RESUMEN
A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone ß-carbon with the furanyl moiety and structural modification of the α,ß-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII-X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays.
Asunto(s)
Antineoplásicos , Hidroquinonas , Simulación del Acoplamiento Molecular , Pirazoles , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Hidroquinonas/química , Hidroquinonas/farmacología , Hidroquinonas/síntesis química , Células MCF-7 , Proliferación Celular/efectos de los fármacos , Chalcona/química , Chalcona/farmacología , Células HT29 , Chalconas/química , Chalconas/farmacología , Chalconas/síntesis química , Relación Estructura-Actividad , Línea Celular Tumoral , AnimalesRESUMEN
In the present study, the effect of sulfonamide-chalcone 185 (SSC185) was investigated against B16-F10 metastatic melanoma cells aggressive actions, besides migration and adhesion processes, by in silico and in vitro assays. In silico studies were used to characterize the pharmacokinetic profile and possible targets of SSC185, using the pkCSM web server, and docking simulations with AutoDock Tools. Furthermore, the antimetastatic effect of SSC185 was investigated by in vitro experiments using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony, scratch, and cell adhesion assays, and atomic force microscopy (AFM). The molecular docking results show better affinity of SSC185 with the metalloproteinases-2 (MMP-2) and α5ß1 integrin. SSC185 effectively restricts the formation of colonies, migration, and adhesion of B16-F10 metastatic melanoma cells. Through the AFM images changes in cells morphology was identified, with a decrease in the filopodia and increase in the average cellular roughness. The results obtained demonstrate the potential of this molecule in inhibit the primordial steps for metastasis, which is responsible for a worse prognosis of late stage cancer, being the main cause of morbidity among cancer patients.
Asunto(s)
Adhesión Celular , Movimiento Celular , Chalcona , Simulación del Acoplamiento Molecular , Sulfonamidas , Movimiento Celular/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Sulfonamidas/farmacología , Sulfonamidas/química , Ratones , Animales , Línea Celular Tumoral , Chalcona/farmacología , Chalcona/química , Chalcona/análogos & derivados , Metaloproteinasa 2 de la Matriz/metabolismo , Melanoma Experimental/patología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Microscopía de Fuerza Atómica , Antineoplásicos/farmacología , Antineoplásicos/química , Chalconas/farmacología , Chalconas/química , HumanosRESUMEN
The study focuses on the anxiolytic potential of chalcone (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (CHALCNM) in adult zebrafish. Successfully synthesized in 58 % yield, CHALCNM demonstrated no toxicity after 96â h of exposure. In behavioral tests, CHALCNM (40â mg/kg) reduced locomotor activity and promoted less anxious behavior in zebrafish, confirmed by increased permanence in the light zone of the aquarium. Flumazenil reversed its anxiolytic effect, indicating interaction with GABAA receptors. Furthermore, CHALCNM (4 and 20â mg/kg) preserved zebrafish memory in inhibitory avoidance tests. Virtual screening and ADMET profile studies suggest high oral bioavailability, access to the CNS, favored by low topological polarity (TPSA≤75â Å2) and low incidence of hepatotoxicity, standing out as a promising pharmacological agent against the GABAergic system. In molecular coupling, CHALCNM demonstrated superior affinity to diazepam for the GABAA receptor. These results reinforce the therapeutic potential of CHALCNM in the treatment of anxiety, highlighting its possible future clinical application.
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Ansiolíticos , Conducta Animal , Chalcona , Pez Cebra , Animales , Conducta Animal/efectos de los fármacos , Chalcona/química , Chalcona/farmacología , Chalcona/análogos & derivados , Ansiolíticos/farmacología , Ansiolíticos/química , Ansiolíticos/síntesis química , Receptores de GABA-A/metabolismo , Acroleína/análogos & derivados , Acroleína/química , Acroleína/farmacología , Estructura Molecular , Simulación del Acoplamiento Molecular , Chalconas/farmacología , Chalconas/química , Chalconas/síntesis química , Locomoción/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Cancer still represents a serious public health problem and one of the main problems related to the worsening of this disease is the ability of some tumors to develop metastasis. In this work, we synthesized a new series of chalcones and isoxazoles derived from eugenol and analogues as molecular hybrids and these compounds were evaluated against different tumor cell lines. This structural pattern was designed considering the cytotoxic potential already known for eugenol, chalcones and isoxazoles. Notably, chalcones 7, 9, 10, and 11 displayed significant activity (4.2-14.5 µM) against two cancer cell lines, surpassing the potency of the control drug doxorubicin. The reaction of chalcones with hydroxylamine hydrochloride provided the corresponding isoxazoles that were inactive against these cancer cells. The dihydroeugenol chalcone 7 showed the most promising results, demonstrating higher potency against HepG2 (CC50: 4.2 µM) and TOV-21G (CC50: 7.2 µM). Chalcone 7 was also three times less toxic than doxorubicin considering HepG2 cells, with a selectivity index greater than 11. Further investigations including clonogenic survival, cell cycle progression and cell migration assays confirmed the compelling antitumoral potential of chalcone 7, as it reduced long-term survival due to DNA fragmentation, inducing cell death and inhibiting HepG2 cells migration. Moreover, in silico studies involving docking and molecular dynamics revealed a consistent binding mode of chalcone 7 with metalloproteinases, particularly MMP-9, shedding light on its potential mechanism of action related to anti-migratory effects. These significant findings suggest the inclusion of compound 7 as a promising candidate for future studies in the field of cancer therapeutics.
Asunto(s)
Antineoplásicos , Chalcona , Chalconas , Neoplasias , Chalcona/farmacología , Chalcona/química , Chalconas/farmacología , Chalconas/química , Eugenol/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Doxorrubicina/farmacología , Isoxazoles/farmacología , Proliferación Celular , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
Leishmaniases are infectious diseases caused by flagellated protozoan parasites belonging to the genus Leishmania that infect cells of the mononuclear phagocytic system. These parasites are transmitted to humans by biting an infected female sandfly belonging to the genera Phlebotomus in the Old World and Lutzomyia in the New World. Despite representing a major public health problem, the therapeutic options are old and have several disadvantages. Given this scenario, developing vaccines or drugs for oral administration is necessary. Therefore, integrating computational and experimental strategies into the studies on molecular targets essential for the survival and virulence of the parasite is fundamental in researching and developing new treatments for leishmaniasis. In the effort to develop new vaccines and drugs, molecular docking methods are widely used as they explore the adopted conformations of small molecules within the binding sites of macromolecular targets and estimate the free energy of target-ligand binding. Privileged structures have been widely used as an effective model in medicinal chemistry for drug discovery. Chalcones are a common simple scaffold found in many compounds of natural and synthetic origin, where studies demonstrate the great pharmacological potential in treating leishmaniasis. This review is based on scientific articles published in the last ten years on molecular docking of chalcone derivatives for essential molecular targets of Leishmania. Thus, this review emphasizes how versatile chalcone derivatives can be used in developing new inhibitors of important molecular targets involved in the survival, growth, cell differentiation, and infectivity of the parasites that cause leishmaniasis.
Asunto(s)
Antiprotozoarios , Chalcona , Chalconas , Leishmania , Leishmaniasis , Femenino , Humanos , Chalconas/farmacología , Chalconas/química , Chalcona/química , Simulación del Acoplamiento Molecular , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Antiprotozoarios/química , Leishmaniasis/tratamiento farmacológico , Descubrimiento de DrogasRESUMEN
Three new styrylquinoline-chalcone hybrids have been synthesized using a three-step pathway starting with Friedländer cyclocondensation between (2-aminophenyl)chalcones and acetone to give 2-methyl-4-styrylquinolines, followed by selective oxidation to the 2-formyl analogues, and finally Claisen-Schmidt condensation between the formyl intermediates and 1-acetylnaphthalene. All intermediates and the final products have been fully characterized by IR and 1H/13C NMR spectroscopy, and by high-resolution mass spectrometry, and the three products have been characterized by single-crystal X-ray diffraction. The molecular conformations of (E)-3-{4-[(E)-2-phenylethenyl]quinolin-2-yl}-1-(naphthalen-1-yl)prop-2-en-1-one, C30H21NO, (IVa), and (E)-3-{4-[(E)-2-(4-fluorophenyl)ethenyl]quinolin-2-yl}-1-(naphthalen-1-yl)prop-2-en-1-one, C30H20FNO, (IVb), are very similar. In each compound, the molecules are linked into a three-dimensional array by hydrogen bonds, of the C-H...O and C-H...N types in (IVa), and of the C-H...O and C-H...π types in (IVb), and by two independent π-π stacking interactions. By contrast, the conformation of the chalcone unit in (E)-3-{4-[(E)-2-(2-chlorophenyl)ethenyl]quinolin-2-yl}-1-(naphthalen-1-yl)prop-2-en-1-one, C30H20ClNO, (IVc), differs from those in (IVa) and (IVb). There are only weak hydrogen bonds in the structure of (IVc), but a single rather weak π-π stacking interaction links the molecules into chains. Comparisons are made with some related structures.
Asunto(s)
Chalcona , Chalconas , Chalcona/química , Chalconas/química , Cristalografía por Rayos X , Enlace de HidrógenoRESUMEN
The sanitary emergency generated by the pandemic COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 20 million people were reported with the infection. Of these, more than 740,000 died. In view of the situation, strategies involving the development of new antiviral molecules are extremely important. The present work evaluated, through molecular docking assays, the interactions of 4'-acetamidechalcones with enzymatic and structural targets of SARS-CoV-2 and with the host's ACE2, which is recognized by the virus, facilitating its entry into cells. Therefore, it was observed that, regarding the interactions of chalcones with Main protease (Mpro), the chalcone N-(4'[(2E)-3-(4-flurophenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPF) has the potential for coupling in the same region as the natural inhibitor FJC through strong hydrogen bonding. The formation of two strong hydrogen bonds between N-(4[(2E)-3-(phenyl)-1-(phenyl)-prop-2-en-1-one]) acetamide (PAAB) and the NSP16-NSP10 heterodimer methyltransferase was also noted. N-(4[(2E)-3-(4-methoxyphenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPM) and N-(4-[(2E)-3-(4-ethoxyphenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPE) chalcones showed at least one strong intensity interaction of the SPIKE protein. N-(4[(2E)-3-(4-dimetilaminophenyl)-1-(phenyl)-prop-2-en-1-one]) acetamide (PAAPA) chalcone had a better affinity with ACE2, with strong hydrogen interactions. Together, our results suggest that 4'-acetamidechalcones inhibit the interaction of the virus with host cells through binding to ACE2 or SPIKE protein, probably generating a steric impediment. In addition, chalcones have an affinity for important enzymes in post-translational processes, interfering with viral replication.
Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Enzima Convertidora de Angiotensina 2/química , Antivirales/farmacología , Chalcona/análogos & derivados , Proteasas 3C de Coronavirus/química , Simulación del Acoplamiento Molecular , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/química , Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/química , Chalcona/química , Chalcona/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , SARS-CoV-2/química , SARS-CoV-2/enzimología , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Identification of allosteric inhibitors of PTPs has attracted great interest as a new strategy to overcome the challenge of discover potent and selective molecules for therapeutic intervention. YopH is a virulence factor of the genus Yersinia, validated as an antimicrobial target. The finding of a second substrate binding site in YopH has revealed a putative allosteric site that could be further exploited. Novel chalcone compounds that inhibit PTPs activity were designed and synthesized. Compound 3j was the most potent inhibitor, interestingly, with different mechanisms of inhibition for the panel of enzymes evaluated. Further, our results showed that compound 3j is an irreversible non-competitive inhibitor of YopH that binds to a site different than the catalytic site, but close to the well-known second binding site of YopH.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Chalcona/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Factores de Virulencia/antagonistas & inhibidores , Sitio Alostérico/efectos de los fármacos , Proteínas de la Membrana Bacteriana Externa/metabolismo , Chalcona/síntesis química , Chalcona/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , Proteínas Tirosina Fosfatasas/metabolismo , Relación Estructura-Actividad , Factores de Virulencia/metabolismoRESUMEN
Transient receptor potential vanilloid 1 (TRPV1) is a polymodal cation channel activated by heat, voltage, and ligands. Also known as the capsaicin receptor, TRPV1 is expressed in numerous tissues by different cell types, including peripheral sensory fibers where acts as a thermal and chemical detector in nociceptive pathways. TRPV1 channels are able to bind a wide range of ligands, including a number of vanilloid derivatives all modulating channel's activity. When expressed by sensory neurons, activation of TRPV1 channels by heat (>40 °C), capsaicin (sub-micromolar), or acid environment (pH < 6), causes depolarization leading to burning pain sensation in mammals. Naturally occurring chalcones (1,3-diaryl-2-propen-1-ones) have been reported as effective inhibitors of TRPV1. Their relatively simple chemical structure and the possibility for handy chemical modification make them attractive ligands for the treatment of peripheral pain. By taking advantage of the structural information available, here we discuss pharmacological properties of chalcones and their putative mechanism of binding to TRPV1 channels.
Asunto(s)
Chalcona , Dolor , Células Receptoras Sensoriales/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Chalcona/química , Chalcona/farmacocinética , Chalcona/uso terapéutico , Humanos , Dolor/tratamiento farmacológico , Dolor/metabolismo , Dolor/patología , Células Receptoras Sensoriales/patologíaRESUMEN
Naturally-occurring chalcones and synthetic chalcone analogues have been demonstrated to have many biological effects, including anti-inflammatory, anti-malarial, anti-fungal, and anti-oxidant/anti-cancerous activities. Compared to other chalcones, trans-chalcone exhibits superior inhibitory activity in cancer cell growth as shown via in vitro assays, and exerts anti-cancerous effects via the activation of the p53 tumor suppressor protein. Thus, characterization of the specific mechanisms, by which trans-chalcone activates p53, can aid development of new chemotherapeutic drugs that can be used individually or synergistically with other drugs. In this report, we found that trans-chalcone modulates many p53 target genes, HSP40 being the most induced gene in the RNA-Seq data using trans-chalcone-treated cells. CRM1 is also inhibited by trans-chalcone, resulting in the accumulation of p53 and other tumor suppressor proteins in the nucleus. Similar effects were seen using trans-chalcone derivatives. Overall, trans-chalcone could provide a strong foundation for the development of chalcone-based anti-cancer drugs.
Asunto(s)
Antineoplásicos/farmacología , Chalcona/farmacología , Proteínas del Choque Térmico HSP40/metabolismo , Carioferinas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Factor de Transcripción Activador 3/metabolismo , Antineoplásicos/química , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Chalcona/química , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Carioferinas/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Proteína Exportina 1RESUMEN
Campomanesia adamantium, a native species of the Brazilian Cerrado, is characterized as a natural source of phenolic compounds and has known potential anticancer activities. This study aimed to evaluate the chemical profile of dichloromethane extracts of pulp (DEGPU) and peel (DEGPE) from the fruits of C. adamantium and to identify compounds with antiproliferative effects in vitro against melanoma cells by sulforhodamine B (SRB) assay, apoptosis induction assay, caspase-3 activation assay, nitric oxide (NO) release in coculture of B16-F10 cells and murine peritoneal macrophages. The chemical profiles of DEGPU and DEGPE were analyzed by high performance liquid chromatography coupled to diode array detector and mass spectrometer using the electrospray ionization interface (HPLC-DAD-ESI-MS/MS). Thirteen compounds were identified in both extracts and the chromatographic study of the most active extract in SRB assay DEGPU (GI50 of 16.17 µg/mL) resulted in the isolation of seven compounds. The isolated compound dimethylchalcone (DMC) had the highest antiproliferative activity against B16-F10 with a GI50 of 7.11 µg/mL. DEGPU extract activated caspase-3 in 29% of cells at 25 µg/mL and caused a 50% decrease in NO release in coculture. DEGPU can be characterized as a source of bioactive compounds such as DMC, as seen from its antiproliferative effect in vitro by inducing B16-F10 cells to undergo apoptosis, essential feature in the search for new anticancer drugs.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Chalcona/farmacología , Melanoma/tratamiento farmacológico , Myrtaceae/química , Extractos Vegetales/farmacología , Animales , Apoptosis/efectos de los fármacos , Brasil , Caspasa 3/genética , Caspasa 3/metabolismo , Chalcona/química , Chalcona/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Humanos , Melanoma/fisiopatología , Melanoma Experimental , Ratones , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Espectrometría de Masas en TándemRESUMEN
Leishmaniasis is a group of infectious neglected tropical diseases caused by more than 20 pathogenic species of Leishmania sp. Due to the limitations of the current treatments available, chalcone moiety has been drawn with a lot of attention due to the simple chemistry and synthesis, being reported with antileishmanial activity in particular against amastigote form. This review aims to provide an overview towards antileishmanial activity of chalcones derivatives against amastigote form for Leishmania major, L. amazonensis, L. panamensis, L. donovani and L. infantum as well as their structure-activity relationship (SAR), molecular targets and in silico ADMET evaluation. In this way, it is expected that this review may support the research and development of new promising chalcones candidates a leishmanicidal drugs.
Asunto(s)
Antiprotozoarios/farmacología , Chalcona/farmacología , Leishmania/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Chalcona/síntesis química , Chalcona/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
Leishmaniasis and Chagas disease are endemic pathologies in tropical countries. These cause high morbidity and a public health problem. Current chemotherapies are based on conventional drugs with variable efficacy and toxicity related with the length of therapeutic schemes and high doses. When two pharmacological agents are combined into a single molecule, the result is the so-called hybrid molecule. In the search for new treatments against Chagas disease and leishmaniasis, several studies have shown that hybrid molecules display high antiprotozoal activity and this emerging strategy is quite promising in the field of new drug discovery and development. This review focuses on the antiprotozoal activity of different hybrids obtained from the hybridization of pharmacophores, showing that the most of the efforts have been concentrated in the molecular hybridization of quinoline, chalcone and hydrazone moieties.
Asunto(s)
Antiprotozoarios/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Leishmaniasis/tratamiento farmacológico , Antiprotozoarios/química , Antiprotozoarios/farmacología , Enfermedad de Chagas/patología , Chalcona/química , Humanos , Hidrazonas/química , Leishmaniasis/patología , Pentamidina/química , Quinolinas/química , Terpenos/química , Triazoles/químicaRESUMEN
Medicinal chemists continue to be fascinated by chalcone derivatives because of their simple chemistry, ease of hydrogen atom manipulation, straightforward synthesis, and a variety of promising biological activities. However, chalcones have still not garnered deserved attention, especially considering their high potential as chemical sources for designing and developing new effective drugs. In this review, we summarize current methodological developments towards the design and synthesis of new chalcone derivatives and state-of-the-art medicinal chemistry strategies (bioisosterism, molecular hybridization, and pro-drug design). We also highlight the applicability of computer-assisted drug design approaches to chalcones and address how this may contribute to optimizing research outputs and lead to more successful and cost-effective drug discovery endeavors. Lastly, we present successful examples of the use of chalcones and suggest possible solutions to existing limitations.
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Chalcona , Diseño de Fármacos , Profármacos , Chalcona/análogos & derivados , Chalcona/síntesis química , Chalcona/química , Profármacos/síntesis química , Profármacos/químicaRESUMEN
trans-Chalcone is a plant flavonoid precursor, which lacks broad investigation on its biological activity in inflammatory processes. In the present study, anti-inflammatory and antioxidant mechanisms of systemic administration with trans-chalcone, a flavonoid precursor, on ultraviolet (UV) irradiation-induced skin inflammation and oxidative stress in hairless mice were investigated by the following parameters: skin edema, myeloperoxidase activity (neutrophil marker), matrix metalloproteinase-9 activity, reduced glutathione levels, catalase activity, lipid peroxidation products, superoxide anion production, gp91phox (NADPH oxidase subunit) mRNA expression by quantitative PCR and cytokine production by ELISA. Systemic treatment with trans-chalcone inhibited skin inflammation by reducing skin edema and neutrophil recruitment, and also inhibited matrix metalloproteinase-9 activity. trans-Chalcone also inhibited oxidative stress, gp91phox mRNA expression, and the production of a wide range of pro-inflammatory cytokines, while it did not affect anti-inflammatory cytokines induced by UV irradiation. However, trans-chalcone did not prevent oxidative stress in vitro, suggesting that its in vivo effect is more related to anti-inflammatory properties rather than a direct antioxidant effect. In conclusion, treatment with trans-chalcone inhibited UV-induced skin inflammation resulting in oxidative stress inhibition in vivo. Therefore, systemic supplementation with this compound may represent an important therapeutic approach in inflammatory skin diseases induced by UV irradiation.
Asunto(s)
Chalcona/farmacología , Citocinas/biosíntesis , Inflamación/prevención & control , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Piel/efectos de los fármacos , Piel/efectos de la radiación , Rayos Ultravioleta , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Chalcona/química , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Ensayo de Inmunoadsorción Enzimática , Inflamación/metabolismo , Masculino , Ratones , Ratones Pelados , Estructura Molecular , Estrés Oxidativo/efectos de la radiación , Piel/metabolismo , Piel/patología , Relación Estructura-ActividadRESUMEN
New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17-20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 µM and <10 µM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11-545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents.
Asunto(s)
Antituberculosos/farmacología , Chalcona/farmacología , Descubrimiento de Drogas , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Animales , Antituberculosos/síntesis química , Antituberculosos/química , Chalcona/síntesis química , Chalcona/química , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Células VeroRESUMEN
Trans-chalcone (TC) is a common precursor of flavonoids. However, the pharmacological properties of TC remain to be fully understood. The present study investigated whether topical formulation containing TC (TFcTC) presents therapeutic effect in UVB radiation-induced skin damage using disease, enzyme activity, antioxidant activity, protein and mRNA parameters. Control topical formulation (CTF) and TFcTC were applied in hairless mice before and after exposure to UVB radiation. Dorsal skin samples were collected after UVB exposure to evaluate: i) skin edema (weight) was measured by punch biopsy; ii) spectrophotometric assays were used to measure myeloperoxidase (MPO) and catalase activities, ferric (FRAP) and ABTS cation reducing antioxidant power, superoxide anion production and levels of reduced glutathione (GSH); iii) enzymography was used to measure matrix metalloproteinase-9 (MMP-9) activity; iv) chemiluminescence was used to measure the lipid peroxidation (LPO); v) enzyme-linked immunosorbent assay (ELISA) was used to measure tumor necrosis factor alpha (TNF-α) levels; vi) reverse transcription quantitative PCR (RT-qPCR) was used to measure cyclooxygenase-2 (COX-2), gp91phox (NADPH oxidase sub-unity), glutathione peroxidase-1 (Gpx1), glutathione reductase (Gr), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) mRNA expression. TFcTC inhibited UVB-induced skin edema, MPO activity, MMP-9 activity, TNF-α production, and COX-2 mRNA expression. TFcTC inhibited UVB-induced LPO, down-regulated superoxide anion levels and gp91phox mRNA expression, and improved antioxidant potential and GSH skin levels. The mRNA expression of detoxification systems such as Nrf2, HO-1, Gpx1 and Gr, and catalase activity were also enhanced by treatment with TFcTC. In conclusion, TFcTC protects mice skin from UVB radiation by inhibiting inflammation, and improving antioxidant and detoxification systems. Therefore, topical treatment with TC is a novel therapeutic approach for the treatment of UVB radiation skin damages, which merits further pre-clinical and clinical investigation.
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Chalcona/farmacología , Estrés Oxidativo/efectos de los fármacos , Piel/efectos de los fármacos , Rayos Ultravioleta , Administración Tópica , Animales , Catalasa/metabolismo , Chalcona/química , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/genética , Glutatión Reductasa/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Inflamación/prevención & control , Isomerismo , Peroxidación de Lípido/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Pelados , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de la radiación , Peroxidasa/genética , Peroxidasa/metabolismo , Piel/metabolismo , Piel/efectos de la radiación , Factor de Necrosis Tumoral alfa/análisis , Glutatión Peroxidasa GPX1RESUMEN
BACKGROUND: A variety of chalcones have demonstrated cytotoxic activity toward several cancer cell lines. This study aimed to investigate the cytotoxicity of four chalcones derivatives of 2-acetylthiophene in human breast cancer cell lines. METHODS: MCF-7 and MDA-MB-231 cells were treated with synthesized chalcones and the cytotoxicity was evaluated by tetrazolium dye (MTT), live/dead, and DAPI assays. RESULTS: Chalcones significantly decreased MCF-7 and MDA-MB-231 cells viability in vitro in a dose dependent manner. After 48h treatment, the IC50 values ranging from 5.52 to 34.23µM. Chalcone 3c displayed the highest cytotoxic activity from all the tested compounds. Cytotoxic effects of compounds were confirmed in the live/dead assay. In addition, DAPI staining revealed that these compounds induce death by apoptosis. CONCLUSION: The data speculate that chalcone derivatives of 2-acetylthiophene may represent a source of therapeutic agents for human breast cancer.
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Apoptosis/efectos de los fármacos , Neoplasias de la Mama , Chalcona/farmacología , Tiofenos/farmacología , Apoptosis/fisiología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Chalcona/química , Chalcona/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Inhibidores de Crecimiento/farmacología , Humanos , Células MCF-7 , Tiofenos/química , Tiofenos/uso terapéuticoRESUMEN
The inclusion complexes formed by chalcone and 2',4'-dihydroxychalcone with ß-cyclodextrin have been studied combining experimental (phase solubility diagrams, Fourier transform infrared spectroscopy) and molecular modeling (molecular dynamics, quantum mechanics/molecular mechanics calculations) techniques. The formation constants of the complexes were determined at different temperatures, and the thermodynamic parameters of the process were obtained. The inclusion of chalcone in ß-cyclodextrin is an exothermic process, while the inclusion of 2',4'-dihydroxychalcone is endothermic. Free energy profiles, derived from umbrella sampling using molecular dynamics simulations, were constructed to analyze the binding affinity and the complexation reaction at a molecular level. Hybrid QM/MM calculations were also employed to obtain a better description of the energetic and structural aspects of the complexes. The intermolecular interactions that stabilize both inclusion complexes were characterized by means of quantum atoms in molecules theory and reduce density gradient method. The calculated interactions were experimentally observed using FTIR.
Asunto(s)
Chalcona/química , Chalconas/química , Simulación de Dinámica Molecular , beta-Ciclodextrinas/química , Teoría Cuántica , TermodinámicaRESUMEN
Cancer chemoprevention involves prevention/delay/reverse of the carcinogenic process through administration of cancer chemopreventive agents (CCA). Compounds which are able to induce detoxification-enzymes, especially monofunctional phase II enzymes, have become in excellent approaches for new CCA. Herein, we report the synthesis of new furoxanyl chalcone-like hybrid compounds as CCA. In vitro studies showed that phenylfuroxanyl derivatives 6 and 9 displayed the best activities being 9 the greatest monofunctional-inducer. Additionally, compounds were non-mutagenic against TA98 Salmonella typhimurium strain (Ames test) and could be used in the prevention of the progression of pre-malignant lesions for their cytotoxic activity against tumoral cells. In vivo proof of concept showed increment on phase II-enzymes activities in liver, colon and mammary gland having derivative 9 the best induction profiles. We probed Nrf2 nuclear translocation is operative for both compounds allowing to exert protective effects via expression of downstream phase-II enzymes.