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1.
Eur J Med Chem ; 244: 114885, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36334451

RESUMO

Bacterial resistance is a growing threat to public health and a significant barrier to anti-infective treatment. Consequently, the development of novel antibacterial strategies to address this issue is critical. Herein, we developed a series of chalcone-alkyl-lysine compounds by mimicking the chemical structure and antibacterial properties of cationic antimicrobial peptides. Most of the compounds showed significant antibacterial activity against Gram-positive and Gram-negative bacteria. Compound 6d displayed potent antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), with MICs of 1-4 µg/mL. In addition, 6d exhibited excellent antibacterial activity against clinical MRSA and NDM-positive isolates, bactericidal properties, low resistance frequency. The mechanism studies revealed that compound 6d destroys bacterial cell membranes by interacting with phosphatidylglycerol (PG), causing the production of reactive oxygen species (ROS) and the leakage of nucleic acids, resulting in bacterial death. Furthermore, compound 6d did not exhibit any observable toxicity in HeLa and HEK293 cells at 8 × MIC. As a result, the findings suggest that compound 6d has potential therapeutic effects against bacterial infections and could be a promising drug candidate for future research.


Assuntos
Chalcona , Chalconas , Humanos , Antibacterianos/química , Bactérias Gram-Positivas , Bactérias Gram-Negativas , Lisina/farmacologia , Chalconas/farmacologia , Chalcona/farmacologia , Células HEK293 , Testes de Sensibilidade Microbiana , Escherichia coli , Peptídeos Catiônicos Antimicrobianos/farmacologia
2.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361718

RESUMO

Inflammation is a major cause of skeletal muscle atrophy in various diseases. 2-Hydroxy-4'-methoxychalcone (AN07) is a chalcone-based peroxisome-proliferator-activated receptor gamma (PPARγ) agonist with various effects, such as antiatherosclerosis, anti-inflammation, antioxidative stress, and neuroprotection. In this study, we examined the effects of AN07 on protein homeostasis pathway and mitochondrial function in inflammation-associated myotube atrophy induced by lipopolysaccharides (LPS). We found that AN07 significantly attenuated NF-κB activation, inflammatory factors (TNF-α, IL-1ß, COX-2, and PGE2), Nox4 expression, and reactive oxygen species levels in LPS-treated C2C12 myotubes. Moreover, AN07 increased SOD2 expression and improved mitochondrial function, including mitochondrial membrane potential and mitochondrial oxygen consumption rate. We also demonstrated that AN07 attenuated LPS-induced reduction of myotube diameter, MyHC expression, and IGF-1/IGF-1R/p-Akt-mediated protein synthesis signaling. Additionally, AN07 downregulated LPS-induced autophagy-lysosomal protein degradation molecules (LC3-II/LC3-I and degraded p62) and ubiquitin-proteasome protein degradation molecules (n-FoxO1a/MuRF1/atrogin-1). However, the regulatory effects of AN07 on protein synthesis and degradation signaling were inhibited by the IGF-1R inhibitor AG1024 and the PI3K inhibitor wortmannin. In addition, the PPARγ antagonist GW9662 attenuated the effects of AN07 against LPS-induced inflammation, oxidation, and protein catabolism. In conclusion, our findings suggest that AN07 possesses protective effects on inflammation-induced myotube atrophy and mitochondrial dysfunction.


Assuntos
Chalcona , Chalconas , Humanos , Lipopolissacarídeos/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , PPAR gama/metabolismo , Chalconas/farmacologia , Chalconas/metabolismo , Chalcona/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo
3.
Int J Mol Sci ; 23(22)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36430768

RESUMO

Resistance to antibiotics is an emerging problem worldwide, which leads to an increase in morbidity and mortality rates. Several mechanisms are attributed to bacterial resistance, overexpression of efflux pumps being one of the most prominent. As an attempt to develop new effective antimicrobial drugs, which could be able to act against resistant bacterial strains and considering the antimicrobial potential of flavonoids and triazolyl flavonoid derivatives, in particular chalcones, a small library of chalcone derivatives was synthesized and evaluated for its potential to act as antimicrobials and/or adjuvants in combination with antibiotics towards resistant bacteria. Although only compound 7 was able to act as antibacterial, compounds 1, 2, 4, 5, 7, and 9 revealed to be able to potentiate the activity of antibiotics in resistant bacteria. Moreover, five compounds (3, 5-8) demonstrated to be effective inhibitors of efflux pumps in Salmonella enterica serovar Typhimurium SL1344, and four compounds (1, 3, 7, and 10) showed higher ability than reserpine to inhibit biofilm formation of resistant Staphylococcus aureus 272123. Together, our results showed the potential of these compounds regarding reversion of bacterial resistance.


Assuntos
Anti-Infecciosos , Chalcona , Chalconas , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Chalcona/farmacologia , Chalconas/farmacologia , Triazóis/farmacologia , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Bactérias , Salmonella typhimurium , Resistência a Múltiplos Medicamentos
4.
Molecules ; 27(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36364321

RESUMO

Isoliquiritigenin (ISL) is a flavonoid with a chalcone structure extracted from the natural herb Glycyrrhiza glabra. Its anti-inflammatory, antibacterial, antioxidant, and anticancer activities have been extensively studied. Moreover, ISL also possess hypolipidemic and atherosclerosis-reducing effects. However, its cholesterol-lowering mechanisms have not been reported yet. Niemann Pick C1 Like 1 (NPC1L1) is a specific transporter of cholesterol uptake. In this study, we found for the first time that ISL downregulates NPC1L1 expression and competitively inhibits cellular cholesterol uptake by binding to NPC1L1 in a concentration-dependent manner in vitro. This study provides a theoretical basis for further investigation of the molecular mechanisms of its cholesterol-lowering effect in vivo and inspired emerging drug research for cholesterol-lowering purposes through NPC1L1 inhibition.


Assuntos
Anticolesterolemiantes , Chalconas , Chalconas/farmacologia , Transporte Biológico , Proteínas de Membrana Transportadoras/metabolismo , Colesterol/metabolismo , Anticolesterolemiantes/farmacologia
5.
Molecules ; 27(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36364405

RESUMO

The plants of the Moraceae family are producers of a great variety of polyphenolic natural products. Among these, the Diels-Alder type adducts (DAAs) are endowed with a unique cyclohexene scaffold, since they are biosynthesized from [4+2] cycloaddition of different polyphenolic precursors such as chalcones and dehydroprenyl polyphenols. To date, more than 150 DAAs have been isolated and characterized from Moraceous and related plants. The main source of DAAs is the mulberry root bark, also known as "Sang-Bai-Pi" in Traditional Chinese Medicine, but they have also been isolated from root bark, stem barks, roots, stems or twigs, leaves, and callus cultures of Moraceous and other related plants. Since 1980, many biological activities of DAAs have been identified, including anti-HIV, antimicrobial, anti-inflammatory, and anticancer ones. For these reasons, natural DAAs have been intensively investigated, and a lot of efforts have been made to study their biosynthesis and to establish practical synthetic access. In this review, we summarized all the updated knowledge on biosynthesis, chemoenzymatic synthesis, racemic and enantioselective total synthesis, and biological activity of natural DAAs from Moraceous and related plants.


Assuntos
Chalconas , Morus , Polifenóis , Medicina Tradicional Chinesa , Antioxidantes , Anti-Inflamatórios
6.
Molecules ; 27(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36364410

RESUMO

Chalcone-1-deoxynojirimycin heterozygote (DC-5), a novel compound which was designed and synthesized in our laboratory for diabetes treatment, showed an extremely strong in vitro inhibitory activity on α-glucosidase in our previous studies. In the current research, its potential in vivo anti-diabetic effects were further investigated by integration detection and the analysis of blood glucose concentration, blood biochemical parameters, tissue section and gut microbiota of the diabetic rats. The results indicated that oral administration of DC-5 significantly reduced the fasting blood glucose and postprandial blood glucose, both in diabetic and normal rats; meanwhile, it alleviated the adverse symptoms of elevated blood lipid level and lipid metabolism disorder in diabetic rats. Furthermore, DC-5 effectively decreased the organ coefficient and alleviated the pathological changes of the liver, kidney and small intestine of the diabetic rats at the same time. Moreover, the results of 16S rDNA gene sequencing analysis suggested that DC-5 significantly increased the ratio of Firmicutes to Bacteroidetes and improved the disorder of gut microbiota in diabetic rats. In conclusion, DC-5 displayed a good therapeutic effect on the diabetic rats, and therefore had a good application prospect in hypoglycemic drugs and foods.


Assuntos
Chalcona , Chalconas , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Ratos , Animais , Glicemia , Diabetes Mellitus Experimental/patologia , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/uso terapêutico , Chalconas/farmacologia , Chalconas/uso terapêutico , Chalcona/farmacologia , Heterozigoto , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico
7.
Food Funct ; 13(23): 12105-12120, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36377761

RESUMO

Prenylated phenolics are antimicrobials found in liquorice (Glycyrrhiza spp.). Liquorice spent is a by-product rich in prenylated phenolics obtained after water extraction of roots, and is currently not valorised. We analysed the prenylated phenolics composition of spent extracts from Glycyrrhiza glabra, G. inflata, and G. uralensis, their antimicrobial activity, cytotoxicity, and effects on Caco-2 cell viability. G. glabra, G. inflata, and G. uralensis spent extracts showed distinct phytochemical profiles. Antibacterial activity (Lactobacillus buchneri, Streptococcus mutans, and Staphylococcus aureus) of G. uralensis and G. inflata (MICs 25-250 µg mL-1) was higher than of G. glabra (MICs 75-1000 µg mL-1). Marker compounds glabridin, licochalcone A, and glycycoumarin were equally potent (MICs 12.5-25 µg mL-1). G. inflata and G. uralensis showed cytotoxicity at 500 µg mL-1, whereas G. glabra was not toxic up to 1000 µg mL-1, but showed reduced viability between 50-500 µg mL-1. Linking antibacterial activity of the liquorice spent extracts with cell viability showed that MICs against S. aureus coincide with concentrations where cell viability was not reduced, whereas for the other bacteria and yeasts MICs concurred at concentrations where cell viability was reduced. In this study we show that liquorice spent is a by-product rich in antibacterial prenylated phenolics that offers interesting oppurtunities for e.g. control of microorganisms and the discovery of novel plant-derived antimicrobials.


Assuntos
Chalcona , Chalconas , Glycyrrhiza , Triterpenos , Humanos , Glycyrrhiza/química , Flavonoides/farmacologia , Flavonoides/análise , Chalconas/farmacologia , Chalconas/análise , Staphylococcus aureus , Células CACO-2 , Raízes de Plantas/química , Extratos Vegetais/química , Triterpenos/análise , Antibacterianos/farmacologia , Antibacterianos/análise
8.
Acta Crystallogr C Struct Chem ; 78(Pt 10): 524-530, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36196785

RESUMO

Three new 2-methyl-4-styrylquinoline derivatives have been synthesized in high yields using Friedländer reactions between chalcones [1-(2-aminophenyl)-3-arylprop-2-en-1-ones] and acetone, and characterized using IR, 1H and 13C NMR spectroscopy, and mass spectrometry, and by crystal structure analysis. In (E)-4-(4-fluorostyryl)-2-methylquinoline, C18H14FN, (I), the molecules are joined into cyclic centrosymmetric dimers by C-H...N hydrogen bonds and these dimers are linked into sheets by π-π stacking interactions. The molecules of (E)-2-methyl-4-[4-(trifluoromethyl)styryl]quinoline, C19H14F3N, (II), are linked into cyclic centrosymmetric dimers by C-H...π hydrogen bonds and these dimers are linked into chains by a single π-π stacking interaction. There are no significant hydrogen bonds in the structure of (E)-4-(2,6-dichlorostyryl)-2-methylquinoline, C18H13Cl2N, (III), but molecules related by translation along [010] form stacks with an intermolecular spacing of only 3.8628 (2) Å. Comparisons are made with the structures of some related compounds.


Assuntos
Chalcona , Chalconas , Quinolinas , Acetona , Cristalografia por Raios X , Ligação de Hidrogênio , Estrutura Molecular , Quinolinas/química
9.
Pharm Biol ; 60(1): 1915-1924, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36205592

RESUMO

CONTEXT: Sevoflurane (Sev) is a commonly used surgical anaesthetic; it has neurotoxic effects on the brain. Echinatin (Ech) is reported to have anti-inflammatory and antioxidant activity. OBJECTIVE: This research confirms the effect of Ech on Sev-induced neurotoxicity and cognitive deficits. MATERIALS AND METHODS: Primary rat hippocampal neurons were treated with 4.1% Sev for 6 h in the presence of Ech (5, 10, and 20 µM) or vehicle, followed by a further 42 h of culture. Male Sprague-Dawley aged rats were divided into 6 groups (n = 6): control, Sev, Sev + Ech (20 mg/kg;), Sev + Ech (40 mg/kg), and Sev + Ech (80 mg/kg). Rats were intraperitoneally injected with Ech or vehicle 1 h before Sev exposure (2% Sev for 5 h). RESULTS: We found that Ech (5, 10, and 20 µM) elevated cell viability (1.29-, 1.51-, 1.68-fold) but mitigated apoptosis (23.87% vs. 16.48%, 12.72%, 9.02%), oxidative stress, and ferroptosis in hippocampal neurons with Sev treatment. Ech activated the Nrf2 expression in Sev-induced in vitro and in vivo models of anaesthetic neurotoxicity. Ech also weakened neurotoxicity in hippocampal neurons with Sev treatment by increasing Nrf2 expression level. Moreover, Ech alleviated hippocampus neurons apoptosis (19.38% vs. 16.05%, 11.71%, 8.88%), oxidative stress, and ferroptosis in rats with Sev treatment. Ech improved Sev-induced cognitive deficits in rats. CONCLUSIONS: Ech alleviates Sev-induced neurotoxicity and cognitive deficits by mitigation of ferroptosis and oxidative stress. Ech may be developed as a new promising therapeutic drug for treatment of cerebral nerve injury caused by surgical anaesthesia.


Assuntos
Sobrecarga de Ferro , Síndromes Neurotóxicas , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Chalconas , Cognição , Hipocampo , Sobrecarga de Ferro/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Sevoflurano/metabolismo , Sevoflurano/toxicidade
10.
Int J Mol Sci ; 23(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36232899

RESUMO

ATP-binding cassette subfamily G and tubulin pharmacological mechanisms decrease the effectiveness of anticancer drugs by modulating drug absorption and by creating tubulin assembly through polymerization. A series of natural and synthetic chalcones have been reported to have very good anticancer activity, with a half-maximal inhibitory concentration lower than 1 µM. By modulation, it is observed in case of the first mechanism that methoxy substituents on the aromatic cycle of acetophenone residue and substitution of phenyl nucleus by a heterocycle and by methoxy or hydroxyl groups have a positive impact. To inhibit tubulin, compounds bind to colchicine binding site. Presence of methoxy groups, amino groups or heterocyclic substituents increase activity.


Assuntos
Antineoplásicos , Chalcona , Chalconas , Acetofenonas/farmacologia , Trifosfato de Adenosina/farmacologia , Antineoplásicos/química , Proliferação de Células , Chalcona/farmacologia , Chalconas/química , Colchicina/metabolismo , Colchicina/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
11.
Molecules ; 27(19)2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36234878

RESUMO

Diarylpentanoids, a class of natural products and their synthetic analogs which are structurally related to chalcones, have gained increasing attention due to their wide array of biological activities, including antitumor, anti-infective, antioxidant, anti-inflammatory, antidiabetic, anti-hyperuricemic, and neuroprotective properties. Previously, we reviewed diarylpentanoids with promising antitumor activity. However, in view of the wide range of biological activities described for this class of compounds, the purpose of this review is to provide a more detailed overview of the synthetic bioactive diarylpentanoids that have been described over the last two decades, beyond simply their antitumor effects. A total of 745 compounds were found, highlighting the main synthetic methodologies used in their synthesis as well as the structure-activity relationship studies and structural features for all activities reported. Collectively, this review highlights the diarylpentanoid scaffold as a promising starting point for the development of new therapeutic agents.


Assuntos
Produtos Biológicos , Chalconas , Antioxidantes/química , Chalconas/química , Hipoglicemiantes , Relação Estrutura-Atividade
12.
Molecules ; 27(19)2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36235163

RESUMO

Angelica keiskei contains a variety of bioactive compounds including chalcone, coumarin, and phytochemicals, endowing it with pharmacological effects such as lipid-lowering activity, antitumor activity, liver protection, and nerve protection. This study aims to study the hypoglycemic and hypolipidemic effects of the flavonoid-rich extract from Angelica keiskei (FEAK) in an effort to exploit new applications of FEAK and increase its commercial value. In this paper, flavonoid compounds in Angelica keiskei were extracted using 50% ethanol, and the contents of the flavonoid compounds were analyzed by UPLC-MS/MS. Then, the hypoglycemic and hypolipidemic activities of the FEAK were investigated through in vitro enzyme activity and cell experiments as well as establishing in vivo zebrafish and Caenorhabditis elegans (C. elegans) models. The UPLC-MS/MS results show that the major flavonoid compounds in the FEAK were aureusidin, xanthoangelol, kaempferol, luteolin, and quercetin. The inhibitory rates of the FEAK on the activity of α-amylase and cholesterol esterase were 57.13% and 72.11%, respectively. In cell lipid-lowering experiments, the FEAK significantly reduced the total cholesterol (TC) and total triglyceride (TG) levels in a dose-dependent manner, with 150 µg/mL of FEAK decreasing the intracellular levels of TC and TG by 33.86% and 27.89%, respectively. The fluorescence intensity of the FEAK group was 68.12% higher than that of the control group, indicating that the FEAK exhibited hypoglycemic effects. When the concentration of the FEAK reached 500 µg/mL, the hypoglycemic effect on zebrafish reached up to 57.7%, and the average fluorescence intensity of C. elegans in the FEAK group was 17% lower than that of the control group. The results indicate that the FEAK had hypoglycemic and hypolipidemic activities. The findings of this study provide theoretical references for the high-value utilization of Angelica keiskei and the development of natural functional food with hypoglycemic and hypolipidemic activities.


Assuntos
Angelica , Chalconas , Angelica/química , Animais , Caenorhabditis elegans , Chalconas/química , Colesterol , Cromatografia Líquida , Cumarínicos , Etanol/química , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Quempferóis , Lipídeos , Luteolina , Extratos Vegetais/farmacologia , Quercetina , Esterol Esterase , Espectrometria de Massas em Tandem , Triglicerídeos , Peixe-Zebra , alfa-Amilases
13.
Molecules ; 27(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36296607

RESUMO

Propolis samples from a geographical part of northwest Greece (Prespa National Park, PNP), which is characterized as a plant endemism center and biodiversity hotspot, were characterized through pollen analysis, chemically analyzed, and biologically evaluated. The majority of the studied propolis showed typical chemical constituents (phenolic acids, flavonoids, and chalcones) of European type, while a sample of Mediterranean-type propolis (rich in diterpenes) was also identified. The palynological characterization was implemented to determine the botanical origin and to explain the chemical composition. The total phenolic content and the DPPH assay showed that the European-type propolis samples possessed strong antioxidant activity (86-91% inhibition at 200 µg/mL). Moreover, promising antibacterial activity of the extracts (MIC values 0.56-1.95 mg/mL) and moderate antifungal activity (MIC values 1.13-2.40 mg/mL) were noticed, while the sample with the highest activity had a significant content in terpenes (Mediterranean type). Propolis samples from the PNP area represent a rich source of antibacterial and antioxidant compounds and confirm the fact that propolis is a significant natural product with potential use for improving human health and stimulating the body's defense. Finally, it is noteworthy that a significant chemical diversity was demonstrated, even in samples from a limited geographical area as this of PNP.


Assuntos
Chalconas , Diterpenos , Própole , Humanos , Própole/química , Antioxidantes/farmacologia , Antioxidantes/química , Antifúngicos/farmacologia , Parques Recreativos , Chalconas/análise , Grécia , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Antibacterianos/farmacologia , Antibacterianos/química , Diterpenos/análise , Terpenos/análise
14.
Molecules ; 27(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36296655

RESUMO

Chalcones have been well examined in the extant literature and demonstrated antibacterial, antifungal, anti-inflammatory, and anticancer properties. A detailed evaluation of the purported health benefits of chalcone and its derivatives, including molecular mechanisms of pharmacological activities, can be further explored. Therefore, this review aimed to describe the main characteristics of chalcone and its derivatives, including their method synthesis and pharmacotherapeutics applications with molecular mechanisms. The presence of the reactive α,ß-unsaturated system in the chalcone's rings showed different potential pharmacological properties, including inhibitory activity on enzymes, anticancer, anti-inflammatory, antibacterial, antifungal, antimalarial, antiprotozoal, and anti-filarial activity. Changing the structure by adding substituent groups to the aromatic ring can increase potency, reduce toxicity, and broaden pharmacological action. This report also summarized the potential health benefits of chalcone derivatives, particularly antimicrobial activity. We found that several chalcone compounds can inhibit diverse targets of antibiotic-resistance development pathways; therefore, they overcome resistance, and bacteria become susceptible to antibacterial compounds. A few chalcone compounds were more active than conventional antibiotics, like vancomycin and tetracycline. On another note, a series of pyran-fused chalcones and trichalcones can block the NF-B signaling complement system implicated in inflammation, and several compounds demonstrated more potent lipoxygenase inhibition than NSAIDs, such as indomethacin. This report integrated discussion from the domains of medicinal chemistry, organic synthesis, and diverse pharmacological applications, particularly for the development of new anti-infective agents that could be a useful reference for pharmaceutical scientists.


Assuntos
Anti-Infecciosos , Antimaláricos , Chalcona , Chalconas , Chalcona/farmacologia , Chalconas/farmacologia , Chalconas/química , Antifúngicos/farmacologia , Vancomicina , Antimaláricos/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Antibacterianos/farmacologia , Antibacterianos/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios não Esteroides/farmacologia , Indometacina , Preparações Farmacêuticas , Lipoxigenases , Tetraciclinas , Relação Estrutura-Atividade
15.
Molecules ; 27(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36296708

RESUMO

Xanthohumol (XH) a prenylated chalcone has diverse therapeutic effects against various diseases. In the present study, a bioanalytical method was developed for XH in rat plasma using reverse phase high performance liquid chromatography. The validation of the method was performed as per ICH M10 guidelines using curcumin as an internal standard. The Isocratic elution method was used with a run time of 10 min, wherein the mobile phase ratio 0.1% v/v OPA (A): Methanol (B) was 15:85 v/v at flow rate 0.8 mL/min and injection volume of 20 µL. The chromatograms of XH and curcumin was recorded at a wavelength of 370 nm. The retention time for XH and curcumin was 7.4 and 5.8 min, respectively. The spiked XH from plasma was extracted by the protein precipitation method. The developed method was linear with R2 value of 0.9996 over a concentration range of 50-250 ng/mL along with LLOQ. The results of all the validation parameters are found to be within the accepted limits with %RSD value less than 2 and the percentage recovery was found to be greater than 95%. Based on the %RSD and percentage recovery results it was confirmed that the method was precise and accurate among the study replicates. LOD and LOQ values in plasma samples were found to be 8.49 ng/mL and 25.73 ng/mL, respectively. The stability studies like freeze thaw, short term and long-term stability studies were also performed, %RSD and percentage recovery of the XH from plasma samples were within the acceptable limits. Therefore, the developed bioanalytical method can be used effectively for estimation of XH in plasma samples.


Assuntos
Chalconas , Curcumina , Ratos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Metanol , Reprodutibilidade dos Testes
16.
Int J Mol Sci ; 23(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36293123

RESUMO

This study was focused on investigating the antiproliferative effects of chalcone hybrids in melanoma cancer cells. Among seven chalcone hybrids, the chalcone-acridine hybrid 1C was the most potent and was selected for further antiproliferative mechanism studies. This in vitro study revealed the potent antiproliferative effect of 1C via cell cycle arrest and apoptosis induction. Cell cycle arrest at the G2/M phase was associated with modulation of expression or phosphorylation of specific cell cycle-associated proteins (cyclin B1, p21, and ChK1), tubulins, as well as with the activation of the DNA damage response pathway. Chalcone 1C also induced apoptosis accompanied by mitochondrial dysfunction evidenced by a decrease in mitochondrial membrane potential, increase in Bax/Bcl-xL ratio and cytochrome c release followed by caspase 3/7 activation. In addition, increased phosphorylation of MAP kinases (Erk1/2, p38 and JNK) was observed in chalcone 1C-treated melanoma cells. The strong antiproliferative activities of this chalcone-acridine hybrid suggest that it may be useful as an antimelanoma agent in humans.


Assuntos
Chalcona , Chalconas , Melanoma , Humanos , Chalcona/farmacologia , Ciclina B1/metabolismo , Chalconas/farmacologia , Fosforilação , Proteína X Associada a bcl-2/metabolismo , Caspase 3/metabolismo , Acridinas/farmacologia , Citocromos c/metabolismo , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Apoptose , Dano ao DNA , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Melanoma/tratamento farmacológico
17.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293443

RESUMO

A new series of sulfonamides, 8a-b, 10, 12, and 14a-b, were synthesized by N-sulfonation reaction with sulfonyl chlorides 6a-b. Five new series of chalcone-sulfonamide hybrids (16-20)a-f were prepared via Claisen-Schmidt condensation of the newly obtained sulfonamides with aromatic aldehydes 15a-f in basic medium. Chalcones substituted with chlorine at position 4 of each series were used as precursors for the generation of their five-membered heterocyclic pyrazoline (22-23)a-d, (24-25)a-b and carbothioamide 27a-f derivatives. The synthesized compounds were evaluated for their anticancer and antituberculosis activities. To determine their anticancer activity, compounds were screened against sixty human cancer cell lines at a single dose (10 µM). Compounds 17a-c were highly active against LOX IMVI (melanoma), with IC50 values of 0.34, 0.73 and 0.54 µM, respectively. Chalcone 18e showed remarkable results against the entire panel of leukemia cell lines with IC50 values between 0.99-2.52 µM. Moreover, compounds 20e and 20f displayed growth inhibition of Mycobacterium tuberculosis H37Rv at concentrations below 10 µM. Although they showed low selectivity in cytotoxicity tests against the Vero cell line, further optimization could advance the potential biological activity of the selected compounds.


Assuntos
Antineoplásicos , Chalcona , Chalconas , Humanos , Chalconas/farmacologia , Chalcona/farmacologia , Nitrogênio , Cloro , Cloretos , Relação Estrutura-Atividade , Antituberculosos/farmacologia , Sulfonamidas/farmacologia , Sulfanilamida , Aldeídos , Antineoplásicos/farmacologia , Estrutura Molecular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais
18.
Int J Mol Sci ; 23(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36293555

RESUMO

Infections with Gram-negative bacteria are still among the leading causes of infection-related deaths. Several studies suggest that the chalcone xanthohumol (XN) found in hop (Humulus lupulus) possesses anti-inflammatory effects. In a single-blinded, placebo controlled randomized cross-over design study we assessed if the oral intake of a single low dose of 0.125 mg of a XN derived through a XN-rich hop extract (75% XN) affects lipopolysaccharide (LPS)-induced immune responses in peripheral blood mononuclear cells (PBMCs) ex vivo in normal weight healthy women (n = 9) (clinicaltrials.gov: NCT04847193) and determined associated molecular mechanisms. LPS-stimulation of PBMCs isolated from participants 1 h after the intake of the placebo for 2 h resulted in a significant induction of pro-inflammatory cytokine release which was significantly attenuated when participants had consumed XN. The XN-dependent attenuation of proinflammatory cytokine release was less pronounced 6 h after the LPS stimulation while the release of sCD14 was significantly reduced at this timepoint. The LPS-dependent activation of hTLR4 transfected HEK293 cells was significantly and dose-dependently suppressed by the XN-rich hop extract which was attenuated when cells were co-challenged with sCD14. Taken together, our results suggest even a one-time intake of low doses of XN consumed in a XN-rich hop extract can suppress LPS-dependent stimulation of PBMCs and that this is related to the interaction of the hop compound with the CD14/TLR4 signaling cascade.


Assuntos
Chalconas , Humulus , Propiofenonas , Humanos , Feminino , Lipopolissacarídeos , Receptores de Lipopolissacarídeos , Receptor 4 Toll-Like , Leucócitos Mononucleares , Endotoxinas , Células HEK293 , Propiofenonas/farmacologia , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Anti-Inflamatórios/farmacologia , Citocinas
19.
J Org Chem ; 87(21): 14422-14432, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36242558

RESUMO

Stimuli-responsive supramolecular receptors are important building blocks for the construction of self-assembled functional materials. We report the design and synthesis of a pH- and light-responsive 2-hydroxychalcone-ß-cyclodextrin conjugate (1-Ct) and its characterization by spectroscopic and computational methods. 1-Ct follows the typical reaction network of trans-chalcone-flavylium photoswitches. Upon light irradiation, 1-Ct can be photochemically converted into the cis-chalcone/hemiketal forms (1-Cc/1-B) under neutral pH conditions or to the flavylium cation (1-AH+) at acidic pH values. This stimuli-responsive ß-cyclodextrin host, 1-Ct, was found to form stronger intramolecular self-inclusion complexes (Kintra = 14) than 1-AH+ (Kintra = 3) and weaker than 1-Cc/1-B (overall Kintra = 179), allowing control over their stability and binding properties by combinations of pH and light stimuli.


Assuntos
Chalcona , Chalconas , beta-Ciclodextrinas , Chalconas/química , beta-Ciclodextrinas/química , Chalcona/química , Concentração de Íons de Hidrogênio
20.
J Org Chem ; 87(21): 14208-14222, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36251770

RESUMO

The oxo-tethered-Ru(II) precatalyst promoted the one-pot C═C/C═O reduction of chalcones using sodium formate as the hydrogen source in water through asymmetric transfer hydrogenation. Twenty-seven 1,3-diarylpropan-1-ols were obtained in good to excellent yields (up to 96%) and enantiomeric purities (up to 98:2). Our data suggested that the enones are first reduced to the corresponding dihydrochalcones (1,4-selectivity) and then into 1,3-diarylpropan-1-ols (C═O reduction). The stereoelectronic effects of electron-donating and electron-withdrawing groups at the ortho, meta and para positions of both aromatic rings were evaluated. The 2-OH group at the B ring was well tolerated, allowing a straightforward enantioselective synthesis of two flavans through the Mitsunobu cyclization, the antiviral (S)-BW683C and the natural flavan (S)-tephrowatsin E.


Assuntos
Chalcona , Chalconas , Hidrogenação , Estereoisomerismo , Água , Polifenóis , Catálise
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