Base de dados : MEDLINE
Pesquisa : D01.928 [Categoria DeCS]
Referências encontradas : 1581 [refinar]
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[PMID]:28841528
[Au] Autor:Lavtizar V; Kimura D; Asaoka S; Okamura H
[Ad] Endereço:Laboratory of Maritime Environmental Management, Research Center for Inland Seas, Kobe University, 5-1-1 Fukaeminami, Higashinada-ku, Kobe, Hyogo 658-0022, Japan.
[Ti] Título:The influence of seawater properties on toxicity of copper pyrithione and its degradation product to brine shrimp Artemia salina.
[So] Source:Ecotoxicol Environ Saf;147:132-138, 2018 Jan.
[Is] ISSN:1090-2414
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Copper pyrithione (CuPT) is a biocide, used worldwide to prevent biofouling on submerged surfaces. In aquatic environments it rapidly degrades, however, one of the degradation products (HPT) is known to react with cupric ion back to its parent compound. Not much is known about the behavior and toxicity of CuPT and its degradation product HPT in different water systems. Hence, our aim was to investigate the ecotoxicity of CuPT, HPT as well as Cu to the brine shrimp Artemia salina in natural seawater and organic matter-free artificial seawater. Moreover, in order to elucidate the influence of ionic strength of water on CuPT toxicity, tests were performed in water media with modified salinity. The results showed that CuPT was the most toxic to the exposed crustaceans in a seawater media with the highest salinity and with no organic matter content. HPT in a presence of cupric ion converted to CuPT, but the measured CuPT concentrations and the mortality of A. salina in natural water were lower than in artificial water. The toxicity of CuPT to A. salina was significantly influenced by the organic matter content, salinity, and proportions of constituent salts in water. In a combination with cupric ion, non-hazardous degradation product HPT exhibits increased toxicity due to its rapid transformation to its parent compound.
[Mh] Termos MeSH primário: Artemia/efeitos dos fármacos
Desinfetantes/toxicidade
Compostos Organometálicos/toxicidade
Piridinas/toxicidade
Água do Mar/química
Tionas/toxicidade
Poluentes Químicos da Água/toxicidade
[Mh] Termos MeSH secundário: Animais
Desinfetantes/análise
Monitoramento Ambiental/métodos
Substâncias Húmicas/análise
Compostos Organometálicos/análise
Piridinas/análise
Salinidade
Tionas/análise
Poluentes Químicos da Água/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Disinfectants); 0 (Humic Substances); 0 (Organometallic Compounds); 0 (Pyridines); 0 (Thiones); 0 (Water Pollutants, Chemical); 0 (copper pyrithione); 6GK82EC25D (pyrithione)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170826
[St] Status:MEDLINE


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[PMID]:28460356
[Au] Autor:de Moraes MM; Treptow TGM; Teixeira WKO; Piovesan LA; D'Oca MGM; Votto APS
[Ad] Endereço:Laboratório de Cultura Celular, Programa de Pós-graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande - FURG, Rio Grande do Sul, Brazil.
[Ti] Título:Fatty-monastrol derivatives and its cytotoxic effect against melanoma cell growth.
[So] Source:Bioorg Chem;72:148-155, 2017 06.
[Is] ISSN:1090-2120
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Melanoma is the most dangerous type of skin cancer due to the occurrence of metastases. This work is aimed at studying the effects of the insertion of palmitic and oleic acid chain into monastrol in the melanoma cell line, B16F10. Cells were treated with monastrol, palmitic-monastrol or oleic-monastrol for periods of 0, 24, 48 and 72 h, and the cytotoxic effect was observed for palmitic-monastrol and oleic-monastrol after 24 h. For monastrol the effects were observed in 48 h on B16F10 cells, and in 24 h for a non-tumour cell line, melan-a. In this cell line, fatty-monastrol derivatives were cytotoxic after 24 h of exposure in the same concentrations as B16F10. However, oleic-monastrol inhibited cell growth at 20µM only after 72 h, in contrast to the B16F10 cell line, in which oleic-monastrol inhibited cell growth at 48 h, showing that at least in this structural modification, melan-a was less sensitive than B16F10. The ability of compounds to induce apoptosis and/or necrosis was measured, and it was observed that monastrol induces apoptosis within 24 h. However, the cells treated with fatty-monastrol derivatives did not remain adhered on the well plate after 3 h of treatment. At this time point, these cells still emitted fluorescence indicating viable cells, suggesting a possible effect of palmitic- and oleic-monastrol in the adhesion proteins found on the cell membrane.
[Mh] Termos MeSH primário: Melanoma/tratamento farmacológico
Ácido Oleico/farmacologia
Ácido Palmítico/farmacologia
Pirimidinas/farmacologia
Tionas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Melanoma/patologia
Estrutura Molecular
Ácido Oleico/química
Ácido Palmítico/química
Pirimidinas/química
Relação Estrutura-Atividade
Tionas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Pyrimidines); 0 (Thiones); 2UMI9U37CP (Oleic Acid); 2V16EO95H1 (Palmitic Acid); 6BSM97YZ8G (monastrol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171214
[Lr] Data última revisão:
171214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:28844711
[Au] Autor:Fallatah MM; Liu S; Sevigny MB; Zou H; Louie MC
[Ad] Endereço:Department of Natural Sciences and Mathematics, Dominican University of California, 50 Acacia Avenue, San Rafael, CA 94901, USA.
[Ti] Título:Novel flexible heteroarotinoid, SL-1-18, promotes ERα degradation to inhibit breast cancer cell growth.
[So] Source:Cancer Lett;408:82-91, 2017 Nov 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:SL-1-18 (1-(chrysen-6-yl)-3-(4-nitrophenyl)thiourea) is new flexible heteroarotinoid (Flex-Het) analog derived from the parent compound, SHetA2, and our previous study showed comparable activity to SHetA2 in terms of inhibiting ER+ breast cancer cell growth. This current study aims to determine the molecular mechanism underlying SL-1-18's effect on breast cancer cell growth. Our results indicate that SL-1-18 inhibits cell proliferation of ER+ breast cancer cells (MCF-7 and T-47D) by preventing cell cycle progression. SL-1-18 treatment correlated positively with decreased expression of key cell-cycle regulators, such as cyclin D1, as well as other ERα-target genes at both the transcript and protein levels. Interestingly, decreased expression of ERα was also observed, with a significant reduction at the protein level within 2 h of SL-1-18 treatment, while the decrease in mRNA occurred at a later time point. ERα degradation was shown to be mediated by the ubiquitination-proteasome pathway. In summary, this is the first study to show that a Flex-Het- SL-1-18- can promote the degradation of ERα via the ubiquitin-proteasome pathway and should be further developed as a therapeutic option for ER+ breast cancer.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Neoplasias da Mama/tratamento farmacológico
Cromanos/farmacologia
Crisenos/farmacologia
Receptor alfa de Estrogênio/metabolismo
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Proteólise/efeitos dos fármacos
Tioureia/análogos & derivados
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Feminino
Seres Humanos
Complexo de Endopeptidases do Proteassoma
Tionas/farmacologia
Tioureia/farmacologia
Células Tumorais Cultivadas
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione); 0 (1-(chrysen-6-yl)-3-(4-nitrophenyl)thiourea); 0 (Antineoplastic Agents); 0 (Chromans); 0 (Chrysenes); 0 (Estrogen Receptor alpha); 0 (Thiones); 0 (estrogen receptor alpha, human); EC 3.4.25.1 (Proteasome Endopeptidase Complex); GYV9AM2QAG (Thiourea)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


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[PMID]:28806600
[Au] Autor:Sahu M; Siddiqui N; Iqbal R; Sharma V; Wakode S
[Ad] Endereço:Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research (Formerly, Faculty of Pharmacy), Jamia Hamdard, New Delhi 110062, India.
[Ti] Título:Design, synthesis and evaluation of newer 5,6-dihydropyrimidine-2(1H)-thiones as GABA-AT inhibitors for anticonvulsant potential.
[So] Source:Bioorg Chem;74:166-178, 2017 Oct.
[Is] ISSN:1090-2120
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Several new 5,6-dihydropyrimidine-2(1H)-thione derivatives have been prepared and investigated for their potencies for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) test in mice. The acute neurotoxicity was measured by rotarod test. Compounds 3c and 3l were found active in both of the animal models. Further, in vitro GABA-AT enzyme activity assay was carried out to investigate the possible mechanism of action through GABA-AT inhibition. The most potent compounds 3c and 3l showed inhibitory potency (IC ) of 18.42µM and 19.23µM, respectively. The molecular modeling was performed for all the synthesized compounds. The docking results were found in concordant with the observed animal studies.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/antagonistas & inibidores
Anticonvulsivantes/farmacologia
Desenho de Drogas
Inibidores Enzimáticos/farmacologia
Pirimidinas/farmacologia
Convulsões/tratamento farmacológico
Tionas/farmacologia
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/metabolismo
Animais
Anticonvulsivantes/síntese química
Anticonvulsivantes/química
Relação Dose-Resposta a Droga
Eletrochoque
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Camundongos
Modelos Moleculares
Estrutura Molecular
Pentilenotetrazol
Pirimidinas/síntese química
Pirimidinas/química
Relação Estrutura-Atividade
Tionas/síntese química
Tionas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5,6-dihydropyrimidine-2(1H)-thione); 0 (Anticonvulsants); 0 (Enzyme Inhibitors); 0 (Pyrimidines); 0 (Thiones); EC 2.6.1.19 (4-Aminobutyrate Transaminase); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE


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[PMID]:28683403
[Au] Autor:Damgaard M; Al-Khawaja A; Nittegaard-Nielsen M; Petersen RF; Wellendorph P; Frølund B
[Ad] Endereço:Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
[Ti] Título:Monastrol, a 3,4-dihydropyrimidin-2(1H)-thione, as structural scaffold for the development of modulators for GHB high-affinity binding sites and α ß Î´ GABA receptors.
[So] Source:Eur J Med Chem;138:300-312, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The α ßδ subtype of the γ-aminobutyric acid (GABA) type A receptors (GABA Rs) has been shown to be implicated in high-affinity binding of the neuromodulator γ-hydroxybutyric acid (GHB), but may not be the only GHB high-affinity binding sites. Monastrol has been identified as a modulator of GHB high-affinity binding and is furthermore reported as an allosteric modulator selective for the α ß Î´ GABA Rs. Therefore, structural determinants for selectivity at the two targets were investigated. 39 structural diverse monastrol analogues were synthesized by employing the Biginelli cyclocondensation and examined for modulation of GHB high-affinity binding using the GHB-specific ligand [ H]NCS-382 [(E,RS)-6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid] in rat brain homogenate. Only limited modifications were allowed on the monastrol scaffold in order to maintain modulation of GHB high-affinity binding. However, three analogues of monastrol (11, 12 and 24) enhanced the maximal binding of [ H]NCS-382 to a higher maximal level than seen for monastrol itself. Selected compounds were further characterized as modulators at α ß Î´, α ß Î³ and α ß GABA Rs. Most of these modulators were shown to have δ-specific GABA-potentiating effects. The dual effect shown for monastrol to modulate the GHB high-affinity binding and α ß Î´ GABA R activity was also shown for the compounds 11, 18 and 24. Compound 29 displayed minimal modulatory effect on GABA Rs and therefore appears to be a GHB high-affinity binding preferring modulator. However, compounds 34 and 37 were shown to be α ß Î´ GABA R selective modulators, without modulatory effects on GHB high-affinity binding. Thus, our study shows that minor modifications in the structure of monastrol affects the selectivity profile for the two targets under study enabling separation of the dual activity.
[Mh] Termos MeSH primário: Pirimidinas/farmacologia
Receptores de GABA-A/metabolismo
Tionas/farmacologia
[Mh] Termos MeSH secundário: Sítios de Ligação/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Pirimidinas/síntese química
Pirimidinas/química
Relação Estrutura-Atividade
Tionas/síntese química
Tionas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pyrimidines); 0 (Receptors, GABA-A); 0 (Thiones); 6BSM97YZ8G (monastrol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE


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[PMID]:28667871
[Au] Autor:Ragab FAF; Abou-Seri SM; Abdel-Aziz SA; Alfayomy AM; Aboelmagd M
[Ad] Endereço:Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box, 11562, Egypt.
[Ti] Título:Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety.
[So] Source:Eur J Med Chem;138:140-151, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC = 56 nM) and 9n against MOLT-4 (IC = 80 nM), more potent than monastrol (IC = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Desenho de Drogas
Oxidiazóis/farmacologia
Pirimidinas/farmacologia
Tionas/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Oxidiazóis/química
Pirimidinas/síntese química
Pirimidinas/química
Relação Estrutura-Atividade
Tionas/síntese química
Tionas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Oxadiazoles); 0 (Pyrimidines); 0 (Thiones); 20O2F20OUR (1,3,4-oxadiazole); 6BSM97YZ8G (monastrol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE


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[PMID]:28651980
[Au] Autor:Balti M; Plas A; Meinguet C; Haufroid M; Thémans Q; Efrit ML; Wouters J; Lanners S
[Ad] Endereço:NAMEDIC-NARILIS, University of Namur, 61 Rue de Bruxelles, 5000 Namur, Belgium; Laboratory of Organic Synthesis and Heterocyclic Chemistry, Department of Chemistry, College of Sciences at Tunis, El Manar University, Campus, 1060 Tunis, Tunisia.
[Ti] Título:Synthesis of 4- and 5-arylthiazolinethiones as inhibitors of indoleamine 2,3-dioxygenase.
[So] Source:Bioorg Med Chem Lett;27(15):3607-3610, 2017 08 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Docking studies of 4-phenylthiazolinethione on human IDO1 suggest complexation of the heme iron by the exocyclic sulfur atom further reinforced by hydrophobic interactions of the phenyl ring within pocket A of the enzyme. On this basis, chemical modifications were proposed to increase inhibition activity. Synthetic routes had to be adapted and optimized to yield the desired substituted 4- and 5-arylthiazolinethiones. Their biological evaluation shows that 5-aryl regioisomers are systematically less potent than the corresponding 4-aryl analogs. Substitution on the phenyl ring does not significantly increase inhibition potency, except for 4-Br and 4-Cl derivatives.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores
Tiazolidinas/química
Tiazolidinas/farmacologia
Tionas/química
Tionas/farmacologia
[Mh] Termos MeSH secundário: Inibidores Enzimáticos/síntese química
Seres Humanos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
Simulação de Acoplamento Molecular
Estereoisomerismo
Relação Estrutura-Atividade
Tiazolidinas/síntese química
Tionas/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (Thiazolidines); 0 (Thiones); 0 (indoleamine 2,3-dioxygenase 1, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE


  8 / 1581 MEDLINE  
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[PMID]:28528410
[Au] Autor:Ohji M; Harino H
[Ad] Endereço:Institute of Symbiotic Science and Technology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, 183-8509, Japan. ohji@cc.tuat.ac.jp.
[Ti] Título:Comparison of Toxicities of Metal Pyrithiones Including Their Degradation Compounds and Organotin Antifouling Biocides to the Japanese Killifish Oryzias latipes.
[So] Source:Arch Environ Contam Toxicol;73(2):285-293, 2017 Aug.
[Is] ISSN:1432-0703
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Japanese killifish Oryzias latipes were exposed to three levels (0, 1, and 10 µg l ) of copper pyrithione (CuPT ), zinc pyrithione (ZnPT ), six of their degradation products, and the organotin compounds tributyltin (TBT) and triphenyltin (TPT) for 48 h at 20 °C. All individual fish exposed to 1 and 10 µg l of CuPT or 10 µg l of ZnPT were dead within 12 h, respectively, and at 24 h the survival rate of the fish exposed to 1 µg l of ZnPT was 50%. All fish exposed to 10 µg l of ZnPT showed morphological abnormalities in the form of vertebral deformity. None of the fish exposed to six of the degradation products of PTs, TBT, and TPT died during a 48-h exposure period, but various biological effects were observed in the fish exposed to these chemicals: abnormalities of respiration and swimming behavior, and decreased hatchability. Our findings suggest that O. latipes has a higher ecological risk of CuPT and ZnPT exposure than of TBT and TPT exposure during their life history. Because these antifouling biocides have been used in both freshwater and marine environments, our results highlight these biocides' deleterious effects on the freshwater fish as well as marine fish, and they indicate freshwater and marine pollution.
[Mh] Termos MeSH primário: Desinfetantes/toxicidade
Metais/toxicidade
Piridinas/toxicidade
Tionas/toxicidade
Testes de Toxicidade
[Mh] Termos MeSH secundário: Animais
Compostos Organometálicos/toxicidade
Compostos Orgânicos de Estanho/toxicidade
Oryzias
Compostos de Trialquitina/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Disinfectants); 0 (Metals); 0 (Organometallic Compounds); 0 (Organotin Compounds); 0 (Pyridines); 0 (Thiones); 0 (Trialkyltin Compounds); 0 (copper pyrithione); 4XDX163P3D (tributyltin); 6GK82EC25D (pyrithione); 95T92AGN0V (triphenyltin); R953O2RHZ5 (pyrithione zinc)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170522
[St] Status:MEDLINE
[do] DOI:10.1007/s00244-017-0367-z


  9 / 1581 MEDLINE  
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[PMID]:28505394
[Au] Autor:Sevaille L; Gavara L; Bebrone C; De Luca F; Nauton L; Achard M; Mercuri P; Tanfoni S; Borgianni L; Guyon C; Lonjon P; Turan-Zitouni G; Dzieciolowski J; Becker K; Bénard L; Condon C; Maillard L; Martinez J; Frère JM; Dideberg O; Galleni M; Docquier JD; Hernandez JF
[Ad] Endereço:Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.
[Ti] Título:1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-ß-lactamases.
[So] Source:ChemMedChem;12(12):972-985, 2017 Jun 21.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Metallo-ß-lactamases (MBLs) cause resistance of Gram-negative bacteria to ß-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC values toward plasmodial glyoxalase II were in the 10 µm range.
[Mh] Termos MeSH primário: Tionas/farmacologia
Triazóis/farmacologia
Inibidores de beta-Lactamases/farmacologia
beta-Lactamases/metabolismo
[Mh] Termos MeSH secundário: Aeromonas hydrophila/enzimologia
Relação Dose-Resposta a Droga
Estrutura Molecular
Stenotrophomonas maltophilia/enzimologia
Relação Estrutura-Atividade
Tionas/síntese química
Tionas/química
Triazóis/síntese química
Triazóis/química
Inibidores de beta-Lactamases/síntese química
Inibidores de beta-Lactamases/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Thiones); 0 (Triazoles); 0 (beta-Lactamase Inhibitors); EC 3.5.2.6 (beta-Lactamases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201700186


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[PMID]:28482143
[Au] Autor:Shin WS; Bergstrom A; Bonomo RA; Crowder MW; Muthyala R; Sham YY
[Ad] Endereço:Center for Drug Design & Bioinformatics and Computational Biology, Program, University of Minnesota, Minneapolis, MN, 55455, USA.
[Ti] Título:Discovery of 1-Hydroxypyridine-2(1H)-thione-6-carboxylic Acid as a First-in-Class Low-Cytotoxic Nanomolar Metallo ß-Lactamase Inhibitor.
[So] Source:ChemMedChem;12(11):845-849, 2017 Jun 07.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:VIM-2 is one of the most common carbapenem-hydrolyzing metallo ß-lactamases (MBL) found in many drug-resistant Gram-negative bacterial strains. Currently, there is a lack of effective lead compounds with optimal therapeutic potential within our drug development pipeline. Here we report the discovery of 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid (3) as a first-in-class metallo ß-lactamase inhibitor (MBLi) with a potent inhibition K of 13 nm against VIM-2 that corresponds to a remarkable 0.99 ligand efficiency. We further established that 3 can restore the antibiotic activity of amoxicillin against VIM-2-producing E. coli in a whole cell assay with an EC of 110 nm. The potential mode of binding of 3 from molecular modeling provided structural insights that could corroborate the observed changes in the biochemical activities. Finally, 3 possesses a low cytotoxicity (CC ) of 97 µm with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.
[Mh] Termos MeSH primário: Ácidos Picolínicos/síntese química
Ácidos Picolínicos/farmacologia
Tionas/síntese química
Tionas/farmacologia
Inibidores de beta-Lactamases/química
Inibidores de beta-Lactamases/farmacologia
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Escherichia coli/efeitos dos fármacos
Células HEK293
Seres Humanos
Concentração Inibidora 50
Testes de Sensibilidade Microbiana
Modelos Moleculares
Ácidos Picolínicos/toxicidade
Pseudomonas aeruginosa/efeitos dos fármacos
Tionas/toxicidade
Inibidores de beta-Lactamases/toxicidade
beta-Lactamases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-hydroxypyridine-2(1H)-thione-6-carboxylic acid); 0 (Picolinic Acids); 0 (Thiones); 0 (beta-Lactamase Inhibitors); EC 3.5.2.6 (beta-Lactamases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170509
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201700182



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