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1.
Chem Biodivers ; : e202401073, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39258811

RESUMO

This work describes the evaluation the potentiating activity of antibiotics by campesterol (1) and its derivatives (2-11) against multiresistant strains of Staphylococcusaureus 10, Escherichia coli 06 and Pseudomonas aeruginosa 24 employing the microdilution test. When subjected to the in vitro potentiating activity bioassay, all compounds showed a potentiating effect associated with norfloxacin against E. coli and P. aeruginosa with a reduction in the MIC of the antibiotic of up to 75%. These compounds also reduced the MIC of gentamicin by 37% to 87% in S. aureus and E. coli. Additionally, molecular docking studies were conducted to gain a deeper understanding of the interactions between the appropriate proteins and the most effective compounds (2, 4, 9, and 10 against E. coli; 1, 2, 3, 5, 8, and 9 against S. aureus), including antibiotics. This paper registers for the first time the in vitro and in silico studies on the action of compounds 1-11 in antibiotic potentiation.

3.
Chem Biodivers ; : e202401207, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39088251

RESUMO

Anxiety and epilepsy are common worldwide and represent a primary global health concern. Fisetin, a flavonoid isolated from Bauhinia pentandra, has a wide range of biological activities may be a promising alternative to combat diseases related to the central nervous system (CNS). The present study aimed to investigate the anxiolytic and anticonvulsant effects of fisetin on adult zebrafish. Furthermore, molecular docking simulations were performed to improve the results. Fisetin did not present toxicity and caused anxiolytic behavior and delayed seizures in animals. This effect may occur through serotonin neurotransmission at 5-HT3A and/or 5-HT3B receptors. Molecular docking simulations showed that fisetin interacts with the orthosteric site of the 5-HT3A receptor with strong H-bond interactions with the Trp156 residue, with a strong contribution from the catechol ring, a behavior similar to that of the antagonist co-crystallized inhibitor granisetron (CWB). Fisetin may be a promising alternative to combat diseases related to the central nervous system.

4.
Planta Med ; 90(12): 938-948, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39159664

RESUMO

Withanolides are steroidal lactones commonly found in plants of the Solanaceae family that have significant medicinal value. In this study, three withanolides extracted from Iochroma arborescens leaves were isolated and characterized. These included withaphysalin F (3: ) and two newly identified epimeric compounds: 18R- and 18S-O-methyl-withaphysalin F (1: and 2: ). Their structures were elucidated by NMR, IR, MS, CD, and X-ray diffraction analysis, and their potential against cell proliferation and migration was investigated. The cytotoxic assay revealed activity against different tumor and non-tumor cell lines. (18S)-O-methyl-withaphysalin F (2: ) presented cell death effects after at least 6 hours of exposure. MDA-MB-231 cells were exposed to 0.06 and 0.6 µM of (18S)-O-methyl-withaphysalin F (2: ), and reductions in cell adhesion, migration, and clonogenicity were observed. Morphological analysis revealed negative regulation in filopodia, salience, and roughness, as well as alterations in cellular microarchitecture. These results provide clues as to the effects of (18S)-O-methyl-withaphysalin F (2: ), allowing new molecular modifications to improve potency and selectivity and increase our antineoplastic arsenal.


Assuntos
Antineoplásicos Fitogênicos , Movimento Celular , Proliferação de Células , Humanos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Vitanolídeos/farmacologia , Vitanolídeos/isolamento & purificação , Vitanolídeos/química , Solanaceae/química , Estrutura Molecular , Folhas de Planta/química
5.
Chem Biodivers ; 21(8): e202400786, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38777789

RESUMO

This study carried out to investigate the anti-inflammatory and antinociceptive effect of tropane alkaloid (EB7) isolated from E. bezerrae. It evaluated the toxicity and possible involvement of ion channels in the antinociceptive effect of EB7, as well as its anti-inflammatory effect in adult zebrafish (Zfa). Docking studies with EB7 and COX-1 and 2 were also performed. The tested doses of EB7 (4, 20 and 40 mg/kg) did not show any toxic effect on Zfa during the 96h of analysis (LD50>40 mg/kg). They did not produce any alteration in the locomotor behavior of the animals. Furthermore, EB7 showed promising pharmacological effects as it prevented the nociceptive behavior induced by hypertonic saline, capsaicin, formalin and acid saline. EB7 had its analgesic effect blocked by amiloride involving the neuromodulation of ASICs in Zfa. In evaluating the anti-inflammatory activity, the edema induced by κ-carrageenan 3.5 % was reduced by the dose of 40 mg/kg of EB7 observed after the fourth hour of analysis, indicating an effect similar to that of ibuprofen. Molecular docking results indicated that EB7 exhibited better affinity energy when compared to ibuprofen control against the two evaluated targets binding at different sites in the cocrystallized COX-1 and 2 inhibitors.


Assuntos
Analgésicos , Simulação de Acoplamento Molecular , Peixe-Zebra , Animais , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/isolamento & purificação , Tropanos/farmacologia , Tropanos/isolamento & purificação , Tropanos/química , Edema/tratamento farmacológico , Edema/induzido quimicamente , Carragenina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 1/metabolismo , Bignoniaceae/química , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/química , Canais Iônicos Sensíveis a Ácido/metabolismo , Canais Iônicos Sensíveis a Ácido/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Estrutura Molecular
6.
Chem Biodivers ; 21(7): e202400538, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38639566

RESUMO

This is the first study to analyze the anti-inflammatory and antinociceptive effect of withanicandrin, isolated from Datura Ferox leaves, and the possible mechanism of action involved in adult zebrafish (ZFa). To this end, the animals were treated intraperitoneally (i. p.) with withanicandrin (4; 20 and 40 mg/kg; 20 µL) and subjected to locomotor activity and acute toxicity. Nociception tests were also carried out with chemical agents, in addition to tests to evaluate inflammatory processes induced by κ-Carrageenan 1.5 % and a Molecular Docking study. As a result, withanicandrin reduced nociceptive behavior by capsaicin at a dose of 40 mg/kg and by acid saline at doses of 4 and 40 mg/kg, through neuromodulation of TRPV1 channels and ASICs, identified through blocking the antinociceptive effect of withanicandrin by the antagonists capsazepine and naloxone. Furthermore, withanicandrin caused an anti-inflammatory effect through the reduction of abdominal edema, absence of leukocyte infiltrate in the liver tissue and reduction of ROS in thel liver tissue and presented better affinity energy compared to control morphine (TRPV1) and ibuprofen (COX-1 and COX-2).


Assuntos
Analgésicos , Peixe-Zebra , Animais , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/isolamento & purificação , Canais Iônicos Sensíveis a Ácido/metabolismo , Simulação de Acoplamento Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Carragenina , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Edema/tratamento farmacológico , Edema/induzido quimicamente , Folhas de Planta/química , Estrutura Molecular
7.
Chem Biodivers ; 21(7): e202301771, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38628065

RESUMO

The crude acetone extract of a marine Micromonospora sp. strain associated with Eudistoma vannnamei was fractioned with hexane and ethyl acetate. The crude extract and both soluble fractions were assayed against several bacteria strains. The new polycyclic quinones 12-hydroxy-9-propyltetracene-6,1-dione (1), 5,12-dihydroxy-4-methoxy-9-propyltetracene-5,12-dione (2), and 4,6-dihydroxy-3-methoxycarbonyl- methyl-6a-(oxobutyl)-5,12-anthraquinone (3), along with the known 4,6-dihydroxy-3-methoxycarbonyl-methyl-6a-(oxo-3-methyl-butyl)-5,12-anthraquinone (4) and 4,6-dihydroxy-3-methoxycarbonyl-methyl-6a-(oxopentyl)-5,12-anthraquinone (5) were isolated from the hexane-soluble fraction, while from the active ethyl acetate fraction were isolated the known 4,6,11-trihydroxy-9-propyltetracene-5,12-dione (6), 4-methoxy-9-propyltetracene-6,11-dione (7), 7,8,9,10-tetrahydro-9-hydroxy-4-methoxy-9-propyltetracene-6,11-dione (8), and 10ß-carbomethoxy-7,8,9,10-tetrahydro-4,6,7α,9α,11-pentahydroxy-9-propyltetracene-5,12-dione (9). The structures of the new compounds were established by interpretation of HRMS and NMR techniques. A study of molecular docking was performed with the compounds from the active ethyl acetate fraction to correlate tentatively with the antimicrobial activity. Molecular docking, RMSD, RMSF, and MM-GBSA evaluations were performed to investigate the inhibitory activity of 6-8 against the protein PDB-codex 1MWT, being considered a promising target for studying drug development responsible for inhibiting replication of Staphylococcus aureus. Penicillin G was used as the standard inhibitory. Anthracyclinones 6-8 were the best hydrolase inhibitor with affinity energy -8.1 to -7.9 kcal/mol compared to penicillin G, which presented -6.9 kcal/mol. Both 8 and 7 present potent inhibitory effects against hydrolase through molecular dynamics simulation and exhibit favorable drug-like properties, promising new hydrolase blockers to fight bacterial infections from Staphylococcus aureus.


Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Micromonospora , Simulação de Acoplamento Molecular , Quinonas , Micromonospora/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Quinonas/química , Quinonas/farmacologia , Quinonas/isolamento & purificação , Estrutura Molecular , Compostos Policíclicos/farmacologia , Compostos Policíclicos/química , Compostos Policíclicos/isolamento & purificação
8.
Chem Biodivers ; 21(3): e202302122, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38354224

RESUMO

Griffinia gardneriana Ravenna, Griffinia liboniana Morren and Griffinia nocturna Ravenna (Amarillydaceae) are bulbous plants found in tropical regions of Brazil. Our work aimed to determine the alkaloid profiles of Griffinia spp. and evaluate their anxiolytic potential through in vivo and in silico assays. The plants grown in greenhouses were dried and their ground bulbs were subjected to liquid-liquid partitions, resulting in alkaloid fractions that were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Anxiolytic activity was evaluated in zebrafish (Danio rerio) through intraperitoneal injection at doses of 40, 100 and 200 mg/kg in light-dark box test. GC-MS analyses revealed 23 alkaloids belonging to different skeleton types: lycorine, homolychorine, galanthamine, crinine, haemanthamine, montanine and narcisclasine. The chemical profiles were relatively similar, presenting 8 alkaloids common to the three species. The major component for G. gardneriana and G. liboniana was lycorine, while G. nocturna consisted mainly of anhydrolycorine. All three alkaloid fractions demonstrated anxiolytic effect. Furthermore, pre-treatment with diazepam and pizotifen drugs was able to reverse the anxiolytic action, indicating involving the GABAergic and serotonergic receptors. Molecular docking showed that the compounds vittatine, lycorine and 11,12-dehydro-2-methoxyassoanine had high affinity with both receptors, suggesting them to be responsible for the anxiolytic effect.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Ansiolíticos , Fenantridinas , Animais , Amaryllidaceae/química , Peixe-Zebra , Ansiolíticos/farmacologia , Simulação de Acoplamento Molecular , Cromatografia Gasosa-Espectrometria de Massas/métodos , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides/farmacologia , Alcaloides/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química
9.
Chem Biodivers ; 21(4): e202400063, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38329295

RESUMO

The xanthone lichenxanthone did not show toxic effects (LC50>1.0 mg/mL). lichenxanthone prevented nociceptive behavior induced by acidic saline, and its analgesic effect was blocked by amiloride, highlighting the involvement of neuromodulation of acid-sensitive ion channels (ASICs). In the analysis of anti-inflammatory activity, concentrations of 0.1 and 0.5 mg/mL of lichenxanthone reduced the edema induced by k-carrageenan 3.5 %, observed from the fourth hour of analysis. This effect was similar to that observed with ibuprofen (positive control). No leukocyte infiltrates were observed in lichenxanthone, suggesting that the compound acts in the acute inflammatory response. The results of the molecular docking study revealed that lichenxanthone exhibited better affinity energy when compared to the ibuprofen control against the two targets evaluated.


Assuntos
Ibuprofeno , Peixe-Zebra , Animais , Simulação de Acoplamento Molecular , Anti-Inflamatórios/farmacologia , Canais Iônicos
10.
J Biomol Struct Dyn ; 42(1): 445-460, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37038661

RESUMO

General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (Danio rerio) of a natural pyrroloformamide (PFD), N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei. The complete structure of PFD was determined by a detailed NMR analysis, including 1H-13C and 1H-15N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (n = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 µL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT1, 5-HT2A/2C and 5-HTR3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.


Pyrroloformamide (PFD), isolated from the marine Streptomyces sp. associated ascidian Eudistoma vannamei, showed no toxicity in adult zebrafish but reduced its locomotor activity.The structural elucidation of PFD was determined by the analysis of 1D and 2D NMR and HRESIMS data.The density functional theory (DFT) study confirmed the existence of two conformers as determined by NMR spectra.The serotonergic system modulated the anxiolytic effect of PFD via the 5-HT receptor in adult zebrafish.Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.


Assuntos
Ansiolíticos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Peixe-Zebra , Serotonina , Flumazenil/farmacologia , Pizotilina , Simulação de Acoplamento Molecular , Granisetron , Ciproeptadina
11.
J Mycol Med ; 34(1): 101451, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38043164

RESUMO

Antifungal resistance has often been found in animal sporotrichosis in Southern Brazil. The biological potential of compounds from plants of the Solanaceae family against infectious diseases is known, however, it is still unknown against Sporothrix brasiliensis. This study evaluated the anti-Sporothrix brasiliensis activity, synergism, cytotoxicity, and action mechanism of steroidal lactones (withanolides) and alkaloids isolated from these plants. Pure compounds of withanolide D (WNOD), physalin F (PHYF), withanicandin (WNIC), nicandin B (NICB), solasonine (SSON), and solamargine (SMAR) were tested against 12 Sporothrix brasiliensis isolated from cats (n = 11) and dogs (n = 2) through M38-A2 CLSI. For the compounds with the best activity, a checkerboard assay for synergism, sorbitol protection, and ergosterol effect for action mechanism; and MTT test for cytotoxicity were performed. The withanolides WNOD, PHYF, WNIC, and NICB were not antifungal, but SSON (MIC 0.125-1 mg/mL) and SMAR (MIC 0.5-1 mg/mL) were both fungistatic and fungicidal (MFC 0.5-1 mg/mL for both) against wild-type (WT) and non-WT isolates. The activity of SSON and SMAR was indifferent when combined with itraconazole. In the mechanism of action, cell wall and plasma membrane by complexation with ergosterol seemed to be two target structures of SSON and SMAR. SSON was selected for cytotoxicity, whose cell viability in MDBK cells ranged from 28.85 % to 101.75 %, and was higher than 87.49 % at concentrations ≤0.0015 mg/ml. Only the steroidal alkaloids SSON and SMAR were active against non-WT isolates, being promising antifungal candidates for the treatment of feline and canine sporotrichosis with low susceptibility to itraconazole.


Assuntos
Alcaloides , Sporothrix , Esporotricose , Vitanolídeos , Animais , Gatos , Cães , Antifúngicos , Itraconazol , Esporotricose/microbiologia , Vitanolídeos/farmacologia , Verduras , Testes de Sensibilidade Microbiana
12.
J Appl Microbiol ; 134(8)2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37496232

RESUMO

AIMS: The aim of this study was to investigate the antibacterial and antibiofilm potential of cordiaquinones B, E, L, N, and O against different Staphylococci strains, in addition to analyzing in silico the observed effect. METHODS AND RESULTS: The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined according to CLSI guidelines. The inhibition of biofilm formation was investigated at sub-MICs. Atomic force microscopy (AFM) and density functional theory method were performed. The tested strains of Staphylococcus spp. were susceptible to cordiaquinones B, E, and L, among which cordiaquinone B exerted a bactericidal effect, confirmed by a bacterial growth curve study, against Staphylococcus saprophyticus. Cordiaquinones B and E showed lowest MBC values against S. saprophyticus. AFM revealed that cordiaquinone L reduced the mean cell size of S. saprophyticus. Cordiaquinones B and E inhibited the biofilm formation ability of S. aureus by ∼90%. The in silico analysis suggested that the antimicrobial activity of cordiaquinones is driven by their electron donation capability. CONCLUSIONS: Cordiaquinones inhibit the growth and biofilm formation (virulence factor) of both methicillin-sensitive and methicillin-resistant Staphylococci strains, indicating their antimicrobial potential.


Assuntos
Antibacterianos , Biofilmes , Staphylococcus aureus Resistente à Meticilina , Naftoquinonas , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Naftoquinonas/farmacologia , Antibacterianos/farmacologia , Simulação por Computador , Testes de Sensibilidade Microbiana , Cordia/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Viabilidade Microbiana/efeitos dos fármacos
13.
Chem Biodivers ; 20(7): e202300536, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37335297

RESUMO

In this study, twelve campesterol derivatives (2-13) were prepared by esterification reaction at the hydroxy group in C-3 and catalytic hydrogenation at the carbon-carbon double bond in C-5(6). All obtained compounds were characterized by IR, 1 H-NMR, 13 C-NMR, and MS spectra. Campesterol (1) and its derivatives (2-13) were evaluated in vitro against Staphylococcus aureus (ATCC 6538), Streptococcus mutans (ATCC 0046), Escherichia coli (ATCC 10536), Pseudomonas aeruginosa (ATCC 15442), and Klebsiella pneumoniae (ATCC 10031) using the microdilution method. Among tested compounds, 4, 6, 9, 11, 12, and 13 displayed the best antibacterial activity. Moreover, to support the antibacterial activity experiments, the investigation of molecular interactions of more active compounds, and also compound 1 and neomycin, used as starting material and positive control, respectively, at the binding site of the target proteins was performed using molecular docking simulations. Four compounds (7, 9, 10 and 11) are herein described for the first time.


Assuntos
Antibacterianos , Fitosteróis , Simulação de Acoplamento Molecular , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química
14.
Planta Med ; 89(10): 979-989, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36940928

RESUMO

Rauvolfia species are well known as producers of bioactive monoterpene indole alkaloids, which exhibit a broad spectrum of biological activities. A new vobasine-sarpagan-type bisindole alkaloid (1: ) along with six known monomeric indoles (2, 3/4, 5: , and 6/7: ) were isolated from the ethanol extract of the roots of Rauvolfia ligustrina. The structure of the new compound was elucidated by interpretation of their spectroscopic data (1D and 2D NMR and HRESIMS) and comparison with published data for analog compounds. The cytotoxicity of the isolated compounds was screened in a zebrafish (Danio rerio) model. The possible GABAergic (diazepam as the positive control) and serotoninergic (fluoxetine as the positive control) mechanisms of action in adult zebrafish were also evaluated. No compounds were cytotoxic. Compound 2: and the epimers 3: /4: and 6: /7: showed a mechanism action by GABAA, while compound 1: showed a mechanism action by a serotonin receptor (anxiolytic activity). Molecular docking studies showed that compounds 2: and 5: have a greater affinity by the GABAA receptor when compared with diazepam, whereas 1: showed the best affinity for the 5HT2AR channel when compared to risperidone.


Assuntos
Alcaloides , Ansiolíticos , Antineoplásicos , Rauwolfia , Animais , Rauwolfia/química , Ansiolíticos/farmacologia , Peixe-Zebra , Simulação de Acoplamento Molecular , Alcaloides Indólicos/química , Diazepam/farmacologia , Receptores de GABA-A , Estrutura Molecular
15.
J Biomol Struct Dyn ; 41(21): 12267-12275, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36690603

RESUMO

Since the global COVID-19 pandemic began, the scientific community has dedicated efforts to finding effective antiviral drugs to treat or minimize the effects caused by the SARS-CoV-2 coronavirus. Some targets can act as inhibitor substrates, highlighting the Main Protease (Mpro), which plays an essential role in the translation and transcription of the virus cycle. Withanolides, a class of natural C28 steroidal lactones, are compounds of interest as possible inhibitors of Mpro and other critical targets of the virus, such as papain-like protease. In this study, the isolation of a new withanolide (1), along with the known 27-deoxywithaferin A (2) and 27-deoxy-2,3-dihydrowithaferin A (3), from the leaves of Athenaea velutina (Solanaceae) is described. Their structures were determined using spectroscopic and spectrometric methods (NMR, IR, HRESIMS). Moreover, the interaction and the stability of withanolides 1-3 and withanolide D (4), previously isolated of Acnistus arborescens, against the Mpro target through molecular docking, molecular dynamics, and binding free energy simulations were analyzed. The molecular dynamics results indicated that the complexes formed by the molecular docking simulations between the Mpro target with each of the withanolides 1-4 exhibited good stability during the simulations due to a slight change in the structure of complexes. The binding free energy results suggested that withanolide (1) can be a natural candidate against COVID-19 disease.Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Solanaceae , Vitanolídeos , Humanos , Simulação de Acoplamento Molecular , Vitanolídeos/farmacologia , Pandemias , Papaína , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia , Simulação de Dinâmica Molecular
16.
Fitoterapia ; 165: 105424, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36603699

RESUMO

Five unusual kaurane diterpenes, designated as bezerraditerpenes A-E (1-5), along with six known ones (6-11), were isolated from the hexane extract of the stems of Erythroxylum bezerrae. Their structures were elucidated based on the interpretation of the NMR spectroscopy, mass spectrometry, and X-ray diffraction analysis. The anti-inflammatory potential of the diterpenes 1-11 was screened through cellular viability and lipopolysaccharide (LPS)-induced nitric oxide (NO) production on murine macrophage-like cells RAW 264.7. Diterpene 6 (cauren-6ß-ol) showed potent cytotoxicity and increased ability to inhibit NO production. Diterpenes 1 (bezerraditerpene A), 2 (bezerraditerpene B), and 8 (ent-kaur-16-ene-3ß,15ß-diol) exhibited the same significant anti-inflammatory activity with NO CI50 inhibition (3.21-3.76 µM) without cytotoxicity, in addition to decreasing the levels of pro-inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 cells.


Assuntos
Diterpenos do Tipo Caurano , Diterpenos , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Óxido Nítrico , Erythroxylaceae/química
17.
Steroids ; 189: 109137, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36375680

RESUMO

Thirteen fucosterol derivatives were prepared by structural modification at the hydroxyl group in C-3 and catalytic hydrogenation at the carbon-carbon double bond in C-5(6) and C-24(28). The structures of all compounds were established based on their spectral data (IR, MS, and NMR). Fucosterol (1) and its derivatives (2-12, and a mixture of 13a and 13b) were evaluated for their in vitro antibacterial activity against Klebsiella pneumoniae (ATCC 10031), Escherichia coli (ATCC 10536), Pseudomonas aeruginosa (ATCC 15442), Streptococcus mutans (ATCC 0046) and Staphylococcus aureus using the microdilution method. Among them, 1, 8, 9, 10, and a mixture of 13a and 13b exhibited the best antibacterial activity. The derivative 7 was inactive against all bacterial strains evaluated (MIC ≥ 2.327 mM). In addition, the investigation of binding interactions of more active compounds (1, 8, 9, 10, and mixture of 13a and 13b) to appropriate proteins was performed using molecular docking. This paper registers for the first time the in silico studies on the antibacterial activity of compounds 1, 8, 9, 10, and mixture of 13a/13b, and the spectral data of compounds 4, 6, and 7.


Assuntos
Antibacterianos , Bactérias , Simulação de Acoplamento Molecular , Testes de Sensibilidade Microbiana , Antibacterianos/química
18.
Front Immunol ; 13: 941757, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439184

RESUMO

Purpose: Some first-line cytotoxic chemotherapics, e.g. doxorubicin, paclitaxel and oxaliplatin, induce activation of the immune system through immunogenic cell death (ICD). Tumor cells undergoing ICD function as a vaccine, releasing damage-associated molecular patterns (DAMPs), which act as adjuvants, and neoantigens of the tumor are recognized as antigens. ICD induction is rare, however it yields better and long-lasting antitumor responses to chemotherapy. Advanced metastatic melanoma (AMM) is incurable for more than half of patients. The discovery of ICD inducers against AMM is an interesting drug discovery strategy with high translational potential. Here we evaluated ICD induction of four highly cytotoxic chromomycins A (CA5-8). Methods: ICD features and DAMPs were evaluated using several in vitro techniques with metastatic melanoma cell line (B16-F10) exposed to chromomcins A5-8 such as flow cytometry, western blot, RT-PCR and luminescence. Additionally in vivo vaccination assays with CA5-treated cells in a syngeneic murine model (C57Bl/6) were performed to confirm ICD evaluating the immune cells activation and their antitumor activity. Results: B16-F10 treated with CA5-8 and doxorubicin exhibited ICD features such as autophagy and apoptosis, externalization of calreticulin, and releasing of HMGB1. However, CA5-treated cells had the best profile, also inducing ATP release, ERp57 externalization, phosphorylation of eIF2α and altering expression of transcription of genes related to autophagy, endoplasmic reticulum stress, and apoptosis. Bona fide ICD induction by CA5 was confirmed by vaccination of C57BL/6 mice with CA5-treated cells which activated antigen-presenting cells and T lymphocytes and stimulated antitumor activity. Conclusion: CA5 induces bona fide immunogenic cell death on melanoma.


Assuntos
Antineoplásicos , Melanoma , Camundongos , Animais , Morte Celular Imunogênica , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Doxorrubicina , Alarminas , Linfócitos T
19.
Phytochemistry ; 203: 113338, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35948140

RESUMO

Withajardins, uncommon modified withanolide-type steroids, have been isolated exclusively from plants of the Solanaceae family so far. Two undescribed withajardins and the known tuboanosigenin were isolated from the hexane/EtOAc 1:1 extract from Athenaea velutina leaves. Their structures were established by an extensive analysis of 1D and 2D-NMR and HRMS data. The absolute configuration was determined by X-ray diffraction (withajardin L and tuboanosigenin) and circular dichroism (CD) analyses (withajardin M). The anti-inflammatory activity of compounds was evaluated through the inhibition of the lipopolysaccharide (LPS)-induced nitric oxide (NO), TNF-α, and IL-6 release in RAW264.7 cells. The cell viability effects to RAW 264.7 cells showed IC50 values of 74.4-354.4 µM. The compounds attenuated LPS-induced release of NO and decreased pro-inflammatory cytokines TNF-α and IL-6 in RAW264.7 cells.


Assuntos
Anti-Inflamatórios , Extratos Vegetais , Solanaceae , Vitanolídeos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Interleucina-6 , Lipopolissacarídeos , Camundongos , Óxido Nítrico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7 , Solanaceae/química , Fator de Necrose Tumoral alfa , Vitanolídeos/química , Vitanolídeos/farmacologia
20.
Photodiagnosis Photodyn Ther ; 39: 102869, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35462056

RESUMO

BACKGROUND: Oncocalyxone A (oncoA) is a quinone extracted from the Cordia oncocalyx plant. This compound has pharmacological properties, such as anti-inflammatory, analgesic, and cytotoxic activities, among others. OncoA presents a similar chemical structure to doxorubicin, a drug used in cancer treatment, which possesses an intrinsic fluorescence explored in various studies, including those using doxorubicin-loaded nanoparticles. Thus, due to the chemical structural similarity, the question arose whether oncoA could also show autofluorescence. Therefore, this study proposed to characterize the absorption and emission spectral profiles of oncoA and analyze if this compound could be used as a fluorescent probe. METHODS: For this, fucoidan-coated polyisobutylcyanoacrylate (PIBCA) nanoparticles containing oncoA were prepared, and an uptake study was performed using a human metastatic breast cancer cell line (MDA-MB-231 cells). RESULTS: OncoA presented a maximum emission wavelength in the blue region, near 430 nm, at 350 nm excitation, compatible with standard microscope optics. Fluorescence microscopy analyses showed that oncoA-loaded PIBCA nanoparticles were internalized by MDA-MB-231 cells under incubation times as shorter as 15 min. CONCLUSION: According to these findings, oncoA-encapsulated nanoparticles are promising fluorescent probes and could be useful for cellular uptake studies.


Assuntos
Nanopartículas , Fotoquimioterapia , Antraquinonas , Linhagem Celular Tumoral , Doxorrubicina , Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Nanopartículas/química , Fotoquimioterapia/métodos
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