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1.
Chem Commun (Camb) ; 55(83): 12487-12490, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31566647

RESUMO

CF2H-Pseudoprolines obtained from difluoroacetaldehyde hemiacetal and serine are stable proline surrogates. The consequence of the incorporation of the CF2H group is an important decrease of the trans to cis amide bond isomerization energy and a remarkable stabilisation of the cis conformer by an hydrogen bond.


Assuntos
Peptídeos/química , Prolina/análogos & derivados , Tiazóis/química , Tolueno/análogos & derivados , Ligações de Hidrogênio , Metilação , Conformação Molecular , Prolina/química , Estereoisomerismo , Tolueno/química
2.
J Agric Food Chem ; 67(45): 12357-12365, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31596575

RESUMO

A series of isothiazole, 1,2,3-thiadiazole, and thiazole-based cinnamamide morpholine derivatives were rationally designed, synthesized, characterized, and evaluated for their fungicidal activities. Bioassay indicated that a combination of 3,4-dichloroisothiazole active substructures with cinnamamide morpholine lead to significant improvement of in vivo antifungal activities of the target compounds; among them, compound 5a exhibited good fungicidal activity against Pseudoperonspera cubensis in vivo with an inhibition rate of 100% at 100 µg/mL. A field experiment indicated that the difference of efficacy between 5a (75.9%) and dimethomorph (77.1%) at 37.5 g ai/667 m2 was not significant; and 5a also exhibited good activity against Botrytis cinerea by triggering accumulation of PAL and NPR1 defense-related gene expression and the defense associated enzyme phenylalanine ammonia-lyase (PAL) expression on cucumber, rather than direct inhibition. These findings strongly supported that 3,4-dichloroisothiazole containing cinnamamide morpholine 5a not only showed good fungicidal activity against P. cubensis but also exhibited plant innate immunity stimulation activity as a promising fungicide candidate with both fungicidal activity and systemic acquired resistance.


Assuntos
Cinamatos/química , Fungicidas Industriais/síntese química , Tiadiazóis/química , Tiazóis/química , Botrytis/efeitos dos fármacos , Botrytis/crescimento & desenvolvimento , Cinamatos/farmacologia , Cucumis sativus/efeitos dos fármacos , Cucumis sativus/genética , Cucumis sativus/metabolismo , Cucumis sativus/microbiologia , Descoberta de Drogas , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Estrutura Molecular , Doenças das Plantas/microbiologia , Relação Estrutura-Atividade , Tiadiazóis/farmacologia
3.
J Agric Food Chem ; 67(38): 10791-10799, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31497956

RESUMO

Very weak signals of fragment ions of nosiheptide could be observed using liquid chromatography-tandem mass spectrometry. The preparation of 4-hydroxymethyl-3-methyl-1H-indole-2-carboxylic acid (HMIA), a specific fragment of nosiheptide, by alkaline hydrolysis is described. HMIA showed a good mass spectrometric signal in negative electrospray ionization mode. In the new method, the nosiheptide residue in muscle tissue was hydrolyzed with sodium hydroxide aqueous solution; this was followed by cleanup using mixed mode cartridges. Identification and quantification of nosiheptide were carried out by analyzing HMIA in hydrolysate of muscles. Nosiheptide showed a good linear relationship (r > 0.996) in the calibration range of 2-500 µg/kg, and a low limit of quantification of 2 µg/kg was obtained in swine, chicken, and fish muscles. Recoveries of nosiheptide from spiked muscle samples were 85-108% with relative standard deviations less than 10%. The proposed method was successfully applied for the detection of the nosiheptide residue in medicated animal tissues samples.


Assuntos
Antibacterianos/química , Cromatografia Líquida de Alta Pressão/métodos , Resíduos de Drogas/química , Contaminação de Alimentos/análise , Carne/análise , Espectrometria de Massas em Tandem/métodos , Álcalis/química , Animais , Galinhas , Peixes , Hidrólise , Limite de Detecção , Músculos/química , Suínos , Tiazóis/química
4.
AAPS PharmSciTech ; 20(7): 307, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515645

RESUMO

Various physiological, anatomical barriers make ocular drug delivery very challenging. Hence, better in vitro screening models are needed for rapid screening of the formulations. In this study, a simple whole-eye perfusion model was designed and its application was explored for screening targeted formulation across the full-thickness cornea using confocal laser scanning microscopy. PEG-cholecalciferol-based integrin targeted coumarin-6 micelles (TC6M) and non-targeted coumarin-6 micelles (NTC6M) were developed by solvent diffusion evaporation technique. The formulations NTC6M and TC6M had particles size 23.5 ± 5 nm and 28.5 ± 6 nm respectively and osmolality of 294-300 mOsml/Kg. The whole-eye perfusion model was developed using porcine eye. TC6M and NTC6M were instilled on the excised porcine eyes as well as in the eyes of NZW rabbits. Corneas were excised from the experimental eyes; coumarin-6 penetration across the corneas was analyzed using confocal microscope. Coumarin-6-loaded micelles had particle size below 50 nm. NTC6M formulations showed penetration to the deeper layers up to 500 µm porcine eyes and up to 50 µm in rabbit corneas. However, TC6M formulations exhibited superior retention, as higher fluorescent intensities were observed in upper layers up to 50 µm depth in the porcine eye and 20 µm depth in rabbit eye. Hence, applicability of whole-eye perfusion model in preliminary screening of the formulations was successfully demonstrated. Whole-eye perfusion model when combined with confocal microscopy has potential to be used as an efficient tool for rapid screening and optimization of various ophthalmic formulations.


Assuntos
Administração Oftálmica , Sistemas de Liberação de Medicamentos , Microscopia Confocal/métodos , Animais , Cumarínicos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Micelas , Perfusão , Coelhos , Suínos , Tiazóis/química
5.
Chem Biol Interact ; 311: 108787, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31400341

RESUMO

Antipsychotic drugs interfere with the antioxidant defense system provoking complex and often toxicological effects. Here we examined differences in plasma albumin reduced free thiol (SH) group content and its reactivity as a consequence of clozapine (CLZ) and ziprasidone (ZIP) binding. Chronic administration of CLZ reduced, whereas treatment with ZIP increased albumin-SH content in rats. Regardless of the ratio of stearic acid (SA) bound to protein, in vitro binding of ZIP to human serum albumin (HSA) increased both the SH group level and reactivity. In contrast, the effect of CLZ on HSA-SH reactivity was dependent on HSA to SA molar ratio. CLZ binding was accompanied by an increase in HSA-SH reactivity in samples with normal, but a reduction of its reactivity level with higher SA/HSA ratio, compared to drug-free samples. We demonstrate by steady-state fluorescence quenching studies that an increase in SA binding to HSA is associated with a significant reduction of binding constant for both antipsychotics. In addition, this is the first report of quantitative characterization of ZIP binding to HSA. Our findings suggest that albumin-SH content and reactivity is modulated by ZIP towards an increased antioxidant defense capacity in circulation, as opposed to CLZ, which can contribute to the safer, more effective treatment of schizophrenia.


Assuntos
Clozapina/química , Ácidos Graxos/química , Piperazinas/química , Albumina Sérica/química , Compostos de Sulfidrila/química , Tiazóis/química , Animais , Clozapina/metabolismo , Ácidos Graxos/metabolismo , Humanos , Masculino , Piperazinas/metabolismo , Ligação Proteica , Ratos , Ratos Wistar , Albumina Sérica/metabolismo , Espectrometria de Fluorescência , Espectrofotometria , Compostos de Sulfidrila/análise , Compostos de Sulfidrila/metabolismo , Tiazóis/metabolismo
6.
J Agric Food Chem ; 67(36): 10018-10031, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31448918

RESUMO

Plant diseases seriously endanger plant health, and it is very difficult to control them. A series of nortopsentin analogues were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities. Most of these compounds displayed higher antiviral activities than ribavirin. Compounds 1d, 1e, and 12a, with excellent antiviral activities, emerged as novel antiviral lead compounds, among which 1e was selected for further antiviral mechanism research. The mechanism research results indicated that these compounds may play an antiviral role by aggregating viral particles to prevent their movement in plants. Further fungicidal activity tests revealed that nortopsentin analogues displayed broad-spectrum fungicidal activities. Compounds 2p and 2f displayed higher antifungal activities against Alternaria solani than the commercial fungicides carbendazim and chlorothalonil. Current research has laid a foundation for the application of nortopsentin analogues in plant protection.


Assuntos
Antivirais/farmacologia , Fungicidas Industriais/farmacologia , Oxazóis/farmacologia , Tiazóis/farmacologia , Alternaria/efeitos dos fármacos , Alternaria/crescimento & desenvolvimento , Antivirais/síntese química , Antivirais/química , Desenho de Drogas , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Oxazóis/química , Relação Estrutura-Atividade , Tiazóis/química , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/crescimento & desenvolvimento
7.
J Enzyme Inhib Med Chem ; 34(1): 1465-1473, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31411081

RESUMO

In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED50 = 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Desenho de Drogas , Imidas/química , Imidas/farmacologia , Tiazóis/química , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidas/síntese química , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.1/efeitos dos fármacos , Óxidos/química , Técnicas de Patch-Clamp , Espectroscopia de Prótons por Ressonância Magnética
8.
Eur J Med Chem ; 182: 111593, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31446245

RESUMO

A novel series of phenylthiazoles bearing cyclic amines at the phenyl-4 position was prepared with the objective of decreasing lipophilicity and improving the overall physicochemical properties and pharmacokinetic profile of the compounds. Briefly, the piperidine ring (compounds 10 and 12) provided the best ring size in terms of antibacterial activity when tested against 16 multidrug-resistant clinical isolates. Both compounds were superior to vancomycin in the ability to eliminate methicillin-resistant Staphylococcus aureus (MRSA), residing within infected macrophages and to disrupt mature MRSA biofilm. Additionally, compounds 10 and 12 exhibited a fast-bactericidal mode of action in vitro. Furthermore, the new derivatives were 160-times more soluble in water than the previous lead compound 1b. Consequently, compound 10 was orally bioavailable with a highly-acceptable pharmacokinetic profile in vivo that exhibited a half-life of 4 h and achieved a maximum plasma concentration that exceeded the minimum inhibitory concentration (MIC) values against all tested bacterial isolates.


Assuntos
Aminas/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Obesidade/tratamento farmacológico , Tiazóis/farmacologia , Aminas/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Obesidade/microbiologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
9.
Chem Biodivers ; 16(8): e1900232, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31287621

RESUMO

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR-2 has been demonstrated as a key method against tumor-associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(3,4-dimethylphenyl)urea) and 3m (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(4-methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC50 =1.65 and 3.52 µm, respectively). Compound 3l also showed the best potency against VEGFR-2 at 50 µm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.


Assuntos
Inibidores da Angiogênese/síntese química , Desenho de Drogas , Pirimidinas/química , Tiazóis/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Eur J Med Chem ; 180: 154-170, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31302448

RESUMO

The strong therapeutic potential of CB2 receptor agonists for use as anti-inflammatory agents that lack psychiatric side effects has attracted substantial interest. We herein describe the rational design and synthesis of novel thiazole and benzothiazole derivatives and the evaluation of their binding affinity and functional activity on CB1 and CB2 receptors. The series with the general formula N-(3-pentylbenzo [d]thiazol-2(3H)-ylidene) carboxamide (compounds 6a-6d) exhibited the highest affinity and selectivity towards CB2 receptors with Kis in the picomolar or low nanomolar range, and selectivity indices (Ki hCB1/Ki hCB2) reaching up to 429 fold. Notably, these compounds also demonstrated an agonistic functional activity in cellular assays with EC50s in the low nanomolar range. More interestingly, compound 6d, the 3-(trifluoromethyl)benzamide derivative, exhibited remarkable protection against DSS-induced acute colitis in mice model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzotiazóis/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Colite/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Tiazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Benzotiazóis/síntese química , Benzotiazóis/química , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/química , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
11.
Eur J Med Chem ; 180: 191-203, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306906

RESUMO

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi. The current chemotherapy is based on benznidazole, and, in some countries, Nifurtimox, which is effective in the acute phase of the disease, but its efficacy in the chronic phase remains controversial. It can also cause serious side effects that lead sufferers to abandon treatment. In the present work, is reported the synthesis and trypanocidal activity of new 2-(phenylthio)ethylidene thiosemicarbazones (4-15) and 1,3-thiazoles (16-26). The cyclization of thiosemicarbazones into 1,3-thiazoles presents an improvement in the cytotoxic profile for T. cruzi parasite, denoting selective compounds. Compound 18 was identified as the most promising of all compounds tested, showing an IC50 of 2.6 µM for the trypomastigote form and a non-cytotoxic effect on mouse spleen cells, reaching a selective index of 95.1. Among the 22 compounds tested, six compounds present a better trypanocidal activity, and five compounds have an equipotent activity compared to benznidazole. Flow cytometry and ultrastructural analysis were performed and indicate that compound 18 causes parasite cell death through apoptosis and acts via an autophagic pathway.


Assuntos
Desenho de Drogas , Tiazóis/farmacologia , Tiossemicarbazonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tripanossomicidas/síntese química , Tripanossomicidas/química
12.
Mar Drugs ; 17(6)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163697

RESUMO

Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the trans alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities. Inspired by such a structural similarity, we hypothesized the fluoroolefin moiety would mimic both the alkene moiety in Largazole and the amide moiety in Psammaplin A, and thus designed and synthesized two novel fluoro olefin analogs of Largazole. The preliminary biological assays showed that the fluoro analogs possessed comparable Class I HDAC inhibitory effects, indicating that this kind of modification on the side chain of Largazole was tolerable.


Assuntos
Organismos Aquáticos/química , Cianobactérias/química , Depsipeptídeos/síntese química , Depsipeptídeos/farmacologia , Dissulfetos/química , Inibidores de Histona Desacetilases/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Tirosina/análogos & derivados , Alcenos/química , Depsipeptídeos/química , Ativação Enzimática/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Tiazóis/química , Tirosina/química
13.
Eur J Med Chem ; 178: 315-328, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31195172

RESUMO

The dormant and resistant form of Mycobacterium tuberculosis presents a challenge in developing new anti-tubercular drugs. Herein, we report the synthesis and evaluation of trisubstituted thiazoles as antituberculosis agents. The SAR study has identified a requirement of hydrophobic substituent at C2, ester functionality at C4, and various groups with hydrogen bond acceptor character at C5 of thiazole scaffold. This has led to the identification of 13h and 13p as lead compounds. These compounds inhibited the dormant Mycobacterium tuberculosis H37Ra strain and M. tuberculosis H37Rv selectively. Importantly, 13h and 13p were non-toxic to CHO cells. The 13p showed activity against multidrug-resistant tuberculosis isolates.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
14.
Eur J Med Chem ; 178: 767-781, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31234030

RESUMO

By the analysis of different binding modes with Bruton's tyrosine kinase (BTK), series of novel diphenylthiazole derivatives were rationally designed, synthesized and characterized. Biologically evaluation in biochemistry and cellular assay indicated that, compounds 5m, 5o, 6b, 6c, 6g, 6i, 7h, 7i, 7k, 7m, 7n, 7o and 7s exhibited improved potency against Ramos cell (IC50 = 1.36-8.60 µM) and Raji cell (IC50 = 1.20-14.04 µM) as compared with ibrutinib (IC50 = 14.69 and 15.99 µM, respectively). Especially, compounds 7m and 7n showed 10-time improved potency against Ramos cell viability over ibrutinib. Compound 6b improved 13-fold activity against Raji cell viability than ibrutinib. In addition, active compound 7o potently inhibited C481S mutant BTK with IC50 value of 0.061 µM. Apoptosis analysis of both Ramos and Raji cells indicated that 7o was remarkably more potent than CGI-1746 and ibrutinib. Compound 7o potently inhibited BTK Y223 phosphorylation in Raji cells, and arrested cell cycle progression in the G0/G1 phase in Raji and Ramos cells. This study expanded the structural diversity of BTK inhibitors and compound 7o was discovered as an active lead inhibitor with great potential for further studies.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Células Tumorais Cultivadas
15.
Can J Vet Res ; 83(2): 149-153, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31097877

RESUMO

Drugs applied on human cancer cells can influence the rate of cell proliferation. The present study investigates the use of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT) colorimetric assay to evaluate canine tumor cell proliferation after exposure to the injectable anesthetic, propofol. Primary (CIPp) and metastatic (CIPm) canine tubular adenocarcinoma cell lines were incubated with cell culture medium (control) or propofol (1, 5, and 10 µg/mL). The MTT assays were performed after 6 and 12 hours of exposure. Measurements of absorbance were obtained for each condition with a spectrophotometer and compared with controls using a 3-way analysis of variance (P < 0.05). An increased cell proliferation rate was observed in CIPp exposed to 5 and 10 µg/mL of propofol for 6 hours and 1, 5, and 10 µg/mL for 12 hours. No significant changes were observed in CIPm after 6 hours of exposure. All propofol concentrations decreased the cell proliferation rate in CIPm after 12 hours of exposure. The MTT assays showed that exposure of CIPp to propofol for 6 and 12 hours increased cell proliferation. A decrease in the CIPm proliferation rate was observed when propofol exposure lasted for 12 hours. Further studies are warranted to better understand the role of propofol on cancer cell proliferation.


Assuntos
Adenocarcinoma/veterinária , Proliferação de Células/efeitos dos fármacos , Colorimetria/veterinária , Hipnóticos e Sedativos/farmacologia , Neoplasias Mamárias Animais , Propofol/farmacologia , Animais , Linhagem Celular Tumoral , Colorimetria/métodos , Corantes/química , Doenças do Cão/metabolismo , Cães , Feminino , Sais de Tetrazólio/química , Tiazóis/química
16.
Chemosphere ; 230: 84-91, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31102875

RESUMO

Low-cost magnesium- and/or carbon-based materials have a great potential to remove soluble contaminants from surface and ground water. This study examined mechanisms that control the removal of nitrate, phosphate and pesticides (tricyclazole, malathion and isoprothiolane) during their transport through calcined magnesia (MgO) and corn stalk biochar. Various miscible column breakthrough experiments were carried out and morphology and crystallographic structures of reactive materials were examined. Approximately 96% (78,950 mg-NO3-/kg) and 48% (27,455 mg-NO3-/kg) of nitrate were removed from biochar and MgO columns, respectively. Chemical adsorption dominated nitrate removal during early phase (i.e., <11 PVs for biochar and <100 PVs for MgO, respectively), and microbial denitrification dominated during the following phase. 92% of the applied phosphate (6168 mg-PO43-/kg) was removed in MgO column, while much less in biochar column (4%, 347 mg-PO43-/kg). Mineral surface analyses confirmed that electrostatic attraction, ligand exchange, and chemical precipitation were responsible for phosphate removal. For the three pesticides, biochar exhibited larger removal capacity (1260-2778 mg/kg) than MgO (28-2193 mg/kg) due to the functional groups on biochar. The removal of pesticides based on their physico-chemical properties. Malathion had highest removal rate (98-100%), attributing to chemical sorption and bio-degradation, followed by isoprothiolane (47-79%) and tricyclazole (6-64%).


Assuntos
Óxido de Magnésio/química , Malation/análise , Nitratos/análise , Praguicidas/análise , Fosfatos/análise , Tiazóis/análise , Tiofenos/análise , Poluentes Químicos da Água/análise , Adsorção , Carbono/química , Carvão Vegetal/química , Desnitrificação/fisiologia , Malation/química , Nitratos/química , Praguicidas/química , Fosfatos/química , Tiazóis/química , Tiofenos/química , Poluentes Químicos da Água/química
17.
Acta Trop ; 196: 42-47, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077641

RESUMO

Over the past decade, insecticide resistance to malaria vectors has been identified in 71 malaria endemic countries. This has posed a major global health challenge in the fight against malaria, with declining rates of indoor residual spraying coverage attributed to pyrethroid-resistance. As part of its vector control monitoring strategies, the Bioko Island Malaria Control Project (BIMCP) in Equatorial Guinea conducted routine insecticide resistance bioassays using the WHO's standard susceptibility tests from 2013 to 2018. During the same period, the frequency of the target-site knockdown resistance allele (kdr) in the local vector population was also determined via PCR for detection of the L1014 F mutation. Biochemical analysis for metabolic resistance was also conducted in 2015. From 2016-2017, Fludora™ fusion, a formulated combination of clothianidin (a neonicotinoid) and deltamethrin (a pyrethroid) was evaluated for 9 months on Bioko Island, using the WHO's standard test procedure for determining residual effectiveness of insecticides on sprayed surfaces. In 2016, the mortality rate of the vectors on 0.05% deltamethrin was as low as 38%. The frequency of the West African form of knockdown resistance allele, L1014 F, in the vector population was as high as 80%, and metabolic resistance analysis indicated high upregulated cytochrome P450 s. However, the residual effectiveness of Fludora™ fusion recorded mortalities above 80% after 72 h of exposure for 8 months. Although both target-site knockdown resistance and metabolic resistance to pyrethroids were implicated in the local malaria vector population, Fludora™ fusion was effective under field conditions in controlling the resistant vectors for a period of 8 months on wooden surfaces on Bioko Island and represents a valuable addition to IRS programs, especially in regions with high levels of pyrethroid resistance.


Assuntos
Anopheles/efeitos dos fármacos , Guanidinas/farmacologia , Controle de Mosquitos/métodos , Mosquitos Vetores/efeitos dos fármacos , Neonicotinoides/farmacologia , Nitrilos/farmacologia , Piretrinas/farmacologia , Tiazóis/farmacologia , Animais , Guiné Equatorial/epidemiologia , Guanidinas/administração & dosagem , Guanidinas/química , Humanos , Resistência a Inseticidas/genética , Inseticidas/administração & dosagem , Inseticidas/química , Inseticidas/farmacologia , Ilhas , Malária/epidemiologia , Malária/prevenção & controle , Neonicotinoides/administração & dosagem , Neonicotinoides/química , Nitrilos/administração & dosagem , Nitrilos/química , Piretrinas/administração & dosagem , Piretrinas/química , Tiazóis/administração & dosagem , Tiazóis/química
18.
Molecules ; 24(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096672

RESUMO

IDO1, a key dioxygenase in tryptophan-kynurenine metabolism, appeared in the last 10 years at the vanguard of druggable targets in cancer therapy due to its well-established role both in immune escape and inflammatory neovascularization. Among the pool of IDO1 inhibitors that have entered clinical trials, none have reached approval. The identification of novel inhibitors endowed with better clinical profile, together with the further comprehension of the interactions with residues in IDO1 active site, are still a need. In this context, we have synthesized a novel class of imidazothiazole derivatives as IDO1 inhibitors and identified three compounds with inhibitory potency in the low micromolar range. This report strengthens the role played by pocket C in the active site of IDO1, providing novel directions in the design of IDO1 inhibitors.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/química , Simulação de Acoplamento Molecular , Tiazóis/síntese química , Tiazóis/farmacologia , Sítios de Ligação , Domínio Catalítico , Química Click , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/química , Conformação Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Tiazóis/química
19.
Molecules ; 24(9)2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31060260

RESUMO

Based on the extensive biological activities of thiazole derivatives against different types of diseases, we are interested in the effective part of many natural compounds, so we synthesized a new series of compounds containing di-, tri- and tetrathiazole moieties. The formation of such derivatives proceeded via reaction of 2-bromo-1-(4-methyl-2-(methylamino)thiazol-5-yl)ethan-1-one with heterocyclic amines, o-aminothiophenol and thiosemicarbazone derivatives. The structure and mechanistic pathways for all products were discussed and proved based on spectral results, in addition to conformational studies. Our aim after the synthesis is to investigate their antimicrobial activity against various types of bacteria and fungi species. Preceeding such an investigation, a molecular docking study was carried out with selected conformers, as representative examples, against three pathogen-proteins. This preliminary stage could support the biological application. The potency of these compounds as antimicrobial agents has been evaluated. The results showed that derivatives which have di- and trithiazole rings displayed high activity that exceeds the used standard antibiotic.


Assuntos
Anti-Infecciosos/síntese química , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Tiazóis/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia
20.
Int J Nanomedicine ; 14: 2609-2618, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043777

RESUMO

Background: EGFP-EGF1-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticle (ENP) has a specific affinity to tissue factor (TF). The aim of this study was to investigate the target delivery of ENP to plaques and its uptake in a mouse model of atherosclerosis in vivo and in vitro. Materials and methods: Coumarin-6- and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbo cyanine iodide (DiR)-loaded ENPs were synthesized using a double-emulsion method. Mouse vascular smooth muscle cells (VSMCs) were induced with MCP-1 to obtain an increased TF expression. Fluorescence microscopy and flow cytometry assay were performed to examine the uptake of coumarin-6-loaded ENPs in cellular models. An animal model of atherosclerosis was established with an ApoE (-/-) mouse fed with continuous high-fat diets for 14 weeks. DiR-loaded ENPs (DiR-ENPs) were injected via the caudal vein. The distribution of DiR-ENPs was examined through organ imaging and confocal laser scanning microscopy. Results: Results indicated TFs were highly expressed in the cellular model. The uptake of coumarin-6-loaded ENPs was significantly higher than that of common PLGA nanoparticles. Thickening of intima and lipid deposition in the aorta could be observed in atherosclerosis mouse models. Confocal laser scanning microscopy organ imaging showed ENPs accumulated in vessels with atherosclerotic plaques, which coincided with high expressions of TF. Conclusion: This study showed that EGFP-EGF1-conjugated PLGA nanoparticles could be effectively delivered to atherosclerotic plaques in vivo and taken up by VSMCs with high TF expressions in vitro. Thus, it could be a promising carrier for targeted therapy of atherosclerosis.


Assuntos
Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Portadores de Fármacos/química , Proteínas de Fluorescência Verde/metabolismo , Nanopartículas/química , Fator G para Elongação de Peptídeos/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Aorta/patologia , Cumarínicos/química , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos , Fluorescência , Humanos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Nanopartículas/administração & dosagem , Tamanho da Partícula , Eletricidade Estática , Tiazóis/química
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