Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.263
Filtrar
1.
Biochem Biophys Res Commun ; 573: 42-47, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34388453

RESUMO

Cisplatin is an approved cancer therapeutic drug used to treat many solid tumors but its accumulation in the kidney, which causes nephrotoxicity, limits its clinical use. Therefore, investigators seek new alternatives to cisplatin that may be more effective and/or safer. Thiosemicarbazides are of great significance due to their expected biological activity including anticancer activities. The aim of this work is the study of the antitumor effect of Schiff base 4-ethyl-1-(pyridin-2-yl) thiosemicarbazide (HEPTS) on Ehrlich solid tumor-bearing mice in comparison to cancer therapeutic drug cisplatin. The experiment was run using sixty adult female Swiss albino mice. Mice were allocated into six groups (n = 10 mice). Healthy control, EAC control (untreated tumor), EAC + cisplatin, EAC + HEPTS, Healthy + HEPTS, and Healthy + solvent. After scarification, blood samples, liver organs, and solid tumors were collected. Tumor weights and volumes were registered. The concentrations of malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase (CAT), total antioxidant capacity (TAC), nitric oxide (NO), uric acid, creatinine, and urea were assessed. Median survival time (MST) and the percentage increase in lifespan (%ILS) were also calculated. Treatment of tumorized mice with HEPTS significantly reduced both tumor volume and weight while it significantly increased the MST, antioxidant marks and prolonged the %ILS. It also, significantly reduced MAD, creatinine, urea, uric acid, and NO levels. Compared to cisplatin, HEPTS effects were better. Our results recommend HEPTS as one of the probable cisplatin-alternatives for tumor treatment after more validation.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/metabolismo , Carcinoma de Ehrlich/tratamento farmacológico , Semicarbazidas/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Antineoplásicos/química , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Feminino , Camundongos , Estrutura Molecular , Bases de Schiff/química , Bases de Schiff/farmacologia , Semicarbazidas/química
2.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199486

RESUMO

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a-3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a-3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.


Assuntos
Acetofenonas/química , Analgésicos/administração & dosagem , Analgésicos/síntese química , Dor/tratamento farmacológico , Receptores Opioides/metabolismo , Semicarbazidas/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Naloxona/administração & dosagem , Naloxona/farmacologia , Dor/metabolismo , Conformação Proteica , Receptores Opioides/química , Receptores Opioides delta/química , Receptores Opioides delta/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo
3.
J Enzyme Inhib Med Chem ; 36(1): 1145-1164, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34074198

RESUMO

We report herein anti-proliferation effects of 4-arylthiosemicarbazides, with a cyclopentane substitution at N1 position, on highly virulent RH strain of Toxoplasma gondii. Among them, the highest in vitro anti-Toxoplasma activity was found with the meta-iodo derivative. Further experiments demonstrated inhibitory effects of thiosemicarbazides on tyrosinase (Tyr) activity, and good correlation was found between percentage of Tyr inhibition and IC50Tg. To confirm the concept that thiosemicarbazides are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites, the most potent Tyr inhibitors were tested for their efficacy of T. gondii growth inhibition. All of them significantly reduced the number of tachyzoites in the parasitophorous vacuoles (PVs) compared to untreated cells, as well as inhibited tachyzoites growth by impeding cell division. Collectively, these results indicate that compounds with the thiosemicarbazide scaffold are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites by deregulation of their crucial enzyme tyrosine hydroxylase (TyrH).


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Semicarbazidas/farmacologia , Toxoplasma/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Testes de Sensibilidade Parasitária , Semicarbazidas/síntese química , Semicarbazidas/química , Relação Estrutura-Atividade , Toxoplasma/crescimento & desenvolvimento
4.
Molecules ; 26(7)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33916423

RESUMO

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (1H, 13C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 µM. In addition, six other synthesized compounds, 5a and 5c-5g, exhibited moderate activity, with MIC ranges between 60 µM to 140 µM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 µM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand-receptor interactions, and to hypothesize potential refinements for the compound.


Assuntos
Inibidores de 14-alfa Desmetilase/síntese química , Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Pirazóis/síntese química , Semicarbazidas/síntese química , Esterol 14-Desmetilase/química , Inibidores de 14-alfa Desmetilase/farmacologia , Antituberculosos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Fluconazol/química , Fluconazol/farmacologia , Isoniazida/química , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Pirazóis/farmacologia , Semicarbazidas/farmacologia , Esterol 14-Desmetilase/metabolismo , Homologia Estrutural de Proteína , Termodinâmica
5.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918623

RESUMO

Compounds targeting bacterial topoisomerases are of interest for the development of antibacterial agents. Our previous studies culminated in the synthesis and characterization of small-molecular weight thiosemicarbazides as the initial prototypes of a novel class of gyrase and topoisomerase IV inhibitors. To expand these findings with further details on the mode of action of the most potent compounds, enzymatic studies combined with a molecular docking approach were carried out, the results of which are presented herein. The biochemical assay for 1-(indol-2-oyl)-4-(4-nitrophenyl) thiosemicarbazide (4) and 4-benzoyl-1-(indol-2-oyl) thiosemicarbazide (7), showing strong inhibitory activity against Staphylococcus aureus topoisomerase IV, confirmed that these compounds reduce the ability of the ParE subunit to hydrolyze ATP rather than act by stabilizing the cleavage complex. Compound 7 showed better antibacterial activity than compound 4 against clinical strains of S. aureus and representatives of the Mycobacterium genus. In vivo studies using time-lapse microfluidic microscopy, which allowed for the monitoring of fluorescently labelled replisomes, revealed that compound 7 caused an extension of the replication process duration in Mycobacterium smegmatis, as well as the growth arrest of bacterial cells. Despite some similarities to the mechanism of action of novobiocin, these compounds show additional, unique properties, and can thus be considered a novel group of inhibitors of the ATPase activity of bacterial type IIA topoisomerases.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/enzimologia , Semicarbazidas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Antibacterianos/química , Sítios de Ligação , DNA Girase/química , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Semicarbazidas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-33872132

RESUMO

An ultra-performance liquid chromatography coupled with electrospray ionisation tandem mass spectrometry (UPLC-ESI-MS/MS) with pre-column derivatisation was developed and validated for the determination of semicarbazide in human urine. Urine samples were derivatised with 2-nitrobenzaldehyde and subsequently extracted with acetonitrile. Extracts were concentrated and then analysed by UPLC-MS/MS. The time per run was 7 min. Good results were observed for the linearity of matrix-matched calibration curves (R2 > 0.99) in the concentration range of 1-100 µg/L. The absolute recovery ranged from 98.7% to 108.6%, with the relative standard deviations (RSDs) of 2.2%-3.6%. The limit of detection and quantification for the semicarbazide was 0.5 µg/L and 1 µg/L, respectively. The method showed good extraction efficiency, high sensitivity, and good reproducibility. It was suitable for the detection of semicarbazide in human urine. Residues of semicarbazide were between 1.0 and 41.5 µg/L in children's 24-h urine. This work is the first report on the quantitative analysis of SEM in 24-h human urine samples.


Assuntos
Semicarbazidas/isolamento & purificação , Semicarbazidas/urina , Acetonitrilas/química , Benzaldeídos/química , Técnicas Biossensoriais , Criança , Pré-Escolar , China , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Limite de Detecção , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
7.
Carbohydr Polym ; 257: 117618, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33541646

RESUMO

A strategy to optimize the labeling of the reducing end of native cellulose nanocrystals (CNCs) with gold nanoparticles (AuNPs) was developed and used to investigate the arrangement of the elementary crystallites constituting these biosourced particles. First, CNCs pre-functionalized with thiosemicarbazide molecules were reacted with presynthesized AuNPs. A second method consisted in synthesizing AuNPs in situ from soluble gold derivatives in the presence of CNCs regioselectively functionalized with thiosemicarbazide molecules. Transmission electron microscopy images revealed that the direct reaction resulted in a low labeling yield and the undesired formation of AuNP aggregates. Oppositely, unprecedent high labeling yields were achieved through the in situ growth approach, with a vast majority of CNCs bearing one or several AuNPs on one end. These results evidence that cotton-derived CNCs are composed of the unidirectional assembly of chemically polar elementary crystallites, implying that the acid hydrolysis isolates fragments of microfibril bundles present in the cell walls.


Assuntos
Celulose/química , Fibra de Algodão , Ouro/química , Nanopartículas Metálicas/química , Microfibrilas/química , Nanopartículas/química , Aldeídos/química , Parede Celular/metabolismo , Hidrólise , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Semicarbazidas/química , Enxofre/química , Madeira , Difração de Raios X
8.
Anal Chem ; 93(10): 4391-4397, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33617243

RESUMO

Intracellular viscosity is a physicochemical factor that determines the outcomes of various biological processes, while nitric oxide (NO) is an essential signaling molecule that controls many cellular processes, including oxidative stress. Anticipating that both may be interrelated with a variety of pathologies, their simultaneous measurement would be highly valuable for the investigation of the pathological condition of cells. However, the development of a sensor for such simultaneous detection has not been attempted yet. Herein, we present the synthesis of naphthalimide-4-(4-nitrophenyl)thiosemicarbazide, probe 1, and its application to living cells under conditions of lipopolysaccharide or nystatin treatment, adopted as oxidative stress and altered intracellular viscosity models, respectively. The probe showed increased fluorescence in response to elevation of viscosity and NO levels at 470 and 550 nm, respectively, in the solution studies. When the probe was used for a confocal microscopic study of HeLa cells under stressed conditions, simultaneous monitoring of viscosity and NO level elevations was possible through fluorescence imaging using band-pass filters of 420-475 and 505-600 nm, respectively, upon excitation at a wavelength of 405 nm. Interestingly, both the cellular viscosity and NO levels increased together under lipopolysaccharide or nystatin treatment. Therefore, we suggest that probe 1 is a fluorescent chemical probe that enables the monitoring of alterations in intracellular viscosity and NO levels in living cells, which would be valuable in studies of various cellular damage models.


Assuntos
Corantes Fluorescentes , Naftalimidas , Células HeLa , Humanos , Microscopia de Fluorescência , Óxido Nítrico , Nitrofenóis , Semicarbazidas , Viscosidade
9.
J Ethnopharmacol ; 272: 113955, 2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-33610704

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: The decoction from the stem bark of Psychotria camptopus (Rubiaceae) is used in the Cameroonian pharmacopoeia to treat neurological pathologies including epilepsy. AIM: The present work was undertaken to study the anticonvulsant properties of the aqueous (AE) and methanol (ME) extracts from the stem bark of P. camptopus in acute models of epileptic seizures in Wistar rats. METHOD: AE and ME were obtained by decoction and maceration of the stem bark powder in water and methanol, respectively. They were tested orally at the doses of 40, 80 and 120 mg/kg, on the latency of onset and duration of epileptic seizures induced by pentylene tetrazole (PTZ, 70 mg/kg, i.p.). The kinetic effect of both extracts at 120 mg/kg was evaluated. Their effects on diazepam (50 mg/kg) induced sleep and strychnine (STR, 2.5 mg/kg, i.p.) induced seizures were determined. ME was further tested on picrotoxin (PIC, 7.5 mg/kg, i.p.) and thiosemicarbazide (TSC, 50 mg/kg, i.p.) induced seizure models. The phytochemical composition of ME was assessed using LC-MS method, as well as its acute toxicity. RESULTS: AE and ME significantly (p < 0.001) reduced the duration of seizures in both PTZ and STR models. Their maximal effect was observed at 1 h after administration, though their effect at 120 mg/kg was maintained (p < 0.05) up to 24 h post-treatment. Both extracts significantly (p < 0.01) reduced sleep duration. ME significantly (p < 0.001) increased the latency of rat death on PIC-induced convulsions. In TSC rats, ME significantly (p < 0.001) delayed the latency to the first convulsion, and decreased the duration and frequency of convulsions. ME showed no acute toxicity while its phytochemical screening revealed the presence of two flavonoids (Rutin and Butin), two triterpenoid saponins (Psycotrianoside B and Bauerenone) and four alkaloids (10-Hydroxy-antirhine, 10-hydroxy-iso-deppeaninol, Emetine and Hodkinsine). In conclusion, AE and ME from the stem bark of P. camptopus have comparable anticonvulsant properties. The effect of ME is likely due to the presence of flavonoids and alkaloid and the activation of GABA pathway. These results further justify and support the use of P. camptopus in traditional medicine for the treatment of epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Extratos Vegetais/farmacologia , Psychotria/química , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/toxicidade , Comportamento Animal/efeitos dos fármacos , Diazepam/farmacologia , Diazepam/uso terapêutico , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Metanol/química , Camundongos , Pentilenotetrazol/toxicidade , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Picrotoxina/toxicidade , Casca de Planta/química , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Caules de Planta/química , Ratos Wistar , Convulsões/induzido quimicamente , Semicarbazidas/toxicidade , Sono/efeitos dos fármacos , Latência do Sono/efeitos dos fármacos , Estricnina/toxicidade , Água/química
10.
Bioorg Med Chem Lett ; 36: 127826, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33513384

RESUMO

Theophylline is long known for its anti-ageing and anti-oxidative properties. Moreover, Tyrosinase is a crucial enzyme that regulates the melanin synthetic pathway, which is involved in various physiological metabolic processes including aging. The current paper describes the synthesis of various heterocyclic systems coupled with theophylline moiety along with their tyrosinase inhibition activity in view to identify the potent nucleus. Around 19 compounds were synthesized and screened for enzyme inhibition. Based on the current study, it is suggested that compound 18 having thiosemicarbazide has strong enzyme inhibition potential. The enzyme kinetics and docking studies provide important insights into how the compound interacts with the mushroom tyrosinase active site. The work will provide clue to developing new, potent tyrosinase inhibitors for drug development.


Assuntos
Complexos de Coordenação/farmacologia , Cobre/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Semicarbazidas/farmacologia , Teofilina/farmacologia , Agaricales/enzimologia , Sítios de Ligação , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Semicarbazidas/química , Relação Estrutura-Atividade , Teofilina/química
11.
J Enzyme Inhib Med Chem ; 36(1): 295-306, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33404277

RESUMO

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5-2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure-activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.


Assuntos
Anti-Infecciosos/síntese química , Proteínas de Bactérias/química , Carbazóis/síntese química , Inibidores Enzimáticos/síntese química , Escherichia coli/efeitos dos fármacos , Tetra-Hidrofolato Desidrogenase/química , Anti-Infecciosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Candida albicans/crescimento & desenvolvimento , Carbazóis/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/crescimento & desenvolvimento , Guanidinas/química , Hepatócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ácidos Isonicotínicos/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Semicarbazidas/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Staphylococcus aureus/crescimento & desenvolvimento , Streptococcus mutans/efeitos dos fármacos , Streptococcus mutans/enzimologia , Streptococcus mutans/crescimento & desenvolvimento , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismo , Triazinas/química
12.
Mol Divers ; 25(1): 13-27, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916112

RESUMO

A new series of 6-substituted quinolin-2-one thiosemicarbazides 6a-j has been synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analyses. All the designed final compounds were evaluated for their in vitro activity against the urease-producing R. mucilaginosa and Proteus mirabilis bacteria as fungal and bacterial pathogens, respectively. Moreover, all compounds were in vitro tested as potential urease inhibitors using the cup-plate diffusion method. Compounds 6a and 6b were the most active with (IC50 = 0.58 ± 0.15 and 0.43 ± 0.09 µM), respectively, in comparison with lead compound I (IC50 = 1.13 ± 0.00 µM). Also, the designed compounds were docked into urease proteins (ID: 3LA4 and ID: 4UBP) using Open Eye® software to understand correctly about ligand-receptor interactions. The docking results revealed that the designed compounds can interact with the active site of the enzyme through multiple strong hydrogen bonds. Moreover, rapid overlay of chemical structures' analysis was described to understand the 3D QSAR of synthesized compounds as urease inhibitors. The results emphasize the importance of polar thiosemicarbazide directly linked to 6-substituted quinolone moieties as promising antimicrobial urease inhibitors.


Assuntos
Anti-Infecciosos/farmacologia , Inibidores Enzimáticos/farmacologia , Semicarbazidas/farmacologia , Urease/antagonistas & inibidores , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Domínio Catalítico/efeitos dos fármacos , Fungos/efeitos dos fármacos , Fungos/metabolismo , Simulação de Acoplamento Molecular/métodos , Quinolonas/farmacologia , Relação Estrutura-Atividade
13.
Molecules ; 25(20)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053830

RESUMO

Docking of over 160 aminothiourea derivatives at the SARS-CoV-2 S-protein-human ACE2 receptor interface, whose structure became available recently, has been evaluated for its complex stabilizing potency and subsequently subjected to quantitative structure-activity relationship (QSAR) analysis. The structural variety of the studied compounds, that include 3 different forms of the N-N-C(S)-N skeleton and combinations of 13 different substituents alongside the extensive length of the interface, resulted in the failure of the QSAR analysis, since different molecules were binding to different parts of the interface. Subsequently, absorption, distribution, metabolism, and excretion (ADME) analysis on all studied compounds, followed by a toxicity analysis using statistical models for selected compounds, was carried out to evaluate their potential use as lead compounds for drug design. Combined, these studies highlighted two molecules among the studied compounds, i.e., 5-(pyrrol-2-yl)-2-(2-methoxyphenylamino)-1,3,4-thiadiazole and 1-(cyclopentanoyl)-4-(3-iodophenyl)-thiosemicarbazide, as the best candidates for the development of future drugs.


Assuntos
Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Semicarbazidas/química , Glicoproteína da Espícula de Coronavírus/química , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/efeitos dos fármacos , COVID-19 , Infecções por Coronavirus/virologia , Humanos , Modelos Estatísticos , Estrutura Molecular , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo
14.
Future Med Chem ; 12(18): 1633-1645, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32892642

RESUMO

Background: Identification of novel Ure inhibitors with high potency has received considerable attention. Methodology & results: Ure inhibition was determined using the indophenol method, the affinities to Ure were estimated via surface plasmon resonance. Seventeen new plus ten known N-monosubstituted thiosemicarbazides were synthesized and identified as novel Ure inhibitors. Out of these compounds, compound b5 shows excellent activity against both crude Ure from Helicobacter pylori (IC50 = 0.04 µM) and Ure in living cell (IC50 = 0.27 µM), with the potency being over 600-fold higher than clinical used drug acetohyroxamic acid, respectively. Surface plasmon resonance demonstrated the high affinity (Kd.#x00A0;= 6.32 nM) of b5 to Ure. Conclusion: This work provides a class of novel and promising Ure inhibitors.


Assuntos
Antibacterianos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Semicarbazidas/farmacologia , Fatores de Virulência/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Helicobacter pylori/citologia , Helicobacter pylori/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Semicarbazidas/síntese química , Semicarbazidas/química , Fatores de Virulência/metabolismo
15.
Bioconjug Chem ; 31(10): 2288-2292, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-32960584

RESUMO

Bioorthogonal click reactions yielding stable and irreversible adducts are in high demand for in vivo applications, including in biomolecular labeling, diagnostic imaging, and drug delivery. Previously, we reported a novel bioorthogonal "click" reaction based on the coupling of ortho-acetyl arylboronates and thiosemicarbazide-functionalized nopoldiol. We now report that a detailed structural analysis of the arylboronate/nopoldiol adduct by X-ray crystallography and 11B NMR reveals that the bioorthogonal reactants form, unexpectedly, a tetracyclic adduct through the cyclization of the distal nitrogen into the semithiocarbazone leading to a strong B-N dative bond and two new 5-membered rings. The cyclization adduct, which protects the boronate unit against hydrolytic breakdown, sheds light on the irreversible nature of this polycondensation. The potential of this reaction to work in a live animal setting was studied through in vivo capture of fluorescently labeled molecules in vivo. Arylboronates were introduced into tissues through intradermal injection of their activated NHS esters, which react with amines in the extracellular matrix. Fluorescently labeled nopoldiol molecules were administered systemically and were efficiently captured by the arylboronic acids in a location-specific manner. Taken together, these in vivo proof-of-concept studies establish arylboronate/nopoldiol bioorthogonal chemistry as a candidate for wide array of applications in chemical biology and drug delivery.


Assuntos
Ácidos Borônicos/química , Semicarbazidas/química , Animais , Ácidos Borônicos/síntese química , Química Click/métodos , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Semicarbazidas/síntese química
16.
Int J Biol Macromol ; 164: 2953-2963, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846183

RESUMO

Naja atra cobrotoxin and cardiotoxin 3 (CTX3) exhibit neurotoxicity and cytotoxicity, respectively. In the present study, we aimed to investigate whether the carboxyl groups of cobrotoxin play a role in structural constraints, thereby preventing cobrotoxin from exhibiting cytotoxic activity. Six of the seven carboxyl groups in cobrotoxin were conjugated with semicarbazide. Measurement of circular dichroism spectra and Trp fluorescence quenching showed that the gross conformation of semicarbazide-modified cobrotoxin (SEM-cobrotoxin) and cobrotoxin differed. In sharp contrast to cobrotoxin, SEM-cobrotoxin demonstrated membrane-damaging activity and cytotoxicity, which are feature more characteristic of CTX3. Furthermore, both SEM-cobrotoxin and CTX3 induced cell death through AMPK activation. Analyses of the interaction between polydiacetylene/lipid vesicles and fluorescence-labeled lipids revealed that SEM-cobrotoxin and cobrotoxin adopted different membrane-bound states. The structural characteristics of SEM-cobrotoxin were similar to those of CTX3, including trifluoroethanol (TFE)-induced structural transformation and membrane binding-induced conformational change. Conversely, cobrotoxin was insensitive to the TFE-induced effect. Collectively, the data of this study indicate that blocking negatively charged residues confers cobrotoxin with membrane-damaging activity and cytotoxicity. The findings also suggest that the structural constraints imposed by carboxyl groups control the functional properties of snake venom α-neurotoxins during the divergent evolution of snake venom neurotoxins and cardiotoxins.


Assuntos
Antineoplásicos/química , Proteínas Cardiotóxicas de Elapídeos/química , Proteínas Neurotóxicas de Elapídeos/química , Naja naja/metabolismo , Semicarbazidas/química , Proteínas Quinases Ativadas por AMP/metabolismo , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Proteínas Cardiotóxicas de Elapídeos/farmacologia , Proteínas Neurotóxicas de Elapídeos/farmacologia , Humanos , Modelos Moleculares , Conformação Proteica
17.
Mini Rev Med Chem ; 20(20): 2135-2152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32811412

RESUMO

The challenges of viral infection have increased in recent decades due to the emergence of resistance, cross-resistance and drying up of antiviral drug discovery. Many neglected tropical viruses including the chikungunya virus, dengue virus & Japanese encephalitis virus have gradually become global pathogens. This has further increased the burden of viral infection which necessitates the continuous development of antiviral therapy. The antiviral chemistry began with the development of thiosemicarbazide derived thiosemicarbazones as antiviral. Although very few thiosemicarbazides have progressed into clinical application, it still inspires antiviral development. During last 3 decades (1990- 2020), several efforts have been made to develop suitable antiviral by using thiosemicarbazide scaffold. Its hybridization with other pharmacophores has been used as a strategy to enhance safety and efficacy. Cyclization and substitution of thiosemicarbazides have also been used to develop potent antiviral. With the ability to form coordinate bonds, thiosemicarbazides have been used either as metal complex or chelator against viruses. This work is an attempt to systematically review the research on the use of thiosemicarbazides as an antiviral scaffold. It also reviews the structure-activity relationship and translational suitability of thiosemicarbazide derived compounds.


Assuntos
Antivirais/farmacologia , Semicarbazidas/farmacologia , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Humanos , Testes de Sensibilidade Microbiana , Semicarbazidas/síntese química , Semicarbazidas/química
18.
Braz J Microbiol ; 51(4): 1465-1473, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32638273

RESUMO

Vulvovaginal candidiasis is a serious health problem affecting numerous women around the world. Its treatment is based on antifungals which may not provide an effective cure because of the resistance presented by its etiological pathogens Candida spp. Candida albicans is the most prevalent species related to vulvovaginal candidiasis. Here, we evaluated the in vivo antifungal potential of thiosemicarbazide and thiosemicarbazide encapsulated within chitosan nanoparticles in a murine model of vulvovaginal candidiasis. The results demonstrated the antifungal capacity of free or nanoencapsulated thiosemicarbazide within chitosan to reduce the fungal load in the vaginal tissue of infected mice. In addition, histological analyses indicated the absence or a mild to moderate infection in thiosemicarbazide-treated groups. Statistical tests confirmed the existence of significant differences between the treated and the control groups. Therefore, our results suggest a potential application of thiosemicarbazide and encapsulated thiosemicarbazide as an alternative vulvovaginal candidiasis therapy.


Assuntos
Antifúngicos , Candidíase Vulvovaginal/tratamento farmacológico , Semicarbazidas , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Quitosana , Avaliação Pré-Clínica de Medicamentos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas , Semicarbazidas/administração & dosagem , Semicarbazidas/farmacologia , Vagina/microbiologia
19.
Sci Rep ; 10(1): 12763, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728062

RESUMO

Bacteria are known to evade ß-lactam antibiotic action by producing ß-lactamases (BLs), including carbapenemases, which are able to hydrolyze nearly all available ß-lactams. The production of BLs represents one of the best known and most targeted mechanisms of resistance in bacteria. We have performed the parallel screening of commercially available compounds against a panel of clinically relevant BLs: class A CTX-M-15 and KPC-2, subclass B1 NDM-1 and VIM-2 MBLs, and the class C P. aeruginosa AmpC. The results show that all BLs prefer scaffolds having electron pair donors: KPC-2 is preferentially inhibited by sulfonamide and tetrazole-based derivatives, NDM-1 by compounds bearing a thiol, a thiosemicarbazide or thiosemicarbazone moiety, while VIM-2 by triazole-containing molecules. Few broad-spectrum BLs inhibitors were identified; among these, compound 40 potentiates imipenem activity against an NDM-1-producing E. coli clinical strain. The binary complexes of the two most promising compounds binding NDM-1 and VIM-2 were obtained at high resolution, providing strong insights to improve molecular docking simulations, especially regarding the interaction of MBLs with inhibitors.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Serina/química , Inibidores de beta-Lactamases/farmacologia , Antibacterianos/farmacologia , Cristalografia por Raios X , Bases de Dados de Proteínas , Desenho de Fármacos , Descoberta de Drogas , Escherichia coli/efeitos dos fármacos , Hidrólise , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Proteínas Recombinantes/química , Semicarbazidas/química , Compostos de Sulfidrila/química , Sulfonamidas/química , Tetrazóis/química , beta-Lactamases
20.
Food Chem ; 333: 127524, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679418

RESUMO

Semicarbazide (SEM) is a protein-bound nitrofurazone metabolite that is detrimental to human health. Therefore, to ensure food safety, it is necessary to detect SEM in food samples. To this end, we developed a novel electrochemical sensor to detect SEM by using a molecularly imprinted polymer (MIP) as the recognition element. Computer-aided molecular modelling was performed to guide the synthesis of the MIP, and subsequently, MIP/carboxylated single-walled carbon-nanotubes/chitosan (MIP/SWNTs-COOH/CS) was prepared as the sensing platform to develop the electrochemical sensor. The linear range of the sensor was 0.04-7.6 ng mL-1, with a detection limit of 0.025 ng mL-1. The sensor was successfully applied to detect SEM in four different real samples, with recoveries ranging from 83.16% to 93.40%. The results indicated that the fabricated electrochemical sensor can be widely applied to detect SEM in the environment and in agri-food products.


Assuntos
Quitosana/química , Técnicas Eletroquímicas/métodos , Impressão Molecular , Nanotubos de Carbono/química , Semicarbazidas/análise , Eletrodos , Mel/análise , Humanos , Limite de Detecção , Carne/análise , Polímeros/química , Reprodutibilidade dos Testes , Alimentos Marinhos/análise
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...