RESUMEN
PURPOSE: Napabucasin (NP) is a natural compound that can suppress cancer cell proliferation and cell cycle by inhibition of the signal transducer and activator of transcription 3 (STAT3) gene. We examined the effects of NP on the proliferation and invasion of neuroblastoma cells (SH-SY5Y). METHODS: Human neuroblastoma SH-SY5Y cell line was used in this study. NP was administered to groups at the doses of 0.3-1 µM. Cell viability was analyzed by MTT assay. Real-time quantitative reverse transcription polymerase chain reaction and western blot analysis assessed the expressions of interleukin (IL)-6 dependent Jak2/Stat3 signaling pathway. The MTT cell viability method was applied to determine the antagonistic-synergistic effects and inhibitory concentration (IC50) doses of doxorubicin (DX) and NP. RESULTS: It was determined that 0.3-1 µM doses of NP killed the cells almost completely after 48 hours, and also that Jak2/Stat3 expressions decreased dose-dependently via IL-6. At the protein level, NP and DX were found to reduce Jak2 and Stat3 levels. CONCLUSIONS: NP showed that it suppresses the proliferation of neuroblastoma cells. Due to its inhibitory effect on Jak2 and Stat3, it can be used to prevent invasion of SH-SY5Y cells. NP, which can inactivate Jak2/Stat3, can be used as a treatment agent by combining with DX in proliferation pathway in neuroblastoma.
Asunto(s)
Benzofuranos , Proliferación Celular , Supervivencia Celular , Doxorrubicina , Janus Quinasa 2 , Neuroblastoma , Factor de Transcripción STAT3 , Transducción de Señal , Humanos , Janus Quinasa 2/metabolismo , Janus Quinasa 2/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Doxorrubicina/farmacología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Supervivencia Celular/efectos de los fármacos , Benzofuranos/farmacología , Interleucina-6/metabolismo , Western Blotting , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , NaftoquinonasRESUMEN
In this work, chitosan/collagen-based membranes loaded with 2,3-dihydrobenzofuran (2,3-DHB) were developed through a simple solvent-casting procedure for use in the treatment of cutaneous Leishmaniasis. The obtained membranes were characterized by elemental analysis, FTIR, TG, DSC, and XRD. Porosity, swelling, mechanical properties, hydrophilicity, and antioxidant activity were analyzed. In addition, assessment to the biocompatibility, through fibroblasts/keratinocytes and in vitro wound healing essays were performed. The obtained results show that the new 2,3-DHB loaded chitosan/collagen membrane presented high porosity and swelling capacity as well as maximum strength, hydrophilicity, and antioxidant activity higher in relation to the control. The tests of antileishmanial activity and the AFM images demonstrate great efficacy of inhibition growth of the parasite, superior to those from the standard therapeutic agent that is currently used: Amphotericin B. The new membranes are biocompatible and stimulated the proliferation of keratinocytes. SEM images clearly demonstrate that fibroblasts were able to adhere, maintained their characteristic morphology. The healing test evidenced that the membranes have adequate environment for promoting cell proliferation and growth. As the conventional treatments often use drugs with high toxicity, the as-developed new membranes proved to be excellent candidate to treat cutaneous Leishmaniasis and can be clearly indicated for further advanced studies in vivo.
Asunto(s)
Benzofuranos , Quitosano , Colágeno , Leishmaniasis Cutánea , Quitosano/química , Quitosano/farmacología , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Benzofuranos/farmacología , Benzofuranos/química , Colágeno/química , Humanos , Membranas Artificiales , Antiprotozoarios/farmacología , Antiprotozoarios/química , Fibroblastos/efectos de los fármacos , Porosidad , Animales , Cicatrización de Heridas/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/química , Queratinocitos/efectos de los fármacosRESUMEN
A synthetic strategy for obtaining a new series of 1,5-disubstituted tetrazole-benzofuran hybrid systems via a one-pot five-component reaction is described. This process involves a Ugi-azide multicomponent reaction coupled to an intramolecular cyclization catalyzed by Pd/Cu, resulting in low to moderate yields from 21 to 67%. This protocol allowed the synthesis of highly substituted benzofurans at the 2-position through an operationally simple process under mild reaction conditions and with high bond forming efficiency due to the formation of six new bonds (two C-C, two C-N, one N-N, and one C-O). Besides, to evaluate the antifungal activity of 1,5-disubstituted tetrazole-benzofurans 9a-n, in vitro studies against Mucor lusitanicus were performed, finding that compound 9b exhibits bioactivity comparable to the commercial antifungal drug Amphotericin B. These results suggest potential for use in controlling mucormycosis infections in animal models, highlighting the importance of these findings given the limited antifungal drug options and high mortality rates associated with this infection.
Asunto(s)
Antifúngicos , Benzofuranos , Pruebas de Sensibilidad Microbiana , Mucor , Tetrazoles , Benzofuranos/farmacología , Benzofuranos/química , Benzofuranos/síntesis química , Mucor/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Tetrazoles/farmacología , Tetrazoles/química , Tetrazoles/síntesis química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
Paeonol is a broadly studied natural product due to its many biological activities. Using a methodology previously employed by our research group, 11 derivatives of paeonol were synthesized (seven of them are unpublished compounds), including four ethers and seven benzofurans. Additionally, we determined the crystal structure of one of these ether derivatives (1 a) and of five benzofuran derivatives (2 a, 2 b, 2 c, 2 f and 2 g) by single crystal X-ray diffraction. To continue studying the cytotoxicity of this natural product and its derivatives, all compounds were tested against two cancer cell lines, HCT116 and MCF-7. Compounds 2 b, 2 e, and 2 g were considered active against the colorectal adenocarcinoma cells HCT116 (Growth inhibition >60 %). Compound 2 e showed an IC50 of 0.2â µM and was selected for further analysis, results reinforce its anticancer potential.
Asunto(s)
Acetofenonas , Antineoplásicos , Benzofuranos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Éteres , Humanos , Benzofuranos/química , Benzofuranos/farmacología , Benzofuranos/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Acetofenonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Éteres/química , Éteres/farmacología , Éteres/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Cristalografía por Rayos X , Línea Celular Tumoral , Células HCT116 , Células MCF-7RESUMEN
Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.
Asunto(s)
Benzofuranos , Privación de Sueño , Animales , Masculino , Ratones , Privación de Sueño/tratamiento farmacológico , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Aprendizaje por Laberinto/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as H4R antagonist (pKi 6.2) and therefore the effects and pharmacological efficacy on a DSS-induced mice model of UC were assessed in this work. Experimental acute colitis was induced in male BALB/c mice (n = 5-10) by administering 3 % DSS in the drinking water for six days. The test compound LINS01007 was administered daily i.p. (5 mg/kg) and compared to control group without treatment. Body weight, water and food consumption, and the presence of fecal blood were monitored during 7-day treatment period. The levels of inflammatory markers (PGE2, COX-2, IL-6, NF-κB and STAT3) were also analyzed. Animals subjected to the acute colitis protocol showed a reduction in water and food intake from the fourth day (p < 0.05) and these events were prevented by LINS01007. Histological signs of edema, hyperplasia and disorganized intestinal crypts, as well as neutrophilic infiltrations, were found in control mice while these findings were significantly reduced in animals treated with LINS01007. Significant reductions in the levels of PGE2, COX-2, IL-6, NF-κB and STAT3 were observed in the serum and tissue of treated animals. The results demonstrated the significant effects of LINS01007 against DSS-induced colitis, highlighting the potential of H4R antagonism as promising treatment for this condition.
Asunto(s)
Benzofuranos , Sulfato de Dextran , Piperazinas , Receptores Histamínicos H4 , Animales , Masculino , Ratones , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Benzofuranos/uso terapéutico , Benzofuranos/farmacología , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Colon/patología , Colon/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Interleucina-6/metabolismo , Interleucina-6/sangre , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Piperazinas/farmacología , Piperazinas/uso terapéutico , Receptores Histamínicos H4/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidoresRESUMEN
Histamine is involved in several central nervous system processes including cognition. In the last years, H3 receptor (H3 R) antagonists have been widely explored for their potential on dementias and other cognitive dysfunctions, and the cooperative role between histamine and acetylcholine neurotransmissions on cognitive processes is widely known in literature. This motivated us to assess the potential of 1-[(2,3-dihydrobenzofuran-1-yl)methyl]piperazines (LINS01 compounds) as inhibitors of cholinesterases, and thus this work presents the inhibitory effect of such compounds against acetyl (AChE) and butyrylcholinesterase. A set of 16 selected compounds were evaluated, being compounds 2d and 2e the most potent inhibitors of both cholinesterases (IC50 13.2-33.9 µM) by competitive mechanism, as indicated by the kinetic assays. Molecular docking simulations suggested that the allylpiperazine and dihydrobenzofuran motifs present in these compounds are important to perform π-interactions with key tryptophan residues from the enzymes, increasing their affinity for both H3 R and cholinesterases. Metric analysis support that compound 2d (LINS01022) should be highlighted due to its balanced lipophilicity (ClogP 2.35) and efficiency (LE 0.32) as AChE inhibitor. The results add important information to future design of dual H3 R-cholinesterases ligands.
Asunto(s)
Enfermedad de Alzheimer , Receptores Histamínicos H3 , Acetilcolina , Acetilcolinesterasa/metabolismo , Benzofuranos/química , Benzofuranos/farmacología , Butirilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Histamina , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Piperazinas/química , Piperazinas/farmacología , Receptores Histamínicos H3/química , Relación Estructura-Actividad , TriptófanoRESUMEN
The GABAergic and glutamatergic neurotransmission systems are involved in seizures and other disorders of the central nervous system (CNS). Benzofuran derivatives often serve as the core in drugs used to treat such neurological disorders. The aim of this study was to synthesize new γ-amino acids structurally related to GABA and derived from 2,3-disubstituted benzofurans, analyze in silico their potential toxicity, ADME properties, and affinity for the GluN1-GluN2A NMDA receptor, and evaluate their potential activity and neuronal mechanisms in a murine model of pentylenetetrazol (PTZ)- and 4-aminopyridine (4-AP)-induced seizures. The in silico analysis evidenced a low risk of toxicity for the test compounds as well as the probability that they can cross the blood-brain barrier (BBB) to reach their targets in the CNS. According to docking simulations, these compounds bind at the active site of the NMDA glutamate receptor with high affinity. The in vivo assays demonstrated that 4 protects against 4-AP-induced seizure episodes, suggesting negative allosteric modulation (NAMs) at the glutamatergic NMDA receptor. Contrarily, 3 (the regioisomer of 4) and its racemic derivatives (cis-2,3-dihydrobenzofurans) were previously described to exacerbate such episodes, pointing to their positive allosteric modulation (PAMs) of the same receptor.
Asunto(s)
Benzofuranos , Receptores de N-Metil-D-Aspartato , Aminoácidos , Animales , Benzofuranos/farmacología , Ligandos , Ratones , Pentilenotetrazol , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Usnic acid is the best-studied lichen metabolite, presenting several biological activities, such as antibacterial, immunostimulating, antiviral, antifungal, anti-inflammatory, and antiparasitic agents; despite these relevant properties, it is a hydrophobic and toxic molecule. In this context, scientific research has driven the development of innovative alternatives, considering usnic acid as a source of raw material in obtaining new molecules, allowing structural modifications (syntheses) from it. The purpose is to optimize biological activities and toxicity, with less concentration and/or response time. This work presents a literature review with an analogy of the hydrophobic molecule of usnic acid with its hydrophilic derivative of potassium usnate, emphasizing the elucidation and structural characteristics, biological activities, and toxicological aspects of both molecules, and the advantages of using the promising derivative hydrophilic in different in vitro and in vivo assays when compared to usnic acid.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Potasio/química , Analgésicos/química , Analgésicos/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Antiparasitarios/química , Antiparasitarios/farmacología , Benzofuranos/toxicidad , Interacciones Hidrofóbicas e Hidrofílicas , Líquenes/metabolismoRESUMEN
In this work, two synthetic aurones revealed moderate schistosomicidal potential in inâ vitro and inâ vivo assays. Aurones (1) and (2) promoted changes in tegument integrity and motor activity, leading to death of adult Schistosoma mansoni worms in inâ vitro assays. When administered orally (two doses of 50â mg/kg) in experimentally infected animals, synthetic aurones (1) and (2) promoted reductions of 56.20 % and 57.61 % of the parasite load and stimulated the displacement towards the liver of the remaining adult worms. The oogram analysis revealed that the treatment with both aurones interferes with the egg development kinetics in the intestinal tissue. Seeking an action target for compounds (1) and (2), the connection with NTPDases enzymes, recognized as important therapeutic targets for S. mansoni, was evaluated. Molecular docking studies have shown promising results. The dataset reveals the anthelmintic character of these compounds, which can be used in the development of new therapies for schistosomiasis.
Asunto(s)
Antihelmínticos/farmacología , Benzofuranos/farmacología , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis/tratamiento farmacológico , Administración Oral , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/química , Benzofuranos/administración & dosificación , Benzofuranos/química , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Estructura MolecularRESUMEN
The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p < 0.05); when aromaticity increased, the antifungal activity decreased for series I and increased for series II. To verify the validity of the obtained equations, a new set of 44 benzofuran-4-ones was designed by replacing the nitrogen atom of the five-membered ring with oxygen in indol-4-ones. The NICS(0) and NICS(1) of benzofuran-4-ones were calculated and used to predict their biological activities using the previous equations. A set of 10 benzofuran-4-ones was synthesized and tested in eight human pathogenic fungi, showing the validity of the equations. The minimum inhibitory concentration (MIC) in yeasts was 31.25 µg·mL-1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 µg·mL-1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.
Asunto(s)
Antifúngicos/farmacología , Benzofuranos/farmacología , Hongos/efectos de los fármacos , Antifúngicos/química , Aspergillus niger/efectos de los fármacos , Aspergillus niger/patogenicidad , Benzofuranos/química , Candida/efectos de los fármacos , Candida/patogenicidad , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pichia/efectos de los fármacos , Pichia/patogenicidad , Hidrocarburos Policíclicos Aromáticos/química , Hidrocarburos Policíclicos Aromáticos/farmacologíaRESUMEN
Schistosomiasis is a public health problem in many developing countries. The mollusc Biomphalaria glabrata is the most important vector of Schistosoma mansoni in South America. The population control of this vector to prevent the spread of schistosomiasis is currently done with the application of highly toxic molluscicide to the environment. The screening of substances in sublethal concentrations that have deleterious effects on physiological parameters is very relevant for the control of schistosomiasis, since the effectiveness of disease prevention increases if it acts on population control of the vector and on reproduction and elimination in S. mansoni cercariae. The objective of this study was to evaluate the reproductive parameters (fecundity and fertility), intra-mollusk effect (sporocysts I (72 h) and II (14 days after)) on the development of cercariae of S. mansoni and the immune cell profile of B. glabrata exposed to sublethal concentrations (LC25 - 0.5 µg/mL and LC50 - 0.92 µg/mL) of the usnic acid potassium salt (potassium usnate). LC 25 and LC 50 significantly reduced (p < 0.05) the fecundity of B. glabrata when treated infected and/or not exposed to infection, while unviable embryos were not observed in sporocyst stage I, being only significant (p < 0.05) for mollusks infected and treated with LC50 on sporocyst II. LC25 and LC50 of the potassium usnate caused significant reductions (p < 0.05) in the production and cercarial shedding when evaluated on sporocysts I and II. In addition, the mortality of infected and treated B. glabrata in the sporocyst II phase was quite marked after the 9th week of infection. Regarding the immunological cell profile of uninfected B. glabrata, both concentrations led to immunomodulatory responses, with significant morphological changes predominant of hemocytes that entered programmed cell death (apoptosis). It was concluded that the application of LC25 and LC50 from the potassium usnate could be useful in the population control of B. glabrata, since it interferes both in their biology and physiology and in the reproduction of the infectious agent of schistosomiasis mansoni.
Asunto(s)
Benzofuranos/farmacología , Biomphalaria , Animales , Biomphalaria/efectos de los fármacos , Biomphalaria/parasitología , Potasio , Schistosoma mansoniRESUMEN
Ethofumesate is a chiral herbicide that may display enantioselective behavior in humans. For this reason, the enantioselective potential of ethofumesate and its main metabolite ethofumesate-2-hydroxy to cause pesticide-drug interactions on cytochrome P450 forms (CYPs) has been evaluated by using human liver microsomes. Among the evaluated CYPs, CYP2C19 had its activity decreased by the ethofumesate racemic mixture (rac-ETO), (+)-ethofumesate ((+)-ETO), and (-)-ethofumesate ((-)-ETO). CYP2C19 inhibition was not time-dependent, but a strong inhibition potential was observed for rac-ETO (IC50 = 5 ± 1 µmol L-1), (+)-ETO (IC50 = 1.6 ± 0.4 µmol L-1), and (-)-ETO (IC50 = 1.8 ± 0.4 µmol L-1). The reversible inhibition mechanism was competitive, and the inhibition constant (Ki) values for rac-ETO (2.6 ± 0.4 µmol L-1), (+)-ETO (1.5 ± 0.2 µmol L-1), and (-)-ETO (0.7 ± 0.1 µmol L-1) were comparable to the Ki values of strong CYP2C19 inhibitors. Inhibition of CYP2C19 by ethofumesate was enantioselective, being almost twice higher for (-)-ETO than for (+)-ETO, which indicates that this enantiomer may be a more potent inhibitor of this CYP form. For an in vitro-in vivo correlation, the Food and Drug Administration's (FDA) guideline on the assessment of drug-drug interactions used in the early stages of drug development was used. The FDA's R1 values were estimated on the basis of the obtained ethofumesate Ki and distribution volume, metabolism, unbound plasma fraction, gastrointestinal and dermal absorption data available in the literature. The correlation revealed that ethofumesate probably inhibits CYP2C19 in vivo for both chronic (oral) and occupational (dermal) exposure scenarios.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Inhibidores del Citocromo P-450 CYP2C19/química , Inhibidores del Citocromo P-450 CYP2C19/farmacología , Citocromo P-450 CYP2C19/metabolismo , Mesilatos/química , Mesilatos/farmacología , Plaguicidas/química , Plaguicidas/farmacología , Citocromo P-450 CYP2C19/química , Inhibidores del Citocromo P-450 CYP2C19/metabolismo , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica , EstereoisomerismoRESUMEN
SARS-CoV and SARS-CoV-2 belong to the subfamily Coronaviridae and infect humans, they are constituted by four structural proteins: Spike glycoprotein (S), membrane (M), envelope (E) and nucleocapsid (N), and nonstructural proteins, such as Nsp15 protein which is exclusively present on nidoviruses and is absent in other RNA viruses, making it an ideal target in the field of drug design. A virtual screening strategy to search for potential drugs was proposed, using molecular docking to explore a library of approved drugs available in the DrugBank database in order to identify possible NSP15 inhibitors to treat Covid19 disease. We found from the docking analysis that the antiviral drugs: Paritaprevir and Elbasvir, currently both approved for hepatitis C treatment which showed some of the lowest free binding energy values were considered as repositioning drugs to combat SARS-CoV-2. Furthermore, molecular dynamics simulations of the Apo and Holo-Nsp15 systems were performed in order to get insights about the stability of these protein-ligand complexes.
Asunto(s)
Antivirales/farmacología , Benzofuranos/farmacología , Tratamiento Farmacológico de COVID-19 , Ciclopropanos/farmacología , Endorribonucleasas/antagonistas & inhibidores , Imidazoles/farmacología , Lactamas Macrocíclicas/farmacología , Prolina/análogos & derivados , SARS-CoV-2/efectos de los fármacos , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , COVID-19/virología , Reposicionamiento de Medicamentos , Endorribonucleasas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida , Prolina/farmacología , SARS-CoV-2/metabolismo , Proteínas no Estructurales Virales/metabolismoRESUMEN
INTRODUCTION AND OBJECTIVES: The activation of hepatic stellate cells (HSCs) is the main cause of liver fibrosis. The beneficial effects of fibroblast growth factor (FGF) 19 on liver fibrosis were recently reported. The S. miltiorrhiza as well as S. miltiorrhiza derived bioactive chemical components has shown prominent antifibrotic effects in liver fibrosis but the mechanism is still not fully understood. We aimed to investigate the bioactive compounds derived from S. miltiorrhiza which exerts antifibrotic effects in HSCs via regulating FGF19. MATERIALS AND METHODS: FGF19 level in culture media was determined by enzyme-linked immunosorbent assay. Cell proliferation was measured by Cell Counting Kit-8 assay. Further, mRNA and protein expressions were assessed by quantitative polymerase chain reaction and western blotting, respectively. Knocking down of FGF receptor 4 (FGFR4) by transfection with siRNA was used to confirm the role of FGF19/FGFR4 signaling. RESULTS: Using the human HSC cell line LX-2, we screened several natural products and found that bioactive compounds isolated from Salvia miltiorrhiza, particularly salvianolic acid B, strongly upregulated FGF19 secretion by LX-2 cells. We further showed that salvianolic acid B inhibited lipopolysaccharide (LPS)-induced HSC proliferation and activation. LPS treatment may also reduce the mRNA and protein levels of FGF19 and its receptor FGFR4. Salvianolic acid B treatment restored the impaired expressions of FGF19 and FGFR4. Finally, FGFR4 knockdown abolished the antifibrotic effects of salvianolic acid B in the LPS-induced HSC activation model. CONCLUSIONS: Salvianolic acid B prevented LPS-induced HSC proliferation and activation by enhancing antifibrotic FGF19/FGFR4 signaling.
Asunto(s)
Benzofuranos/farmacología , Factores de Crecimiento de Fibroblastos/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos , Técnicas de Cultivo de Célula , Proliferación Celular/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Humanos , Salvia miltiorrhizaRESUMEN
Schistosomiasis is a neglected disease caused by helminth flatworms of the genus Schistosoma, affecting over 240 million people in more than 70 countries. The treatment relies on a single drug, praziquantel, making urgent the discovery of new compounds. Aurones are a natural type of flavonoids that display interesting pharmacological activities, particularly as chemotherapeutic agents against parasites. In pursuit of treatment alternatives, the present work conducted an in vitro and in vivo antischistosomal investigation with aurone derivatives against Schistosoma mansoni. After preparation of aurone derivatives and their in vitro evaluation on adult schistosomes, the three most active aurones were evaluated in cytotoxicity and haemolytic assays, as well as in confocal laser-scanning microscope studies, showing tegumental damage in parasites in a concentration-dependent manner with no haemolytic or cytotoxic potential toward mammalian cells. In a mouse model of schistosomiasis, at a single oral dose of 400 mg/kg, the selected aurones showed worm burden reductions of 35% to 65.0% and egg reductions of 25% to 70.0%. The most active thiophenyl aurone derivative 18, unlike PZQ, had efficacy in mice harboring juvenile S. mansoni, also showing significant inhibition of oviposition by parasites, giving support for the antiparasitic potential of aurones as lead compounds for novel antischistosomal drugs.
Asunto(s)
Benzofuranos/farmacología , Flavonoides/farmacología , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomicidas/farmacología , Animales , Modelos Animales de Enfermedad , Femenino , Flavonoides/uso terapéutico , Ratones , Pruebas de Sensibilidad Parasitaria , Praziquantel/uso terapéutico , Esquistosomiasis mansoni/parasitología , Esquistosomicidas/uso terapéuticoRESUMEN
Ischemia-reperfusion (I/R) injury causes oxidative stress, leading to severe cardiac dysfunction. Thus, biologically active compounds with antioxidant properties may be viewed as a promising therapeutic strategy against oxidative-related cardiac disorders. Usnic acid (UA), a natural antioxidant, was complexed with ß-cyclodextrin (ßCD) to improve its bioavailability. Wistar male rats were orally treated with the free form of UA (50 mg/kg) or the inclusion complex UA/ßCD (50 mg/kg) for seven consecutive days. Afterward, hearts were subjected to I/R injury, and the cardiac contractility, rhythmicity, infarct size, and antioxidant enzyme activities were evaluated. Here, we show that neither UA nor UA/ßCD treatments developed signs of toxicity. After I/R injury, animals treated with UA/ßCD showed improved post-ischemic cardiac functional recovery while the release of cell injury biomarkers decreased. Following reduced cardiac damage, a lower incidence of ventricular arrhythmias and smaller myocardial infarct size were associated with reduced lipid peroxidation, along with preserved activity of antioxidant enzymes compared to untreated rats. Surprisingly, uncomplexed UA did not protect hearts against IR injury. Altogether, our results indicate that the inclusion complex UA/ßCD is a critical determining factor responsible for the cardioprotection action of UA, suggesting the involvement of an antioxidant-dependent mechanisms. Moreover, our findings support that UA/ßCD is a structurally engineered compound with active cardioprotective properties.
Asunto(s)
Benzofuranos/farmacología , Cardiotónicos/farmacología , beta-Ciclodextrinas/química , Animales , Benzofuranos/química , Benzofuranos/uso terapéutico , Cardiotónicos/química , Cardiotónicos/uso terapéutico , Masculino , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Ratas Wistar , Espectroscopía Infrarroja por Transformada de Fourier , TermogravimetríaRESUMEN
INTRODUCTION: Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran N-acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC. METHODS: Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study. Metabolic parameters, cardiovascular function, left ventricle histology and inflammatory protein expression were analyzed in the experimental groups. RESULTS: LASSBio-2090 administration in ZDF rats reduced glucose levels to 85.0 ± 1.7 mg/dL (p < 0.05). LASSBio-2090 also lowered the cholesterol and triglyceride levels from 177.8 ± 31.2 to 104.8 ± 5.3 mg/dL and from 123.0 ± 11.4 to 90.9 ± 4.8 mg/dL, respectively, in obese diabetic rats (p < 0.05). LASSBio-2090 normalized plasma insulin, insulin sensitivity and endothelial function in aortas from diabetic animals (p < 0.05). It also enhanced systolic and diastolic left-ventricular function and reverted myocardial remodeling by blocking the threefold elevation of TNF-α levels in hearts from ZDF rats. CONCLUSION: LASSBio-2090 alleviates metabolic disturbance and cardiomyopathy in an obese and diabetic rat model, thus representing a novel strategy for the treatment of cardiovascular complications in obesity-associated type 2 diabetes mellitus.
Asunto(s)
Benzofuranos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiomiopatías Diabéticas/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Animales , Benzofuranos/administración & dosificación , Benzofuranos/química , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Inyecciones Intraperitoneales , Masculino , Estructura Molecular , Obesidad/metabolismo , Ratas , Ratas ZuckerRESUMEN
The isobenzofuran-1(3H)-ones (phthalides) exhibit various biological activities, including antioxidant activity on reactive oxygen species (ROS). An excess of ROS that cannot be naturally contained by cellular enzymatic systems is called redox imbalance, which damage cell membranes, proteins, and DNA, thereby possibly triggering neuronal death in several neurodegenerative diseases. Considering our ongoing efforts to find useful compounds to control redox imbalance, herein we evaluated the antioxidant activity of two phtalides (compounds 3 and 4), using primary cultures of hippocampal neurons. Spectrophotometric assays showed that compound 3 significantly reduced (p ≤ 0.05) ROS levels and lipid peroxidation compared to the control treatment, while compound 4 was unable at any of the tested concentrations. Despite their structural similarity, these compounds behave differently in the intracellular environment, which was reliably corroborated by the determination of oxidation potentials via cyclic voltammetry. It was demonstrated that compound 3 presents a lower oxidation potential. The combination of the mentioned methods allowed us to find a strong correlation between the chemical structure of compounds and their biological effects. Taking together, the results indicate that compound 3 presents desirable characteristics to act as a candidate pharmacological agent for use in the prevention and treatment of neurodegenerative diseases.
Asunto(s)
Antioxidantes/farmacología , Benzofuranos/farmacología , Neuronas/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Femenino , Hipocampo/citología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Espectrofotometría/métodosRESUMEN
2-arylbenzofuran-containing compounds are chemical entities that can be naturally produced by several organisms. A wide-range of activities is described for several compounds of this kind and they are, therefore, valuable moieties for a lead finding from nature. Although there are in-vitro data about the activity of 2-arylbenzofuran-related compounds against cyclooxygenase (COX) enzymes, the molecular level of these COX-inhibiting constituents had not been deeply explored. Thus, 58 2-arylbenzofurans were initially screened through molecular docking within the active site of nine COX-2 crystal structures. The resulting docking scores were statistically analyzed and good reproducibility and convergence were found to discriminate the best-docked compounds. Discriminated compounds exhibited the best performance in molecular dynamics simulations as well as the most-favorable binding energies and the lowest in-vitro IC50 values for COX-2 inhibition. A three-dimensional quantitative activity-structure relationship (3D-QSAR) was also demonstrated, which showed some crucial structural requirements for enhanced enzyme inhibition. Therefore, four hits are proposed as lead structures for the development of COX-2 inhibitors based on 2-arylbenzofurans in further studies.