Series Of Chalcones Research Articles

Synthesis, Spectroscopic Studies, Antibacterial Activity, and Colorimetric Evaluation of the Time-Killing Assay for Newly Synthesized Chalcones Using Resazurin

An attempt was made to synthesize and screen chalcones active against some Gram-positive and Gram-negative bacteria by adopting modified colorimetric technique for time-killing assay. A series of chalcones were synthesized from 1-(2-bromophenyl) ethanone and various substituted aromatic aldehydes with good yield and analyzed on the basis of spectral data (FT/IR, 1H NMR, and 13C NMR). The synthesized chalcones were screened for antibacterial activity against selected Gram-positive and Gram-negative bacteria. The pharmacokinetic profiles of chalcones were established by time-kill assay performed by colorimetry using resazurin dye as an indicator which colors only the viable cells. The ethoxy (compound I-4) and para-hydroxy (I-5) derivatives were found to be more potent against Gram-positive bacteria. The colorimetric time-kill assay was found to be more convenient and less time consuming than traditional cell viable count.

Tariquidar-Related Chalcones and Ketones as ABCG2 Modulators.

ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse anticancer drugs. In order to investigate their role in resistance, potent and selective ABCG2 modulators have been described in the literature. A leading class of modulators are the tariquidar analogues; however, their susceptibility to hydrolysis limits their applicable use. To overcome this, we synthesized a novel series of chalcone- and ketone-based compounds inspired by reported tariquidar analogues. Compounds were characterized and evaluated for their ABCG2 modulatory activity and ABC transporter selectivity. When compared to transporters ABCB1 and ABCC1, the chalcone-based compounds exhibited selectivity for ABCG2, while the ketone-based compounds showed only a slight preference for ABCG2. From the former series, chalcone 16d (UR-DP48) displayed similar activity to the reference fumitremorgin C, both producing comparable maximal effects. The compound exhibited marked antiproliferative activity, while cytotoxicity was less pronounced for the most active compound 17f from the ketone series. Chalcone-containing tariquidar analogues are promising modulators to aid in functional investigations of ABCG2 transporters.

Abstract 1965: Biologic evaluation of chalcone derivatives as ABCG2- and ABCB1-mediated drug resistance reversal agents

Abstract The overexpression of ATP-binding (ABC) transporters, including ABCG2 and ABCB1, has been shown to be related to multidrug resistance (MDR). In this work, we investigated a series of chalcones and bis-chalcones as ABCG2- and ABCB1-mediated resistance reversal agents. The results revealed that methoxyl chalcones have better reversal activities than hydroxyl chalcones toward ABCG2-mediated resistance. One methoxyl chalcone has good reversal activities in both ABCG2 and ABCB1 overexpressing cell lines. The compound can increase the accumulation of anticancer drugs in ABCG2 or ABCB1 overexpressing cell lines while combined with anticancer drugs, due to its inhibition of ABCG2 and ABCB1 (IC50 (ABCB1) =1.54 μM, IC50 (ABCG2) = 1.15 μM). In addition, this compound did not significantly alter the expression and localization of ABCG2 or ABCB1 in ABCG2 or ABCB1 overexpressing cell lines. Citation Format: Chaoyun Cai. Biologic evaluation of chalcone derivatives as ABCG2- and ABCB1-mediated drug resistance reversal agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1965.

Amberlyst-15 catalyzed synthesis of novel thiophene–pyrazoline derivatives: spectral and crystallographic characterization and anti-inflammatory and antimicrobial evaluation

Increasing instances of antimicrobial drug resistance and Inflammation-mediated disorders requires the design and synthesis of new small-molecules with higher affinity and specificity for their potential targets to serve as antibiotics or anti-inflammatory drugs, respectively. The current study presents the synthesis of a series of chalcones, 3(a–h) by the reaction of 3-methylthiophene-2-carbaldehyde, 1 and acetophenones, 2(a–h) by Claisen–Schmidt approach. The chalcones were efficiently transformed into thienyl-pyrazolines, 5(a–h) by their reaction with thiosemicarbazide hydrochloride, 4 in the presence of Amberlyst-15 as a catalyst in acetonitrile at room temperature. Alternatively, the compounds 5(a–h) were prepared by conventional method using acetic acid (40%) medium. Structures were characterized by spectral and single crystal X-ray diffraction studies. Preliminary assessment of the anti-inflammatory properties of the compounds showed that, amongst the series, compounds 5b and 5c have excellent anti-inflammatory activities. Further, compound 5c showed excellent activity against Escherichia coli (MIC, 15 µg/mL), Bacillus subtilis (MIC, 20 µg/mL), Aspergillus niger (MIC, 20 µg/mL), and Aspergillus flavus (MIC 15 µg/mL), respectively. Compounds 5a and 5b were also found to be active against the tested microorganisms.

Synthesis and antimicrobial evaluation of some heterocyclic compounds from 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehydes

Abstract A new series of chalcones, pyrazolinyl-pyrazoles, pyrazole-4-carbaldehyde oximes, pyrazole-4-carbonitriles, 5-pyrazolyl-1,2,4-triazolidine-3-thiones, and Knoevenagel condensation products was synthesized from 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehydes. Most reactions were carried out either without solvent or in the presence of water as a green solvent. The structure of synthesized compounds was characterized by spectral and elemental analysis. The synthesized compounds were tested in vitro for their antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans in comparison with imipenem (intravenous β-lactam antibiotic) and clotrimazole (antifungal medication) as reference drugs by using the agar diffusion technique. 3-Aryl-1-phenyl-1H-pyrazole-4-carbonitriles 8b, 8c, and 8d showed significant antifungal activity against the fungus C. albicans.

Synthesis and Evaluation of Antiplasmodial Activity of 2,2,2-Trifluoroethoxychalcones and 2-Fluoroethoxy Chalcones against Plasmodium falciparum in Culture.

A new class of compounds comprising two series of chalcones with 2,2,2-trifluoroethoxy group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay. Chalcones with 2,2,2-trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl ring showed weak antiplasmodial activity, while compounds substituted on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the 34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC50 values of 3.0 μg/mL and 2.2 μg/mL, respectively. Moreover, these compounds 3a and 3f showed profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules, 3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2-trifluoroethoxychalcones (Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future further development.

The Synthesis of Chalcones as Anticancer Prodrugs and their Bioactivation in CYP1 Expressing Breast Cancer Cells.

Although the expression levels of many P450s differ between tumour and corresponding normal tissue, CYP1B1 is one of the few CYP subfamilies which is significantly and consistently overexpressed in tumours. CYP1B1 has been shown to be active within tumours and is capable of metabolising a structurally diverse range of anticancer drugs. Because of this, and its role in the activation of procarcinogens, CYP1B1 is seen as an important target for anticancer drug development. To synthesise a series of chalcone derivatives based on the chemopreventative agent DMU-135 and investigate their antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1. A series of chalcones were synthesised in yields of 43-94% using the Claisen-Schmidt condensation reaction. These were screened using a MTT assay against a panel of breast cancer cell lines which have been characterised for CYP1 expression. A number of derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing significantly lower toxicity towards a non-tumour breast cell line with no CYP expression. Experiments using the CYP1 inhibitors acacetin and α-naphthoflavone provided supporting evidence for the involvement of CYP1 enzymes in the bioactivation of these compounds. Chalcones show promise as anticancer agents with evidence suggesting that CYP1 activation of these compounds may be involved.

Tetrahydronaphthalene as a precursor of new series of chalcones, flavanones, and flavone

An efficient synthetic route for a novel series of chalcones 2a-2d as well as for the corresponding flavanones 3a-3d and flavones 4a-4d, using functionalized tetrahydronaphthalene (THN), is described herein. The Claisen-Schmidt condensation of such THN and aromatic aldehydes, in the presence of an aqueous solution of KOH (40%), selectively gives the expected chalcones 2a-2d, which may further undergo an intramolecular oxa-Michael addition using piperidine, affording the corresponding flavanones 3a-3d in high yields. Alternatively, treatment of such chalcones 2a-2d with I$_{2}$/DMSO provides rapidly, in a one-pot oxidative cyclization, a series of flavones 4a-4d in excellent yields ranging from 85% to 90%.

Chalcones and Five-Membered Heterocyclic Isosteres Bind to Alpha Synuclein Fibrils in Vitro.

A series of chalcone and heterocyclic isosteres, in which the enone moiety was replaced with an isoxazole and pyrazole ring system, was synthesized and their affinities for alpha synuclein (Asyn), amyloid beta (Aβ), and tau fibrils were measured in vitro. The compounds were found to have a modest affinity and selectivity for Asyn versus Aβ fibrils and low affinity for tau fibrils. Insertion of a double bond to increase the extendable surface area resulted in an increase in affinity and improvement in selectivity for Asyn versus Aβ and tau fibrils. The results of this study indicate that compound 11 is a secondary lead compound for structure–activity relationship studies aimed at identifying a suitable compound for positron emission tomography-imaging studies of insoluble Asyn aggregates in Parkinson’s disease.

Trans-chalcone enhances insulin sensitivity through the miR-34a/SIRT1 pathway.

Objective(s):Trans-chalcone as the parent member of the chalcone series reduces circulating levels of insulin and glucose. However, the cellular mechanism of these effects is poorly understood. Sirtuin 1 (SIRT1) as a direct target of miR-34a controls homeostasis of glucose, and also improves insulin sensitivity. Therefore, the present study for the first time investigated the influence of trans-chalcone on the miR-34a/SIRT1 pathway as a possible mechanism for its hypoglycemic and hypoinsulinemic effects.Materials and Methods:In this study, thirty male rats were randomly divided into three groups (n=10): solvent control (NS), oral administration of trans-chalcone for 2 (N2T) and 6 weeks (N6T) groups. Then, hepatic levels of miR-34a and SIRT1 were measured through the qRT-PCR method.Results:Trans-chalcone reduced food intake, body weight gain, and serum glucose as well as insulin levels. Also, this chalcone inhibited hepatic miR-34a expression and significantly elevated SIRT1 mRNA level.Conclusion:Trans-chalcone as an insulin-sensitizing chalcone partly acts through the miR-34a/SIRT1 pathway.

Molecular docking based screening of a simulated HIF-1 protein model for potential inhibitors.

Hypoxia inducible factor-1(HIF-1) is a bHLH-family transcription factor that control genes involved in glucolysis, angiogenesis, migration, as well as invasion factors that are important for tumor progression and metastasis. HIF-1, a hetero dimer of HIF-1α and HIF-1β, binds to the hypoxia responsive genes, such as vascular endothelial growth factor (VEGF). It is one the molecular target for angiogenesis. A series of Chalcone - like compounds described that preferentially inhibit HIF-1 dimer, which can interact with amino acids within the active site of the protein. It is of interest model the HIF-1 dimer protein and protein was subjected to molecular dynamics simulations using NAMD 2.9 software with CHARMM27 force field in water and the protein structure was minimized with 25000 steps for 500 ps and simulation with 1000000 steps for 2ns. 2500 compounds were screened from Zinc database through structure based virtual screening with references to Chalcone natural drug compound. The screened compounds were docked into the active site of the protein using AutoDock Vina in PyRx Virtual screening tool. The docking result showed the compounds Zinc04280532, Zinc04280533, Zinc04280469, Zinc04280534, Zinc16405915, Zinc04277060, Zinc04280538, Zinc04582923, Zinc05280554 and Zinc05943723 have high binding affinities then query compound. The lead hit compounds were also testing for toxicity and bioavailability using Osiris and Molinspiration online server. The active site amino acids such as TYR-21, ASN-34, VAL-35, MET-18, LYS-17, SER-36, ARG- 46 and ARG-14 are key role in the inhibitors activity. This is useful in the design of small molecule therapeutics or the treatment of different abnormalities associated with impaired HIF-1α.

Synthesis, biological evaluation and molecular docking studies of a new series of chalcones containing naphthalene moiety as anticancer agents

A series of chalcones containing naphthalene moiety 4a–4p have been synthesized, characterized by 1H NMR and 13C NMR and evaluated for their in vitro anticancer activity. The majority of the screened compounds displayed potent anticancer activity against both HCT116 and HepG2 human cancer cell lines. Among the series, compound 4h with a diethylamino group at the para position of the phenyl ring exhibited the most potent anticancer activity against HCT116 and HepG2 cell lines with IC50 values of 1.20 ± 0.07 and 1.02 ± 0.04 μM, respectively. The preliminary structure–activity relationship has been summarized. Tubulin polymerization experiments indicated that 4h effectively inhibited tubulin polymerization and flow cytometric assay revealed that 4h arrests HepG2 cells at the G2/M phase in a dose-dependent manner. Furthermore, molecular docking studies suggested that 4h binds to the colchicine binding site of tubulin.

(E)-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a heterocyclic chalcone is a potent and selective CYP1A1 inhibitor and cancer chemopreventive agent

The overexpression of CYP1 family of enzymes is reported to be associated with development of human carcinomas. It has been well reported that CYP1A1 specific inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in Sacchrosomes™ and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on non-heterocyclic ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of 58 and 65 nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown >10-fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 sub-family and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes. The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected human cells from CYP1A1-mediated B[a]P toxicity in human cells. This potent and selective inhibitor of CYP1A1 enzyme have a potential for development as cancer chemopreventive agent.

Synthesis and Antibacterial Activity of Benzo[4,5]isothiazolo[2,3-a]pyrazine-6,6-dioxide Derivatives.

Using a routine procedure, a number of derivatives of the benzo[4,5]isothiazolo[2,3-a]pyrazine-6,6-dioxide ring system have been synthesized from readily available starting materials. A series of chalcones were synthesized, which were subsequently reacted with chlorosulfonic acid to generate chalcone sulfonyl chlorides. The chalcone sulfonyl chlorides were then treated with bromine to generate dibromo chalcone sulfonyl chlorides. These were subsequently reacted with 1,2-diaminopropane and 2-methyl-1,2-diaminopropane in boiling ethanol resulting in compounds 2–10 and 11–19 respectively, in 12–80% yields. The products were characterized by spectral analysis and the definitive structure of compound 11 was determined by X-ray crystallography. The synthesized compounds were screened for potential antibacterial properties against Bacillus subtilis, Escherichia coli, Proteus vulgaris and Staphylococcus aureus.

13C NMR spectroscopy of heterocycles: 1-phenyl-3-aryl/t-butyl-5-arylpyrazoles

Abstract A series of chalcones 1–12 were converted to pyrazolines (1Pi–12Pi) by reaction with phenylhydrazine followed by DDQ oxidation to produce the corresponding pyrazoles (1Pz–12Pz). Three 1-phenyl-3-t-butyl-5-arylpyrazoles (13Pz–15Pz) were synthesized using an analogous approach. Molecular modeling studies predicted the 5-aryl group of the pyrazoles for both series to have a torsion angle of 52°–54° whereas the 1-phenyl group was predicted to have 35°–37° torsion angles. The 3-aryl group was predicted to be essentially coplanar (−3°) with the pyrazole system in the first series. 13C NMR data for both series, 1Pz–12Pz and 13Pz–15Pz, were collected in DMSO-d 6 at 50°C. A plot of the C4 chemical shifts for 1Pz–12Pz versus Hammet constants for 5-aryl substituents yielded a very good linear correlation (R2=0.96) with a slope of 1.5. The chemical shift data for C4 showed little or no dependence on 3-aryl substituents. The result for 13Pz–15Pz, despite only three points, was consistent with the first series results and yielded a ρ value of 2.0. Distal transmission of substituent effects (5-aryl groups) to C4 of the pyrazole system was reduced by roughly 50–60% of that of the analogous planar isoxazole system, but are not consistent with results for the similarly twisted 4-bromoisoxazoles.

Synthesis and Estimations of Antimicrobial Properties of Novel Pyrazoline Derivatives

Chalcones are the condensation product of acetophenone in combination with aromatic aldehydes in the presence of strong base. Chalcones and their metal complexes having prominent role in modern coordination chemistry. These compounds possessing novel structural features, interesting spectral and magnetic properties, have been the subject of intensive research due to their importance in medical, agriculture, analytical, biological and industrial fields. A series of chalcones were prepared by claisen Schmidt condensation of substituted 3cinnamoyl-4-hydroxy-6-methyl-2-pyrones were synthesized by base catalyzed condensation of 3-acetyl-4-hydroxy-6-methyl-2-oxa-2H-pyran (DHA) with different aromatic aldehyde. Biologically active pyrazoline derivatives were synthesized using ethanol via cyclization reaction with phenyl hydrazine hydrates from chalcones. The entire synthesized compounds were confirmed by IR, 1HNMR and Mass spectral analysis. It was found that the synthesized compounds possess standard pick at desired functional groups, protons and mass of compound. The newly synthesized pyrazoline derivatives (MBPI-MBPV) were tested for their antimicrobial activities which reflects moderate to good activity against different strain of bacterial and fungi species. The pyrazoline derivatives synthesized in this research having applicability in the medical, pharmaceutical and agricultural filed.

Synthesis and Cytotoxic Activity of New Chalcones and their Flavonol Derivatives

A series of chalcones and respective flavonols have been synthesized to explore their anti-cancer activities. All the chalcones were synthesized by the reaction between aldehydes and substituted acetophenones in typical base carried Claisen-Schmidt condensation and their corresponding flavonols were synthesized by hydrogen peroxide oxidized Flynn-Algar-Oymada epoxidation and cyclization. The synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR and Mass spectrometry and subjected for cytotoxicity test on MCF-7, HT-29 and HeLa cell lines. Maximum number of compounds demonstrated anti-proliferative activity with IC50 in the range of 18.67-174.3 μM. Compound 3h with a chloro group and 1-phenyl-3(4-methoxy phenyl)-4-pyrazolyl moiety and the flavonol 4a with 3-thienyl group were found to be most potent compounds among all the tested compounds against MCF-7 cell lines with IC50 18.67 and 23.79 μM respectively. The most active compound 3h also showed high docking score of -8.825.

Synthesis and in-vitro anti-inflammatory activity of novel pyrazoline derivatives

A new series of Chalcones (2a-j) were prepared by reacting 2-acetyl Pyrrole and substituted ketones in alcohol medium in presence of NaOH. The Chalcones undergoes selective cyclization with phenoxy acetic acid hydrazide (1) in glacial acetic acid medium to yield the title compounds 1,3,5-trisubstituted Pyrazolines (3a-j). The newly synthesized compounds were evaluated for their In-vitro anti-inflammatory activity by egg albumin denaturation and protein denaturation method. All the new compounds were established on the basis of 1H-NMR, IR and Mass spectral data. Some of the tested compounds 3a, 3f showed good anti-inflammatory activity when compared to the standard drug diclofenac sodium.

Synthesis, Antibacterial and Antifungal Evaluation of Novel Pyrazoline Derivatives

A novel series of Chalcones (2a-j) were prepared by reacting Furfuraldehyde and substituted ketones in alcohol medium in presence of NaOH. The Chalcones undergoes selective cyclization with Benzhydrazide (1) in glacial acetic acid medium to yield the title compounds 1,3,5-trisubstituted Pyrazolines (3a-j). All the newly synthesized compounds were evaluated for their In-Vitro antibacterial and antifungal activities. The new compounds were assigned on the basis of 1H-NMR, IR, Mass spectral data and elemental analysis. Some of the tested compounds showed potent activity against antifungal organism A.fumigatus.

In Silco Molecular Modeling of Chalcone Based Aryloxyethylamines as Antihyperglycemic Agents

Despite enormous efforts have been made in the search for new drugs, diabetes mellitus (DM) still remains the cause of mortality worldwide. A series of chalcone based aryloxyethylamines were synthesized and evaluated for their anti-hyperglycemic activity in SLM and STZ rat models. The majority of the compounds exhibited temperate to good activity ranging from 18.0% to 39.8% in SLM and 14.6% to 31.5% in STZ models, respectively. The most potent compound 31 exhibited glucose lowering of 27.0% in SLM and 31.5% in STZ models. A definite structure–activity relationship was observed while varying the nature and position of the different amines in ring-A of chalcone.