties. The structures of newly synthesized compounds were confirmed using different spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, and mass spectral analysis, and elemental analysis. The newly synthesized pyrimidines derivatives were screened for their in vitro antibacterial and antifungal activities. It was observed that some of the newly synthesized compounds had shown promising activity against several bacterial and fungal stains. Anti-bacterial activity and anti-fungal activity studies revealed that pyrimidine derivatives consisting of nitro group in their molecular structure possess better activity than their corresponding chalcones.

Microwave‐Assisted Synthesis and Tyrosinase Inhibitory Activity of Chalcone Derivatives

A series of chalcones and their derivatives were synthesized, and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that some of the synthesized compounds exhibited significant inhibitory activity, and four compounds exhibited more potent tyrosinase inhibitory activity than the reference standard inhibitor kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one). Specifically, 1-(-1-(4-methoxyphen- yl)-3-phenylallylidene)thiosemicarbazide (18) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 0.274 μM. The inhibition mechanism analysis of 1-(-1-(2,4-dihydroxyphenyl)-3-phenylallylidene) thiosemicarbazide (16) and 1-(-1-(4-methoxyphenyl)-3-phenylallylidene) thiosemicarbazide (18) demonstrated that the inhibitory effects of the two compounds on the tyrosinase were irreversible. Preliminary structure activity relationships' analysis suggested that further development of such compounds might be of interest.

Fragmentation Behavior Studies of Chalcones Employing Direct Analysis in Real Time (DART)

Chalcones are naturally occurring, biologically active molecules generating interest from a wide range of researchapplications including synthetic methodology development, biological activity investigation and studying fragmentation patterns. Inthis article, a series of chalcones has been synthesized and their fragmentation behavior was studied using modern ambient ionizationtechnique Direct Analysis in Real Time (DART). DART ion source connected with an ion trap mass spectrometer wasused for the fragmentation of various substituted chalcones. The chalcones were introduced to the DART source using a glasscapillary without sample preparation step. All the chalcones showed prominent molecular ion peaks [M]•+ corresponding to thestructures. Multistage mass spectral data MSn (MS2 and MS3) were collected for all the chalcones studied. The chalcones withsubstitutions at 3, 4 or 5 positions gave product ion peaks with the loss of a phenyl radical (Ph•) by radical initiated α-cleavage,while substitution at 2 position of chalcone in the A-ring gave a product ion peak with the loss of substituted styryl radical(PhCH = CH•). In case of the chalcones with the substituent at 4 positions in A and B rings gave both types of fragmentation patterns. In conclusion, chalcones can be easily characterized using modern DART interface in very short time and efficientlywithout any cumbersome sample pretreatment.

Regiospecificity of Human UDP-glucuronosyltransferase Isoforms in Chalcone and Flavanone Glucuronidation Determined by Metal Complexation and Tandem Mass Spectrometry

The glucuronidation of a series of chalcones (2'-hydroxychalcone, 2',4'-dihydroxychalcone, 3,2'-dihydroxychalcone, 4,2'-dihydroxychalcone, and cardamonin) and their corresponding cyclized flavanones (7-hydroxyflavanone, 3'-hydroxyflavanone, 4'-hydroxyflavanone, and alpinetin) by eight human UDP-glucuronosyltransferase (UGT) 1A enzymes was evaluated. A postcolumn metal complexation LC-MS/MS strategy was used successfully to produce characteristic mass spectrometric product ions that were utilized in combination with elution order trends to identify chalcone and flavanone monoglucuronides unambiguously, thus allowing determination of the regioselectivities of the UGT1A isoforms. The presence of hydroxy groups on the A- or B-ring had a significant effect on the glucuronide product yield and the site where glucuronidation occurred. For example, for reaction with UGT1A9, formation of the 2'-O-glucuronide was increased for dihydroxychalcones with A-ring hydroxy substituents. In contrast, although UGT1A8 reacted with 3,2'-dihydroxychalcone and 4,2'-dihydroxychalcone to yield 2'-O-glucuronide products, the presence of a B-ring hydroxy group at the 4' position on cardamonin and 2',4'-dihydroxychalcone quenched the reaction at the OH-2' position. Moreover, the A-ring OH-4 group promoted glucuronidation at the 2' position for the reaction of 4,2'-dihydroxychalcone with UGT1A1 and 1A3. For UGT1A7, hydroxy group substituents on the chalcone A-ring also promoted cyclization and formation of the corresponding flavanone glucuronide.

Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin

A series of chalcone and flavonol derivatives were synthesized in good yield by an eco-friendly approach. A pharmacological evaluation was performed with the human colorectal carcinoma cell line HCT116 and revealed that the anticancer activity of flavonols was higher when compared with that of the respective chalcone precursors. The antiproliferative activity of halogenated derivatives increases as the substituent in the 3- or 4-positon of the B-ring goes from F to Cl and to Br. In addition, halogens in position 3 enhance anticancer activity in chalcones whereas for flavonol derivatives the best performance was registered for the 4-substituted derivatives. Flow cytometry analysis showed that compounds 3p and 4o induced cell cycle arrest and apoptosis as demonstrated by increased S, G2/M and sub-G1 phases. These data were corroborated by western blot and fluorescence microscopy analysis. In summary, halogenated chalcones and flavonols were successfully prepared and presented high anticancer activity as shown by their cell growth and cell cycle inhibitory potential against HCT116 cells, superior to that of quercetin, used as a positive control.

In vitro and in silico exploration of IL-2 inhibition by small drug-like molecules

Interleukin-2 (IL-2) is an immunoregulatory cytokine produced by T lymphocytes in response to antigen. It is a potent growth and differentiation factor for several cell-types and is structurally related to the four-helix bundle family of cytokines. Here, we report IL-2 inhibitory potential and computational studies on different series of chalcones, benzothiazepines, semicarbazones, and dihydropyrimidines. These compounds were synthesized in wet lab and were then tested for their potency as IL-2 inhibitors through in vitro T cell proliferation, IL-2 cytokine production as well as their effect on oxidative burst. Compounds that showed significant suppressive activity were further evaluated for their cytotoxicity on normal two cell lines. Most of the chalcones were found to have a powerful inhibitory effect on T-lymphocytes proliferation and cytokine production. Among the aza heterocycles benzothiazepines, benzoxazepines, and benzodiazepinones were found to be the strongest IL-2 inhibitors. Molecular docking and MD simulation studies were carried out to correlate experimental and theoretical results whereby a good correlation was observed which indicated that computational studies could provide an alternate tool for the identification and designing of more potent IL-2 inhibitors.

Antimicrobial and Cytotoxicity Potential of Acetamido, Amino and Nitrochalcones

Chalcones constitute one of the major classes of natural products belonging to the flavonoid family, and they have been reported as having a range of important therapeutic activities, including some chalcones are effective as antimicrobial agents. Currently, the search for new structures with antimicrobial activity has been intensified due to the emergence of many strains resistant to antibiotics currently used to treat infectious diseases.3 chalcone series (amino, acetamido and nitrochalcones) were prepared (23 compounds) and evaluated for their antimicrobial and cytotoxic potential. The effects of substituents on their respective activities also was evaluated.The results showed that 4 aminochalcones (2, 4, 8, 9), 3 acetoamidochalcones (10, 14, 18) and 3 nitrochalcones (20, 22, 23), exhibited antifungal effects. The aminochalcones were more toxic than the acetamidochalcones, while the nitrochalcones did not present any toxic effect. It was verified that there seems to be structure-activity correlation in some electron-donating and withdrawing substituents groups in rings A and B of the synthetized chalcone analogues and its antifungal and cytotoxic activity.

Synthesis and antibacterial and antifungal evaluation of some chalcone based sulfones and bisulfones

Two series of chalcone based sulfone and bisulfone derivatives were synthesized using chalcone, thiophenol and sodium metal at room temperature, followed by oxidation of chalcone sulfides with m-CPBA at 0 °C in a novel method. Both sulfones and bisulfones were evaluated for their antimicrobial activities against Aspergillus niger and Candida albicans (yeast), Bacillus subtilis and Staphylococcus aureus (Gram (+) bacteria) and Pseudomonas aeruginosa and Salmonella typhimurium (Gram (−) bacteria) strains. Among them, compounds 2c, 3c, 6c, 7c, 8c and 9c have shown high antifungal activity against C. albicans compare to reference drugs viz. Amphotericin-B and Nystatin. Compound 1c has shown slightly better antibacterial activity against B. subtilis and compounds 5c, 6c and 7c have shown excellent antibacterial activity against S. typhimurium in compare to reference drugs Ampicillin and Kanamycin.

Synthesis of β-ionone derived chalcones as potent antimicrobial agents

A series of chalcones (3a–v) have been synthesized by condensation of β-ionone (1) with a variety of aldehydes (2a–v). The synthesized compounds have been screened for their in vitro antimicrobial activity against five bacterial and five fungal strains, using disc diffusion assay. The evaluated compounds display a wide range of activities, from completely inactive to the highly active compounds. Some of the compounds are also active against methicillin resistant staphylococcus aureus (MRSA).