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1.
Med Chem ; 16(1): 93-103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30526466

RESUMO

BACKGROUND: New drugs and strategies to treat tuberculosis (TB) are urgently needed. In this context, thiourea derivatives have a wide range of biological activities, including anti-TB. This fact can be illustrated with the structure of isoxyl, an old anti-TB drug, which has a thiourea as a pharmacophore group. OBJECTIVE: The aim of this study is to describe the synthesis and the antimycobacterial activity of fifty-nine benzoylthioureas derivatives. METHODS: Benzoylthiourea derivatives have been synthesized and evaluated for their activity against Mycobacterium tuberculosis using the MABA assay. After that, a structure-activity relationship study of this series of compounds has been performed. RESULTS AND DISCUSSION: Nineteen compounds exhibited antimycobacterial activity between 423.1 and 9.6 µM. In general, we observed that the presence of bromine, chlorine and t-Bu group at the para-position in benzene ring plays an important role in the antitubercular activity of Series A. These substituents were fixed at this position in benzene ring and other groups such as Cl, Br, NO2 and OMe were introduced in the benzoyl ring, leading to the derivatives of Series B. In general, Series B was less cytotoxic than Series A, which indicates that the presence of a substituent at benzoyl ring contributes to an improvement in both antimycobacterial activity and toxicity profiles. CONCLUSION: Compound 4c could be considered a good prototype to be submitted to further structural modifications in the search for new anti-TB drugs, since it is 1.8 times more active than the first line anti-TB drug ethambutol and 0.65 times less active than isoxyl.


Assuntos
Antibacterianos/farmacologia , Desenho de Drogas , Mycobacterium tuberculosis/efeitos dos fármacos , Tioureia/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Macaca mulatta , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Relação Estrutura-Atividade , Tioureia/análogos & derivados , Tioureia/química
2.
J Enzyme Inhib Med Chem ; 35(1): 344-353, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31851852

RESUMO

Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01-TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC50 of 0.21 µM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-RasG12V protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Tioureia/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química
3.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540462

RESUMO

In this investigation, the reaction of 2-dithiomethylcarboimidatebenzothiazole with a series of six chiral amino-acids was studied. The reaction proceeds through the isolable sodium salt of SMe-isothiourea carboxylates as intermediates, whose reaction with methyl iodide in stirring DMF as solvent affords SMe-isothiourea methyl esters. The presence of water in the reaction leads to the corresponding urea carboxylates as isolable intermediates, whose methyl esters were obtained. Finally, the urea N-methyl amide derivatives were isolated when SMe-isothiourea or urea methyl esters were reacted with methylamine in the presence of water. The structures of synthesized compounds were established by 1H and 13C nuclear magnetic resonance and the structures of SMe-isothiourea methyl esters derived from (l)-glycine, (l)-alanine, (l)-phenylglycine, and (l)-leucine, by X-ray diffraction analysis. This methodology allows to functionalize 2-aminobenzothiazole with SMe-isothiourea, urea, and methylamide groups derived from chiral amino acids to get benzothiazole derivatives containing coordination sites and hydrogen bonding groups. Further research on the biological activities of some of these derivatives is ongoing.


Assuntos
Aminoácidos/química , Benzotiazóis/química , Tioureia/química
4.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470567

RESUMO

BACKGROUND: The development of new antifungal agents has always been a hot research topic in pesticide development. In this study, a series of derivatives of natural compound ß-pinene were prepared, and the antifungal activities of these derivatives were evaluated. The purpose of this work is to develop some novel molecules as promising new fungicides. METHODS: Through a variety of chemical reactions, ß-pinene was transformed into a series of ß-pinene-based derivatives containing amide moieties and acylthiourea moieties. The antifungal activities of these derivatives against five plant pathogens including Colletotrichum gloeosporioides, Fusarium proliferatum, Alternaria kikuchiana, Phomopsis sp. and Phytophthora capsici were tested; preliminary structure-activity relationship was discussed. RESULTS: Some derivatives exhibited moderate or significant antifungal activity due to the fusion of the amide moiety or the acylthiourea moiety with the pinane skeleton. The structure-activity relationship analysis showed that the fluorine atom and the strong electron withdrawing nitro group, or trifluoromethyl group on the benzene ring of the derivatives had a significant effect on the improvement of the antifungal activity against Colletotrichum gloeosporioides, Fusarium proliferatum, Alternaria kikuchiana and Phomopsis sp. Meanwhile, the introduction of an ethyl group at the meta-position on the benzene ring of the derivatives could improve the antifungal activity against Phytophthora capsici. Compounds 4e, 4h, 4q, 4r exhibited broad-spectrum antifungal activity against the tested strains. Compound 4o had significant antifungal activity against Phytophthora capsici (IC50 = 0.18 µmol/L). These derivatives were expected to be used as precursor molecules for novel pesticide development in further research.


Assuntos
Alternaria/efeitos dos fármacos , Colletotrichum/efeitos dos fármacos , Fungicidas Industriais/síntese química , Fusarium/efeitos dos fármacos , Phytophthora/efeitos dos fármacos , Sordariales/efeitos dos fármacos , Alternaria/crescimento & desenvolvimento , Amidas/química , Colletotrichum/crescimento & desenvolvimento , Fungicidas Industriais/farmacologia , Fusarium/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Phytophthora/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Doenças das Plantas/terapia , Plantas/microbiologia , Sordariales/crescimento & desenvolvimento , Relação Estrutura-Atividade , Tioureia/química
5.
Inorg Chem ; 58(15): 10129-10138, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31310108

RESUMO

A series of 16 "3 + 2" mixed-ligand complexes of the general composition [ReO(L1)(L2)] (H2L1a-H2L1d = tridentate thiosemicarbazones having a phenyl group with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents; HL2a-HL2d = bidentate N,N-diethyl-N'-benzoylthioureas with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents at the benzoyl groups) have been synthesized and characterized by spectroscopic methods and X-ray diffraction. Irrespective of the individual fluorine substitution, the complexes are stable and possess the same general structure. Some systematic electronic effects of the fluorine-substitution patterns of the ligands have been found on the 13C NMR chemical shifts of the N-C═N carbon atoms of the {L1}2- and the C═O carbon atoms of the {L2}- ligands. Antiparasitic properties of the rhenium complexes have been tested against epimastigotes and trypomastigotes forms of two Trypanosoma cruzi strains and the amastigotes form of one of them. The results of this study indicate that the activity of the rhenium complexes can clearly be modulated by fluorine substitution of their ligands. Some of the fluorinated compounds show a high activity against epimastigotes and trypomastigotes forms of the parasites. Reactions between (NBu4)[TcOCl4] and two representatives of the fluorinated ligands (H2L1b, 4-F-substituted, and H2L1c, 4-CF3-substituted) form stable complexes of the composition [TcOCl(L1b)] and [TcOCl(L1c)]. Subsequent reactions of these products with HL2b (4-F-substituted) give the corresponding [TcO(L1)(L2)] mixed-ligand complexes. Also, the technetium compounds are stable as solids and in solutions and have structures corresponding to those of their rhenium analogues.


Assuntos
Complexos de Coordenação/farmacologia , Halogenação , Rênio/farmacologia , Tiossemicarbazonas/farmacologia , Tioureia/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Haplorrinos , Ligantes , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Rênio/química , Tiossemicarbazonas/química , Tioureia/química , Tripanossomicidas/síntese química , Tripanossomicidas/química
6.
Int J Biol Macromol ; 137: 107-118, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31254581

RESUMO

N-allylthiourea chitosan (ATUCS), a chelating material, was prepared, characterized, and studied for the removal of arsenazo III (As (III)) dye from aqueous solution. Scanning electron microscopy (SEM), energy-dispersive X-ray (EDX), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and 1H- and 13C-nuclear magnetic resonance (NMR) were used to characterize the prepared adsorbent and to investigate the adsorption mechanism. Furthermore, the adsorption behavior of chitosan (CS) and ATUCS were studied under various conditions. The equilibrium adsorbed amount of As (III) onto ATUCS was found to be 116.3 mg/g, compared to 87.3 mg/g with respect to CS. The regeneration of the loaded CS and ATUCS were studied using 1:1 solution of H2O2-H2SO4 and reused with certain change in efficiency after the third cycle. The adsorption process was found to fit well with pseudo-second-order kinetic model. The equilibrium data were better described with the Freundlich isotherm. The monolayer adsorption capacity was found to be 204.08 and 90.90 mg/g for the As (III)/ATUCS and As (III)/CS systems, respectively, at 25 °C. The pH of the higher uptake of As (III) onto ATUCS and CS was 4-5 and 8.0, respectively. The results demonstrated improved adsorption of As (III) using ATUCS as compared to the CS.


Assuntos
Arsenazo III/química , Arsenazo III/isolamento & purificação , Quitosana/química , Quitosana/síntese química , Tioureia/química , Água/química , Adsorção , Técnicas de Química Sintética , Corantes/química , Corantes/isolamento & purificação , Concentração de Íons de Hidrogênio , Cinética , Soluções , Termodinâmica , Poluentes Químicos da Água/química , Poluentes Químicos da Água/isolamento & purificação
7.
Sensors (Basel) ; 19(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252618

RESUMO

Urea is used in a wide variety of industrial applications such as the production of fertilizers. Furthermore, urea as a metabolic product is an important indicator in biomedical diagnostics. For these applications, reliable urea sensors are essential. In this work, we present a novel hydrogel-based biosensor for the detection of urea. The hydrolysis of urea by the enzyme urease leads to an alkaline pH change, which is detected with a pH-sensitive poly(acrylic acid-co-dimethylaminoethyl methacrylate) hydrogel. For this purpose, the enzyme is physically entrapped during polymerization. This enzyme-hydrogel system shows a large sensitivity in the range from 1 mmol/L up to 20 mmol/L urea with a high long-term stability over at least eight weeks. Furthermore, this urea-sensitive hydrogel is highly selective to urea in comparison to similar species like thiourea or N-methylurea. For sensory applications, the swelling pressure of this hydrogel system is transformed via a piezoresistive pressure sensor into a measurable output voltage. In this way, the basic principle of hydrogel-based piezoresistive urea biosensors was demonstrated.


Assuntos
Técnicas Biossensoriais , Enzimas Imobilizadas/química , Ureia/isolamento & purificação , Urease/química , Resinas Acrílicas/química , Humanos , Hidrogéis/química , Concentração de Íons de Hidrogênio , Compostos de Metilureia/química , Compostos de Metilureia/isolamento & purificação , Tioureia/química , Tioureia/isolamento & purificação , Ureia/química
8.
Talanta ; 202: 460-468, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171208

RESUMO

A new on-line solid phase preconcentration method using an ion-imprinted polymer with restrict access material based on copper-imprinted poly(allylthiourea) modified with 2-hydroxyethyl methacrylate and bovine serum (IIP-HEMA-BSA) to preconcentrate Cu2+ ions and exclude protein from milk samples via FIA-FAAS was developed. The samples were on-line preconcentrated at pH 4.5 through a mini-column packed with 50.0 mg of IIP-HEMA-BSA at a flow rate of 7.6 mL min-1 followed by a counter-current elution with 1.00 mol L-1 HCl towards the FAAS detector. The interference of ions commonly found in milk samples and the presence of BSA were investigated in the Cu2+ ions preconcentration. The method provided an analytical curve ranging from 3.6 to 100.0 µg L-1, preconcentration factor of 24-fold, limit of detection of 1.1 µg L-1 and sample throughput of 20 h-1. The accuracy of the method was attested by Cu2+ ions addition/recovery tests as well as by using GFAAS of samples microwave-assisted digested. The proposed method was successfully applied to the copper determination in milk samples, requiring only pH adjustment followed by preconcentration step as sample pretreatment. Copper content in bovine milk sample was 0.635 ±â€¯0.042 mg kg-1, while to soybean milk samples were between 0.048 ±â€¯0.008 and 0.094 ±â€¯0.005 mg kg-1. To the best of our knowledge, the potential of IIP-HEMA-BSA for Cu2+ ions extraction from biological samples and simultaneous removal of macromolecules employing minimal sample pretreatment was demonstrated for the first time. The proposed extraction method stands out by being simple, fast and a low-cost analytical strategy when compared to the conventional microwave-assisted acid digestion.


Assuntos
Cobre/análise , Grafite/química , Leite/química , Impressão Molecular , Polímeros/química , Tioureia/análogos & derivados , Animais , Espectrofotometria Atômica , Tioureia/química
9.
Talanta ; 200: 494-502, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31036214

RESUMO

An effective dithiourea-appended 1,8-naphthalimide fluorescent probe was designed and synthesized. This probe could recognize Hg2+ and Ag+ sensitively and selectively in neutral and alkaline conditions. Moreover, the probe detected Hg2+ alone at pH between 2 and 6. The sensing ability of the probe was explored by UV-vis, fluorescence, FTIR and 1H NMR spectroscopy. The probe was quenched by Hg2+ and Ag+ with 1:1 binding ratios in MeCN/H2O (4/1, v/v) mixed solution with binding constants of 3.76 × 104 L mol-1 and 2.47 × 104 L mol-1, respectively. The linear concentration ranges for Hg2+ and Ag+ were 0-17 µmol L-1 and 0-24 µmol L-1 with detection limits of 0.83 µmol L-1 and 1.20 µmol L-1, respectively, which allowed for the quantitative determination of Hg2+ and Ag+. The new probe, 3a, was successfully applied to the fluorescence imaging of Hg2+ and Ag+ in HepG2 cells, demonstrating its potential application in biological science. Moreover, 3a was used to measure Hg2+ and Ag+ in tap water, drinking water and ultrapure water samples. The recoveries of Hg2+ and Ag+ in water samples were 96-99% and 98-103%, respectively. Therefore, the proposed method showed promising perspectives for its application, aimed at detecting Hg2+ and Ag+ in fluorescence imaging and real water samples.


Assuntos
Corantes Fluorescentes/química , Mercúrio/análise , Naftalimidas/química , Imagem Óptica , Prata/análise , Tioureia/química , Corantes Fluorescentes/síntese química , Células Hep G2 , Humanos , Imagem Molecular , Estrutura Molecular , Células Tumorais Cultivadas
10.
J Enzyme Inhib Med Chem ; 34(1): 877-897, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30938202

RESUMO

A combination of biochemical, biophysical and biological techniques was used to study calf thymus DNA interaction with newly synthesized 7-MEOTA-tacrine thiourea 12-17 and urea heterodimers 18-22, and to measure interference with type I and II topoisomerases. Their biological profile was also inspected in vitro on the HL-60 cell line using different flow cytometric techniques (cell cycle distribution, detection of mitochondrial membrane potential dissipation, and analysis of metabolic activity/viability). The compounds exhibited a profound inhibitory effect on topoisomerase activity (e.g. compound 22 inhibited type I topoisomerase at 1 µM concentration). The treatment of HL-60 cells with the studied compounds showed inhibition of cell growth especially with hybrids containing thiourea (14-17) and urea moieties (21 and 22). Moreover, treatment of human dermal fibroblasts with the studied compounds did not indicate significant cytotoxicity. The observed results suggest beneficial selectivity of the heterodimers as potential drugs to target cancer cells.


Assuntos
Antineoplásicos/farmacologia , Tacrina/farmacologia , Tioureia/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Células HL-60 , Humanos , Relação Estrutura-Atividade , Tacrina/química , Tioureia/química
11.
Org Biomol Chem ; 17(16): 3934-3939, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30942247

RESUMO

The mechanism of the enantioselective Michael addition of diethyl malonate to trans-ß-nitrostyrene catalyzed by a tertiary amine thiourea organocatalyst is explored using experimental 13C kinetic isotope effects and density functional theory calculations. Large primary 13C KIEs on the bond-forming carbon atoms of both reactants suggest that carbon-carbon bond formation is the rate-determining step in the catalytic cycle. This work resolves conflicting mechanistic pictures that have emerged from prior experimental and computational studies.


Assuntos
Tioureia/química , Catálise , Teoria da Densidade Funcional , Malonatos/química , Estrutura Molecular , Estereoisomerismo , Estirenos/síntese química , Estirenos/química
12.
Molecules ; 24(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986928

RESUMO

A series of symmetrical and unsymmetrical alkyl tren based tris-thiourea anion transporters were synthesised and their anion binding and transport properties studied. Overall, increasing the steric bulk of the substituents resulted in improved chloride binding and transport abilities. Including a macrocycle in the scaffold enhanced the selectivity of chloride transport in the presence of fatty acids, by reducing the undesired H⁺ flux facilitated by fatty acid flip-flop. This study demonstrates the benefit of including enforced steric hindrance and encapsulation in the design of more selective anion receptors.


Assuntos
Ânions/química , Transporte de Íons/fisiologia , Bicamadas Lipídicas/química , Cloretos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Tioureia/química
13.
Arch Biochem Biophys ; 666: 83-98, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30951683

RESUMO

Aroylthiourea derivatives of ciprofloxacin drug - [1-cyclopropyl-6-fluoro-7-(4-((4-methoxybenzoyl)carbamothioyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] ATU-1, [1-cyclopropyl-7-(4-((2,4-dibromobenzoyl)carbamothioyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] ATU-2, and [1-cyclopropyl-7-(4-((3,5-dinitrobenzoyl)carbamothioyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] ATU-3 were synthesized, characterized and investigated for DNA binding at stomach pH (4.7) and at 37 °C. All findings by using DFT, molecular docking, spectroscopic (UV-, fluorescence; FL-), cyclic voltammetric (CV) and viscometric techniques revealed that these compounds have the potency to bind with DNA via a mixed mode of interaction. The binding affinity of ATU-1 was evaluated comparatively greater with Kb × 104/M-1 (docking; 5.55, UV-; 7.93, FL-; 5.62, CV; 6.06), ΔG/kJmol-1(docking; -27.07, UV-; -29.07, FL-; -28.18, CV; -28.38) and n (FL-; 1.20, CV; 2.72). Stern-Volmer quenching constant (Ksv) further pointed towards comparatively greater binding affinity of ATU-1 for DNA, while bimolecular quenching constant (Kq) values showed the involvement of static quenching mechanism in the compound - DNA interaction. Comparatively lesser IC50 (7.1 µM) value obtained from biological work on Huh-7 cancer cell line further confirmed the greater anticancer potential of ATU-1 than that of ATU-2&3.


Assuntos
Antibacterianos/química , Ciprofloxacino/química , DNA/química , Técnicas Eletroquímicas/métodos , Análise Espectral/métodos , Tioureia/química , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Simulação de Acoplamento Molecular
14.
ACS Appl Mater Interfaces ; 11(18): 16328-16335, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30964983

RESUMO

Resembling soft tissues, stretchable hydrogels are promising biomaterials for many biomedical applications due to their excellent mechanical robustness. However, conventional stretchable hydrogels with a synthetic polymer matrix are usually bioinert. The lack of cell and tissue adhesiveness of such hydrogels limits their applications. An easy but reliable postgelation functionalization method is desirable. Herein, we report the fabrication of stretchable supramolecular hydrogels cross-linked by multivalent host-guest interactions. Such hydrogels containing thiourea ( TU) functionalities can be bioactivated with a catechol-modified peptide (Cat-RGD) via thiourea-catechol ( TU-Cat) coupling reaction. This postgelation bioactivation of the otherwise bioinert hydrogels not only conjugates bioactive ligands for cell attachment but also introduces and preserves the catechol structures for tissue adhesion. This straightforward fabrication and one-stone-two-bird bioactivation of the stretchable hydrogels may find broad applications in developing advanced soft biomaterials for tissue repair, wound dressing, and lesion sealing.


Assuntos
Materiais Biocompatíveis/farmacologia , Sistemas de Liberação de Medicamentos , Hidrogéis/farmacologia , Bandagens , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Catecóis/química , Catecóis/farmacologia , Adesão Celular/efeitos dos fármacos , Humanos , Hidrogéis/síntese química , Hidrogéis/química , Ligantes , Polímeros/química , Tioureia/química , Tioureia/farmacologia , Aderências Teciduais
15.
ACS Comb Sci ; 21(5): 380-388, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-30848875

RESUMO

In this study, we synthesized 2-amino-5-carboxamide thiazole derivatives on solid phase. The synthesis of the library starts with the reductive amination of the 4-formyl-3-methoxy phenoxy resin to prevent isomer formation. The dehydrative cyclization of thiourea intermediate resin, which is the key step in the synthetic process, was successfully synthesized using α-bromoketone in the presence of the DMF so as to afford 2-amino-5-carboxylate thiazole resin. The resulting resin is coupled with various amines. Finally, the 2-amino-5-carboxamide thiazole resin was cleaved from the polymer support using a TFA and DCM cocktail. The physicochemical properties of the proposed 2-amino-5-carboxamide thiazole derivatives were calculated and showed potential to be an reasonable oral bioavailability drug properties as determined by Lipinski's Rule.


Assuntos
Técnicas de Síntese em Fase Sólida/métodos , Tiazóis/síntese química , Tioureia/química , Aminas/química , Técnicas de Química Combinatória , Ciclização , Oxirredução , Resinas Sintéticas/química , Tiazóis/química
16.
Molecules ; 24(5)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857175

RESUMO

Functional carbon materials have been developed and applied in various sewage treatment applications in recent years. This article reports the fabrication, characterization, and application of a new kind of poly (allylthiourea-co-acrylic acid) (PAT⁻PAC) hydrogel-based carbon monolith. The results indicated that the poly acrylic acid component can endow the PAT⁻PAC hydrogel with an increased swelling ratio and enhanced thermal stability. During the carbonization process, O⁻H, N⁻H, C=N, and ⁻COO⁻ groups, etc. were found to be partly decomposed, leading to the conjugated C=C double bonds produced and the clear red shift of C=O bonds. Particularly, it was found that this shift was accelerated under higher carbonization temperature, which ultimately resulted in the complex conjugated C=C network with oxygen, nitrogen, and sulfur atoms doped in-situ. The as-obtained carbon monoliths showed good removal capacity for Ni(II) ions, organic solvents, and dyes, respectively. Further analysis indicated that the Ni(II) ion adsorption process could be well described by pseudo-second-order and Freundlich models under our experimental conditions, respectively. The adsorption capacity for Ni(II) ions and paraffin oil was as high as 557 mg/g and 1.75 g/g, respectively. More importantly, the as-obtained carbon monoliths can be recycled and reused for Ni(II) ions, acetone, and paraffin oil removal. In conclusion, the proposed PAT⁻PAC-based carbonaceous monoliths are superior adsorbents for wastewater treatment.


Assuntos
Acrilatos/química , Carbono/química , Polímeros/química , Águas Residuárias/química , Poluentes Químicos da Água/química , Adsorção , Tioureia/análogos & derivados , Tioureia/química , Purificação da Água/métodos
17.
Molecules ; 24(5)2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30813539

RESUMO

Here, we introduced a novel thiourea-based rhodamine compound as a chromo-fluorogenic indicator of nerve agent Soman and its simulant diethyl chlorophosphate (DCP). The synthesized probe N-(rhodamine B)-lactam-2-(4-cyanophenyl) thiourea (RB-CT), which has a rhodamine core linked by a cyanophenyl thiosemicarbazide group, enabled a rapidly and highly sensitive response to DCP with clear fluorescence and color changes. The detection limit was as low as 2 × 10-6 M. The sensing mechanism showed that opening of the spirolactam ring following the phosphorylation of thiosemicarbazides group formed a seven-membered heterocycle adduct, according to MS analysis and TD-DFT calculations. RB-CT exhibited high detecting selectivity for DCP, among other organophosphorus compounds. Moreover, two test kits were employed and successfully used to detect real nerve agent Soman in liquid and gas phase.


Assuntos
Corantes Fluorescentes/síntese química , Compostos Organofosforados/análise , Rodaminas/química , Soman/análise , Tioureia/química , Substâncias para a Guerra Química/análise , Substâncias para a Guerra Química/química , Corantes Fluorescentes/química , Limite de Detecção , Estrutura Molecular , Agentes Neurotóxicos/análise , Agentes Neurotóxicos/química , Compostos Organofosforados/química , Soman/química
18.
Bioconjug Chem ; 30(3): 741-750, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30726065

RESUMO

A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 µM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 µM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 µM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 µM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Concentração de Íons de Hidrogênio , Pró-Fármacos/farmacologia , Tioureia/química , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Doxorrubicina/química , Fluoresceína/química , Transferência Ressonante de Energia de Fluorescência , Humanos , Masculino , Naftalenos/química , Pró-Fármacos/química , Neoplasias da Próstata/patologia
19.
J Enzyme Inhib Med Chem ; 34(1): 620-630, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30727782

RESUMO

In an attempt to improve anti-breast cancer activity, a new series of 4-piperazinylquinoline derivatives based on the urea/thiourea scaffold were designed and synthesised by a pharmacophore hybrid approach. We then examined for their antiproliferative effects on three human breast tumor cell lines, MDA-MB231, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Among those 26 novel compounds examined, 5, 9, 17, 18, 21, 23 and 29 showed significantly improved antiproliferative activity on breast cancer cells. Compound 23 (4-(7-chloro-quinolin-4-yl)-piperazine-1-carbothioic acid (2-morpholin-4-yl-ethyl)-amide) (RL-15) is especially desirable, since its antigrowth/cell-killing activity is 7-11 fold higher on cancer than non-cancer cells. Data from cell biological studies demonstrated that cancer cells compromised plasma membrane integrity in the presence of compound 23. The cancer cell-specific property of compound 23 shown in cell culture stands in vivo test, this compound can be an excellent lead for effective and safe anticancer drug.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenho de Drogas , Piperazinas/farmacologia , Quinolinas/farmacologia , Tioureia/farmacologia , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Tioureia/química , Células Tumorais Cultivadas , Ureia/química
20.
Science ; 363(6429): 875-880, 2019 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-30792303

RESUMO

Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K2P) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca2+)-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design.


Assuntos
Clorobenzenos/farmacologia , Canal de Potássio ERG1/agonistas , Canal de Potássio ERG1/química , Ativação do Canal Iônico/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Alta/agonistas , Canais de Potássio Ativados por Cálcio de Condutância Alta/química , Tetra-Hidronaftalenos/farmacologia , Tetrazóis/farmacologia , Tioureia/análogos & derivados , ortoaminobenzoatos/farmacologia , Animais , Células CHO , Clorobenzenos/química , Cricetulus , Cristalografia por Raios X , Desenho de Drogas , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Domínios Proteicos , Tetra-Hidronaftalenos/química , Tetrazóis/química , Tioureia/química , Tioureia/farmacologia , Xenopus , ortoaminobenzoatos/química
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