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1.
Eur J Med Chem ; 188: 112021, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901743

RESUMO

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/toxicidade , Domínio Catalítico , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/toxicidade , Pirróis/síntese química , Pirróis/toxicidade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade
2.
Environ Pollut ; 256: 113550, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31706782

RESUMO

Per- and polyfluoroalkyl substances (PFASs) have been used for decades within industrial processes and consumer products, resulting in frequent detection within the environment. Using zebrafish embryos, we screened 38 PFASs for developmental toxicity and revealed that perfluorooctanesulfonamide (PFOSA) was the most potent developmental toxicant, resulting in elevated mortality and developmental abnormalities following exposure from 6 to 24 h post fertilization (hpf) and 6 to 72 hpf. PFOSA resulted in a concentration-dependent increase in mortality and abnormalities, with surviving embryos exhibiting a >12-h delay in development at 24 hpf. Exposures initiated at 0.75 hpf also resulted in a concentration-dependent delay in epiboly, although these effects were not driven by a specific sensitive window of development. We relied on mRNA-sequencing to identify the potential association of PFOSA-induced developmental delays with impacts on the embryonic transcriptome. Relative to stage-matched vehicle controls, these data revealed that pathways related to hepatotoxicity and lipid transport were disrupted in embryos exposed to PFOSA from 0.75 to 14 hpf and 0.75 to 24 hpf. Therefore, we measured liver area as well as neutral lipids in 128-hpf embryos exposed to vehicle (0.1% DMSO) or PFOSA from 0.75 to 24 hpf and clean water from 24 to 128 hpf, and showed that PFOSA exposure from 0.75 to 24 hpf resulted in a decrease in liver area and increase in yolk sac neutral lipids at 128 hpf. Overall, our findings show that early exposure to PFOSA adversely impacts embryogenesis, an effect that may lead to altered lipid transport and liver development.


Assuntos
Fluorcarbonetos/toxicidade , Sulfonamidas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Fluorcarbonetos/metabolismo , Substâncias Perigosas/metabolismo , RNA Mensageiro/metabolismo , Testes de Toxicidade , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
3.
Pestic Biochem Physiol ; 158: 12-17, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378346

RESUMO

Lithospermum arvense is a troublesome dicotyledonous winter annual weed of wheat in China. A L. arvense population (HN01) suspected of being resistant to acetolactate synthase (ALS) inhibitors was found in Henan Province, China. This study aimed to testify the sensitivity of this HN01 population to eight herbicides from 3 different modes of action, and to explore the potential target-site-resistance mechanism to tribenuron-methyl. The whole-plant bioassays indicated that the population was highly resistant to tribenuron-methyl (SU, 350-fold), pyrithiobac sodium (PTB, 151-fold), pyroxsulam (TP, 62.7-fold), florasulam (TP, 80.6-fold), and imazethapyr (IMI, 136-fold), but was sensitive to carfentrazone-ethyl and fluroxypyr-meptyl. ALS gene sequencing revealed that the Trp (TGG) was substituted by Leu (TTG) at codon 574 in resistant plants. In in vitro ALS assays, the concentration of tribenuron-methyl required to inhibit 50% ALS activity (I50) for HN01 was 117-fold greater than that required to inhibit a susceptible population (HN05), indicating that resistance was due to reduced sensitivity of the ALS enzyme to tribenuron-methyl. To the best of our knowledge, this is the first report of ALS gene Trp-574-Leu amino acid mutation confer resistance to tribenuron-methyl in L. arvense.


Assuntos
Acetolactato Sintase/genética , Lithospermum/efeitos dos fármacos , Lithospermum/enzimologia , Mutação/genética , Sulfonatos de Arila/toxicidade , Benzoatos/toxicidade , Resistência a Herbicidas/genética , Herbicidas/toxicidade , Lithospermum/genética , Ácidos Nicotínicos/toxicidade , Proteínas de Plantas/genética , Pirimidinas/toxicidade , Sulfonamidas/toxicidade
4.
Sci Total Environ ; 689: 245-257, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271990

RESUMO

In this study, the degradation of Nimesulide (NIM), a non-steroidal anti-inflammatory drug, using photolysis, heterogeneous (TiO2 in dispersion) and homogeneous (photo-Fenton reactant) photocatalysis, under simulated solar light (SSL) radiation, was investigated. Various parameters affecting the degradation rate of the target compound during the applied processes were optimized. The efficiency of all treatments used (direct photolysis; TiΟ2/SSL; TiΟ2/Η2Ο2/SSL; TiΟ2/S2Ο82-/SSL; Fe3+/H2O2/SSL; Fe3+/S2O82-/SSL and [Fe(C2O4)3]3-/H2O2/SSL) was evaluated by means of initial reaction rate and mineralization. Moreover, the generated transformation products (TPs) by each basic process (photolysis; TiΟ2/SSL and Fe3+/H2O2/SSL) were identified, using liquid chromatography coupled to high resolution mass spectrometry, and their formation kinetic profiles were given. The main transformation routes of NIM were hydroxylation and fragmentation, for all three treatments applied. Finally, toxicity measurements were conducted using Microtox bioassay in order to evaluate the potential risk of NIM and its TPs to aqueous organisms. Although, the acute toxicity increased during the first stages of treatment the final outcome lead to very low toxicity levels even within 60 min of TiO2/SSL treatment. Concluding, the obtained results suggest that the photocatalytic degradation of NIM can lead to its complete elimination and simultaneously to the detoxification of the solution.


Assuntos
Anti-Inflamatórios não Esteroides/análise , Fotólise , Sulfonamidas/análise , Titânio/química , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/análise , Aliivibrio fischeri/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/toxicidade , Catálise , Cinética , Sulfonamidas/toxicidade , Luz Solar , Testes de Toxicidade Aguda , Águas Residuárias/toxicidade
5.
Environ Sci Pollut Res Int ; 26(23): 23242-23256, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31190300

RESUMO

The aim of this study was to verify the effects of the isolated forms of Boral® SC 500, Glifosato® Biocarb herbicides, and a blend of both herbicides on metabolism and oxidative balance markers of Rana catesbeiana tadpoles and on their nutritional condition. Groups of tadpoles were divided into different treatments: control (no herbicides), Boral® 500 SC (sulfentrazone: 130 µg/L), Glifosato® Biocarb (glyphosate: 234 µg/L), and a blend of both herbicides. After 7 days, the liver, caudal muscle, and blood samples were taken to subsequently perform the biomarkers determination by spectrophotometry. The intestinal condition factor increased in animals exposed to glyphosate and herbicide blends, suggesting a hyperphagic effect. This hypothesis was confirmed by the rise of triglycerides and circulating very low-density lipoprotein (VLDL). There was a significant increase in the levels of uric acid in tadpoles exposed to the herbicide blend. Corticosterone levels reduced significantly in animals exposed to glyphosate and the herbicide blend. Oxidative stress markers had a tissue-dependent response. In the liver, glutathione S-transferase increased, and superoxide dismutase and catalase decreased in animals exposed to sulfentrazone and glyphosate. Lipoperoxidation was reduced in the glyphosate treatment. In the caudal muscle, superoxide dismutase and catalase activities were maintained, and there was a decline in the levels of glutathione S-transferase and TBARS only in the blend group.


Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Larva/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sulfonamidas/toxicidade , Triazóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Glicina/metabolismo , Glicina/toxicidade , Herbicidas/metabolismo , Larva/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculos/efeitos dos fármacos , Músculos/metabolismo , Rana catesbeiana , Sulfonamidas/metabolismo , Triazóis/metabolismo , Poluentes Químicos da Água/metabolismo
6.
Ecotoxicol Environ Saf ; 181: 138-145, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176248

RESUMO

While N-ethyl perfluorooctane sulfonamidoethanol (EtFOSE) is a precursor of perfluorooctane sulfonate (PFOS), its bioaccumulation, transformation and toxicological effects in earthworms (Eisenia fetida) exposed to quartz sands are poorly understood. The present study showed that except for parent EtFOSE, N-ethylperfluorooctane sulfonamide acetate (EtFOSAA), N-ethyl perfluorooctane sulfonamide (EtFOSA), perfluorooctane sulfonamide acetate (FOSAA), perfluorooctane sulfonamide (FOSA) and PFOS were detected in earthworms, with EtFOSAA as the primary biotransformation product. The biota-to-sand accumulation factor (BSAF) and uptake rate coefficient (ku) of EtFOSE were 5.7 and 0.542/d, respectively. The elimination rate constants (ke) decreased in the order EtFOSA (0.167/d) ∼ FOSAA (0.147/d) > FOSA (0.119/d) ∼ EtFOSAA (0.117/d) > EtFOSE (0.095/d) > PFOS (0.069/d). No significant effects were observed in malondialdehyde (MDA) contents and acetylcholinesterase (AChE) activities between EtFOSE treatments and controls. EtFOSE could cause significant accumulation of reactive oxygen species (ROS) in earthworms. Peroxidase (POD), superoxide dismutase (SOD) and catalase (CAT) were significantly activated by 41.4-74.3%, 37.2-44.4% and 32.4-52.3% from day 4-10, respectively, while 8-Hydroxy-2-deoxyguanosine (8-OHdG) levels were elevated by 47.7-70.3% from day 8-10, demonstrating that EtFOSE induced oxidative stress and oxidative DNA damage in earthworms. Significant increase of glutathione-S-transferase (GST) with 41.6-62.8% activation (8-10 d) gave indirect evidence on the conjugation of EtFOSE or its corresponding metabolites during phase II of detoxication. This study provides important information on the fate and potential risks of EtFOSE to terrestrial invertebrates.


Assuntos
Hidrocarbonetos Fluorados/toxicidade , Oligoquetos/metabolismo , Quartzo , Sulfonamidas/toxicidade , Animais , Biodegradação Ambiental , Biotransformação , Dano ao DNA , Fluorcarbonetos/metabolismo , Hidrocarbonetos Fluorados/farmacocinética , Estresse Oxidativo , Dióxido de Silício , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética
7.
Talanta ; 201: 111-118, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122400

RESUMO

Thiophenols as high toxic environmental pollutants are poisonous for animals and aquatic organisms. Therefore, it is indispensable to monitor thiophenols in the environment. Herein, a novel near-infrared fluorescent probe was developed for the detection of thiophenols, which was easily prepared by one-step coupling of 2,4-dinitrobenzenesulfonyl chloride with Nile blue. The probe showed a significant near infrared (∼675 nm) fluorescence "turn-on" response to thiophenols with some good features including chromogenic reaction, high sensitivity and selectivity, fast response, near-infrared emission along with low detection limit (1.8 nM). The probe was employed to rapidly and visually determine thiophenols in several industrial wastewaters with good recoveries (90-110%). Moreover, this probe has been demonstrated good capability for imaging thiophenol in HeLa cells.


Assuntos
Corantes Fluorescentes/química , Oxazinas/química , Fenóis/análise , Compostos de Sulfidrila/análise , Sulfonamidas/química , Águas Residuárias/análise , Poluentes Químicos da Água/análise , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Limite de Detecção , Microscopia Confocal/métodos , Modelos Químicos , Oxazinas/síntese química , Oxazinas/efeitos da radiação , Oxazinas/toxicidade , Espectrometria de Fluorescência/métodos , Sulfonamidas/síntese química , Sulfonamidas/efeitos da radiação , Sulfonamidas/toxicidade
8.
Eur J Med Chem ; 176: 50-60, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096118

RESUMO

New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 µM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 µM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 µM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 µM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 µM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.


Assuntos
Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Chalconas/farmacologia , Sulfonamidas/farmacologia , Células 3T3 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/toxicidade , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Chalconas/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/toxicidade
9.
Hum Exp Toxicol ; 38(7): 775-784, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30943761

RESUMO

Our aim was to investigate the effects of resveratrol, auraptene, and curcumin on the spatial learning and spatial memory retention in the Morris water maze (MWM). The effects of 4-day bilateral intrahippocampal (i.h.) infusions of dimethyl sulfoxide (DMSO), H-89 as a protein kinase AII inhibitor, auraptene/H-89, resveratrol/H-89, and curcumin/H-89 were investigated on spatial memory acquisition in MWM. The rats were trained for 4 days; each day included one block of four trials. Post-training probe tests were performed on day 5 in acquisition test. For retention assessments, different animals were trained for 4 days and then infused (i.h.) with either DMSO, H-89, auraptene/H-89, resveratrol/H-89, or curcumin/H-89. The retention test was performed 48 h after the last training trial. The bilateral infusion of H-89 led to a significant impairment in spatial memory in acquisition and retention tests accompanied with a significant decrease in expressions of cAMP response-element binding (CREB) and pCREB proteins in hippocampus. Resveratrol and curcumin reversed the H-89-induced spatial memory acquisition and retention impairments with significant increases in both CREB and pCREB proteins expressions compared to H-89-treated animals. Auraptene showed significant effects in reversing H-89-induced impairments in spatial memory retention but not spatial memory acquisition.


Assuntos
Cumarínicos/administração & dosagem , Curcumina/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Resveratrol/administração & dosagem , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Infusões Parenterais , Isoquinolinas/toxicidade , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Ratos Wistar , Sulfonamidas/toxicidade
10.
PLoS One ; 14(1): e0209264, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30677025

RESUMO

OBJECTIVE: This study aimed to evaluate the risk for hepatotoxicity with nimesulide, a non-steroidal anti-inflammatory drug (NSAID) available in Republic of Korea but withdrawn from the market in several countries. METHODS: A systematic review and meta-analysis were conducted of studies retrieved from PubMed, EMBASE, Cochrane, the Research Information Sharing Service and ClinicalTrials.gov up to September 2017. All studies reporting nimesulide-associated hepatotoxicity in patients as compared with the unexposed or the exposed to other NSAIDs were included. Studies using spontaneous reporting databases were included to estimate reporting odds ratio (ROR) of hepatotoxicity associated with nimesulide exposure. The association between nimesulide use and hepatotoxicity was estimated using relative risk (RR) and ROR with 95% confidence interval (CI). RESULTS: A total of 25 observational studies were eligible for review. In a meta-analysis of five observational studies, nimesulide was significantly associated with hepatotoxicity [RR 2.21, 95% CI 1.72-2.83]. From studies using spontaneous reporting databases (n = 6), rates of reported hepatotoxicity were significantly higher in patients using nimesulide, compared with those treated with other NSAIDs [pooled ROR 3.99, 95% CI 2.86-5.57]. Of a total of 33 patients from case studies and series, the majority (n = 28, 84.8%) were female, and the mean age (± standard deviation) was 56.8 (± 15.6) years. Almost half of the patients on nimesulide (45.5%) either required liver transplantation or died due to fulminant hepatic failure, of whom a third developed hepatotoxicity within less than 15 days of nimesulide administration. CONCLUSIONS: Our study findings support previous reports of an increased risk for hepatotoxicity with nimesulide use and add to existing literature by providing risk estimates for nimesulide-associated hepatotoxicity. As the limited number of studies with primarily observational study designs were included in the analysis, more studies are needed to further describe the effects of dose and length of treatment on the risk for hepatotoxicity.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Sulfonamidas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Feminino , Humanos , Falência Hepática Aguda/epidemiologia , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/mortalidade , Transplante de Fígado , Masculino , Razão de Chances , República da Coreia/epidemiologia , Risco
11.
Xenobiotica ; 49(6): 655-670, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29897827

RESUMO

To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.


Assuntos
Antineoplásicos/toxicidade , Fígado/efeitos dos fármacos , Pirimidinas/toxicidade , Sulfonamidas/toxicidade , Alanina Transaminase/sangue , Animais , Antineoplásicos/metabolismo , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/fisiologia , Fígado/metabolismo , Fígado/patologia , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Análise Multivariada , Estresse Oxidativo/efeitos dos fármacos , Pirimidinas/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Sulfonamidas/metabolismo
12.
Curr Radiopharm ; 12(1): 40-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30173658

RESUMO

BACKGROUND: The SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]SRF101) is a Sulforhodamine 101 derivative that was previously synthesised by our group. The fluorescent dye SR101 has been reported as a marker of astroglia in the neocortex of rodents in vivo. OBJECTIVE: The aim of this study was to perform a toxicological evaluation of [18F]SRF101 and to estimate human radiation dosimetry based on preclinical studies. METHODS: Radiation dosimetry studies were conducted based on biokinetic data obtained from a mouse model. A single-dose toxicity study was carried out. The toxicological limit chosen was <100 µg, and allometric scaling with a safety factor of 100 for unlabelled SRF101 was selected. RESULTS: The absorbed and effective dose estimated using OLINDA/EXM V2.0 for male and female dosimetric models presented the same tendency. The highest total absorbed dose values were for different sections of the intestines. The mean effective dose was 4.03 x10-3 mSv/MBq and 5.08 x10-3 mSv/MBq for the male and female dosimetric models, respectively, using tissue-weighting factors from ICRP-89. The toxicity study detected no changes in the organ or whole-body weight, food consumption, haematologic or clinical chemistry parameters. Moreover, lesions or abnormalities were not found during the histopathological examination. CONCLUSION: The toxicological evaluation of SRF101 verified the biosafety of the radiotracer for human administration. The dosimetry calculations revealed that the radiation-associated risk of [18F]SRF101 would be of the same order as other 18F radiopharmaceuticals used in clinical applications. These study findings confirm that the novel radiotracer would be safe for use in human PET imaging.


Assuntos
Radioquímica/métodos , Compostos Radiofarmacêuticos/toxicidade , Rodaminas/toxicidade , Sulfonamidas/toxicidade , Animais , Feminino , Fluordesoxiglucose F18/química , Masculino , Camundongos , Doses de Radiação , Radiometria , Compostos Radiofarmacêuticos/síntese química , Rodaminas/química , Sulfonamidas/síntese química
13.
Chemosphere ; 218: 26-35, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30465972

RESUMO

Biochars derived from rice straw (RS), corn straw (CS), chicken manure (CM) and tire rubber (TR) were applied to soil to investigate their effects on the dissipation of cyazofamid and its metabolite CCIM (4-chloro-5-p-tolylimidazole-2-carbonitrile), with high acute toxicity compared to cyazofamid. The enhancement of cyazofamid dissipation followed the order of CS > RS > CM, whereas TR depressed the cyazofamid dissipation. Adsorption, hydrolysis and microbial degradation were all involved in cyazofamid dissipation. CM and CS enhanced the contribution of biodegradation to cyazofamid dissipation, which might be related with the shifted microbial community. More importantly, CCIM residual was drastically increased by 8-15 times after biochar application, regardless of biochar type. In total, this study shed light on the issue of build-up of metabolites in biochar-amended soil, especially for metabolites having higher toxicities than parent compounds, providing new insights into potential risk of biochar application for soil remediation.


Assuntos
Carvão Vegetal/efeitos adversos , Imidazóis/metabolismo , Solo/química , Sulfonamidas/metabolismo , Adsorção , Antifúngicos , Biodegradação Ambiental , Imidazóis/análise , Imidazóis/toxicidade , Poluentes do Solo/análise , Sulfonamidas/análise , Sulfonamidas/toxicidade
14.
Bioorg Chem ; 82: 246-252, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30391855

RESUMO

Tuberculosis (TB) is the leading cause of death worldwide due to bacterial infection. The scarcity of effective drugs to treat the disease and the compounded problems due to the development of resistance to the available therapeutics and TB-HIV synergism drive medicinal chemists to search for new anti-Mtb chemotypes. Towards this endeavor, the α-sulfonamidophosphonate moiety has been identified as new anti-Mtb chemotype through the scaffold hopping as the design strategy, development of an effective synthetic methodology using green chemistry tools, and evaluation of anti-TB activity of the synthesized compounds against Mtb (Mycobacterium tuberculosis) H37Rv. Out of the sixteen compounds, five have been found to have MIC values of 1.56 µg/mL and one 3.125 µg/mL. The five most active compounds are non-cytotoxic to RAW 264.7 (mouse leukemic monocyte macrophage) cell lines. The compounds are found to possess acceptable values of the various parameters for drug likeness in accordance with the Lipinski rule with the topological surface area (tPSA) of >70 that suggest eligibility of these new molecular entities for further consideration as potential drug candidates.


Assuntos
Antituberculosos/farmacologia , Organofosfonatos/farmacologia , Sulfonamidas/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/toxicidade , Desenho de Drogas , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Organofosfonatos/síntese química , Organofosfonatos/química , Organofosfonatos/toxicidade , Células RAW 264.7 , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/toxicidade
15.
Carbohydr Polym ; 206: 653-663, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30553370

RESUMO

The rapid emergence of antibiotic-resistant Gram-negative bacteria (GNB) is becoming a global healthcare concern, and it urgently needs novel strategies to match the clinical challenge. In this work, we conjugated chitosan (CS) with LED 209, a highly selective inhibitor of QseC of GNB, to create the novel selective antimicrobial agent CS/LED. The data of FT-IR, NMR and elemental analysis for CS/LED conjugates proved the successful conjugation of CS with LED 209. Interestingly, the fluorescence signal detected in MDR-E. coli of CS/LED-FITC was about 2 times than that of CS-FITC at 3 h. The results shown that compared with CS, CS/LED exhibited higher selective antimicrobial on MDR-E. coli. Moreover, CS/LED exhibited the lower selectivity and cytotoxicity to mammalian cell than CS. Additionally, an unexpected enhancement of anti-adhesion activity against MDR-E. coli was determined by cellulose membrane coating CS/LED. The results demonstrated that CS/LED could reduce the adhesion of bacteria to the cellulose membrane by about 67.8%, while CS only reduced by about 45.3%. The dressings coated with CS/LED possessed the stronger ability to prevent microbial adhesion compared to the CS-coated dressing. Our present work firstly demonstrated that CS/LED had a highly selective activity and anti-adhesion activity against MDR-E. coli, which offered a potent and selective antimicrobial for combating multidrug-resistant GNB infections.


Assuntos
Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Quitosana/análogos & derivados , Quitosana/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Biofilmes/efeitos dos fármacos , Quitosana/síntese química , Quitosana/toxicidade , Escherichia coli/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Sulfonamidas/síntese química , Sulfonamidas/toxicidade
16.
Acta Pharmacol Sin ; 40(7): 895-907, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573812

RESUMO

The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.


Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade
17.
J Water Health ; 16(6): 914-920, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30540265

RESUMO

The abuse of antibiotics is becoming more serious as antibiotic use has increased. The sulfa antibiotics, sulfamerazine (SM1) and sulfamethoxazole (SMZ), are frequently detected in a wide range of environments. The interaction between SM1/SMZ and bacterial diversity in drinking water was investigated in this study. The results showed that after treatment with SM1 or SMZ at four different concentrations, the microbial community structure of the drinking water changed statistically significantly compared to the blank sample. At the genus level, the proportions of the different bacteria in drinking water may affect the degradation of the SM1/SMZ. The growth of bacteria in drinking water can be inhibited after the addition of SM1/SMZ, and bacterial community diversity in drinking water declined in this study. Furthermore, the resistance gene sul2 was induced by SM1 in the drinking water.


Assuntos
Antibacterianos/toxicidade , Água Potável/microbiologia , Sulfonamidas/toxicidade , Antibacterianos/análise , Bactérias , Microbiota , Sulfametoxazol , Sulfonamidas/análise , Microbiologia da Água
18.
ACS Sens ; 3(11): 2311-2319, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30375854

RESUMO

Nitric oxide (NO) is a vital gaseous signal molecule and plays an important role in diverse physiological and pathological processes including regulation of vascular functions. Endoplasmic reticulum (ER) stress is caused by the accumulation of misfolded or unfolded protein in the ER. Besides, ER stress induced by NO can be involved in the pathogenesis of various vascular diseases. Unfortunately, to the best of our knowledge, no ER-targeting probe for NO is reported to study the relationship between ER stress and the level of NO in a biological system. Herein, an ER-targeted fluorescent probe named ER-Nap-NO for imaging of NO is designed and synthesized. ER-Nap-NO consists of three main parts: naphthalimide (two-photon fluorophore), o-phenylenediamino (NO recognition group), and methyl sulfonamide (ER-targetable group). The probe itself is nonfluorescent because a photoinduced electron transfer (PET) process exists. After the addition of NO, the PET process is inhibited and thus strong fluorescence is released. Moreover, the response mechanism is confirmed by 1H NMR and mass spectra and DFT calculation in detail. In addition, from the experimental results, we can conclude that the probe displays several obvious advantages including high sensitivity, selectivity, and ER-targetable ability. Based on these excellent properties, the probe is used for the two-photon imaging of exogenous and endogenous NO in ER of living cells. Most importantly, the ER-targetable probe has potential capability as a tool for investigating the level of NO during tunicamycin-induced ER stress in cells and tissues, which is beneficial for revealing the role of NO in ER-associated vascular diseases.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Corantes Fluorescentes/química , Naftalimidas/química , Óxido Nítrico/análise , Animais , Teoria da Densidade Funcional , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Limite de Detecção , Camundongos , Microscopia de Fluorescência/métodos , Modelos Químicos , Naftalimidas/síntese química , Naftalimidas/efeitos da radiação , Naftalimidas/toxicidade , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Fenilenodiaminas/toxicidade , Fótons , Espectrometria de Fluorescência/métodos , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/toxicidade , Tunicamicina/farmacologia
20.
Plasmid ; 100: 14-21, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30248363

RESUMO

We have identified an IncX1 plasmid named pQJDSal1 from Salmonella enterica subsp. enterica serovar Pullorum (S. Pullorum). The plasmid is 67,685 bp in size and has 72 putative genes. pQJDSal1 harbors a conserved IncX1-type backbone with predicted regions for conjugation, replication and partitioning, as well as a toxin/antitoxin plasmid addiction system. Two regions (A and B) that have not been previously reported in IncX1 plasmids are inserted into the backbone. Region A (10.7 kb), inserted between parA and taxD, consists of a new Tn6168-like transposon containing an arsenic resistant operon arsB2CHR and sulfonamide resistance gene sul2. Region B contains another arsenic resistant operon arsADHR, resistance gene blaTEM-1B and three transposable elements. Conjugation experiments showed that pQJDSal1 could transfer from S. Pullorum to Escherichia coli (E. coli) J53. Statistical analysis of 70 sequenced IncX1 plasmids revealed that IncX1 plasmids harbored various antibiotic resistance genes. The results highlight the importance of IncX1 plasmids in disseminating antibiotic resistance genes.


Assuntos
Arsênico/toxicidade , Farmacorresistência Bacteriana/genética , Genoma Bacteriano , Plasmídeos/química , Salmonella enterica/genética , Mapeamento Cromossômico , Conjugação Genética , Replicação do DNA , Elementos de DNA Transponíveis , Escherichia coli/genética , Escherichia coli/metabolismo , Óperon , Plasmídeos/metabolismo , Salmonella enterica/efeitos dos fármacos , Salmonella enterica/metabolismo , Sulfonamidas/toxicidade
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