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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.
Neurochem Res ; 44(11): 2670-2680, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31630317

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in memory and cognitive impairment. The use of somatostatin receptor subtype-4 (SSTR4) agonists have been proposed for AD treatment. This study investigated the effects of selective SSTR4 agonist NNC 26-9100 on mRNA expression of key genes associated with AD pathology (microglia mediators of Aß phagocytosis, amyloid-beta (Aß)-degrading enzymes, anti-oxidant enzymes and pro-inflammatory cytokines) in 3xTg-AD mice. Mice were administered NNC 26-9100 (0.2 µg, i.c.v.) or vehicle control, with cortical and subcortical brain tissue collected at 6 h and 24 h post-treatment. At 6 h, NNC 26-9100 treatment decreased cortical expression of cluster of differentiation-33 (Cd33) by 25%, while increasing cortical and subcortical macrophage scavenger receptor-1 (Msr1) by 1.8 and 2.0-fold, respectively. The Cd33 downregulation and Msr1 upregulation support a state of microglia associated Aß phagocytosis. At 24 h, NNC 26-9100 treatment increased the cortical expression of Sstr4 (4.9-fold), Aß-degrading enzymes neprilysin (9.3-fold) and insulin degrading enzyme (14.8-fold), and the antioxidant catalase (3.6-fold). Similar effects at 24 h were found in subcortical tissue with NNC 26-9100 treatment, but did not reach statistical significance. No changes in pro-inflammatory cytokine expression were found. These data demonstrated NNC 26-9100 facilitates transcriptional changes in brain tissue identified with Aß phagocytosis and clearance, further supporting SSTR4 as a treatment target for AD.


Assuntos
Encéfalo/metabolismo , Microglia/metabolismo , RNA Mensageiro/metabolismo , Receptores de Somatostatina/metabolismo , Doença de Alzheimer/patologia , Aminopiridinas/farmacologia , Animais , Encéfalo/citologia , Catalase/genética , Regulação para Baixo/efeitos dos fármacos , Insulisina/genética , Camundongos Transgênicos , Neprilisina/genética , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Receptores Depuradores Classe A/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Tioureia/análogos & derivados , Tioureia/farmacologia , Regulação para Cima/efeitos dos fármacos
4.
Pain Res Manag ; 2019: 2612534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281556

RESUMO

Objective: To explore the role of purine family member P2Y6 receptors in regulating neuropathic pain (NP) via neuroinflammation in the spinal cord. Methods: Chronic constriction injury of the sciatic nerve (CCI) of NP was classic in setting up models on Sprague-Dawley (SD) rats. Experiments were performed on rats with sham surgery, CCI, CCI + MRS2578 (a P2Y6 receptor antagonist), and UDP (a P2Y6 receptor agonist). The hyperalgesia intensity was mirrored by paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL). Immunofluorescence staining and western blot were used to evaluate activated microglial marker Iba-1. Enzyme-linked immunosorbent assay (ELISA) was used to access levels of IL-6. Conventional reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis were used to detect the expression of P2Y6 mRNA and activation of JAK/STAT signaling. Results: Among all groups, CCI caused decreased PWT and TWL compared to sham surgery, meaning a successful establishment of the NP model. These decreased values of PWT and TWL tests could be prevented by intraperitoneally injected MRS2578 and enhanced by UDP administration. Similarly, CCI induced increase of Iba-1 protein, P2Y6 mRNA expression, and circulating IL-6 secretion, as well as increased JAK2/STAT3 mRNA expression and phosphorylating modification in spinal cord tissues could also be diminished by MRS2578 treatment and exacerbated by UDP. Conclusions: These findings indicated the crucial role of the P2Y6 receptor in modulating the microglial and inflammatory responses in the process of NP in vivo. Results from this study would provide insights into targeting the P2Y6 receptor to treat NP in the near future.


Assuntos
Neuralgia/metabolismo , Receptores Purinérgicos P2/metabolismo , Animais , Hiperalgesia/metabolismo , Isotiocianatos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Tioureia/análogos & derivados , Tioureia/farmacologia , Difosfato de Uridina/farmacologia
5.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356185

RESUMO

A suitable inflammatory signal influences extracellular matrix accumulation and determines the quality of the myocardial infarction scar. The aim of the present study was to determine the influence of mast cell sonicates or histamine on collagen accumulation in heart myofibroblast culture and on the deposition of collagen in the myocardial infarction scar. The histamine receptor involved in the process was investigated. Myocardial infarction was induced by ligation of the left coronary artery. Myofibroblasts were isolated from the scar of myocardial infarction. The effects of mast cell sonicates, histamine and its receptor antagonists, i.e. ketotifen (H1-receptor inhibitor), ranitidine (H2-receptor inhibitor), ciproxifan (H3-receptor inhibitor), JNJ7777120 (H4-receptor inhibitor), imetit (H3 receptor agonist), were investigated. The mast cell sonicates or histamine (10-10 - 10-5M) augmented collagen content in myofibroblast cultures; however, histamine-induced elevation was reduced by ciproxifan (10-5M, 10-6M). Imetit (10-9 - 10-5M) elevated collagen content in the culture. H3 receptor expression on myofibroblasts was confirmed. Our findings indicate that histamine increases the deposition of collagen in cultures of myofibroblasts isolated from the myocardial infarction scar. This effect is dependent on H3 receptor activation.


Assuntos
Cicatriz/metabolismo , Colágeno/metabolismo , Histamina/metabolismo , Miofibroblastos/metabolismo , Receptores Histamínicos/metabolismo , Animais , Células Cultivadas , Coração/efeitos dos fármacos , Imidazóis/farmacologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Ratos , Ratos Wistar , Tioureia/análogos & derivados , Tioureia/farmacologia
6.
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
7.
Fish Physiol Biochem ; 45(4): 1233-1244, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31115741

RESUMO

Flatfish pigmentation is a complex process, affected by environmental factors including light, nutrients, and hormones. Of those, the thyroid hormone has been reported to increase the albinism rate of Japanese flounder (Paralichthys olivaceus). However, the underlying mechanism remains unclear. In the present study, triiodothyronine (T3), thyroxine, and thiourea were introduced into P. olivaceus larvae from 16 to 57 days after hatching (DAH). By comparison of albinism rate, T3 treatment and control larvae of 42 DAH were chosen for mRNA and miRNA high-throughput sequencing analyses. A total of 337 miRNAs were identified via miRNA-seq, and 12 miRNAs exhibited significantly differential expression patterns in D42_T3 versus D42_Con (TPM > 10, fold change ≥ 1.5 or ≤ 0.67 and q ≤ 0.05). These differentially expressed miRNAs targeted 3658 putative genes, which further enriched to 10 GO terms (q < 0.05). RNA-seq identified 146 differentially expressed genes (DEGs) in D42_T3 versus D42_Con (|log2 fold change| > 1 and q < 0.005), including pigmentation-related genes such as the receptor tyrosine-protein kinase erbB-3, pro-opiomelanocortin A, and melanotransferrin, and the growth-related gene somatotropin. These DEGs were significantly enriched to 15 GO terms and 8 KEGG pathways (q < 0.05), which included several sugar metabolic pathways (glycolysis/gluconeogenesis and the pentose phosphate pathway). Integrated analysis revealed that 26 overlapping genes between DEGs and mRNAs were targeted by miRNAs. Furthermore, seven mRNA-miRNA pairs exhibited reversed regulation patterns. This provides important clues to understand the role of thyroid hormones in flatfish pigmentation.


Assuntos
Linguado/genética , Larva/efeitos dos fármacos , Tioureia/farmacologia , Tiroxina/farmacologia , Tri-Iodotironina/farmacologia , Animais , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Larva/genética , MicroRNAs/genética , Pigmentação/efeitos dos fármacos , RNA Mensageiro/genética
8.
Eur J Pharmacol ; 855: 285-293, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31100414

RESUMO

Fetal hemoglobin (HbF) induction is a cost-effective therapeutic approach for the treatment of ß-hemoglobinopathies like ß-thalassemia and sickle cell anemia. The present study discusses the potential of thiourea derivatives as new class of compounds that induce the fetal hemoglobin production. HbF inducing effect of thiourea derivatives was studied using experimental cell system, the human erythroleukemic K562 cell line. Erythroid induction of K562 cells was studied by the benzidine/H2O2 reaction, total hemoglobin production was estimated by plasma hemoglobin assay kit, and γ-globin gene expression by RT-qPCR, whereas fetal hemoglobin production was estimated by flow cytometry and immunofluorescence microscopy. The results indicated that newly synthesized thiourea derivative are potent inducers of erythroid differentiation of K562 cells with an increased γ-globin gene expression and fetal hemoglobin production. Moreover, these compounds showed no cytotoxic effect and inhibition on K562 cells at HbF inducing concentrations. It is important to note that hydroxyurea is a cytotoxic chemotherapeutic agent and have deleterious side effects, reflecting the need to identify new safe and effective HbF induces. These results signify thiourea derivatives as promising HbF inducers, with the potential to be studied against hematological disorders, including ß-thalassemia and sickle cell anemia.


Assuntos
Hemoglobina Fetal/biossíntese , Tioureia/análogos & derivados , Tioureia/farmacologia , Talassemia beta/tratamento farmacológico , Talassemia beta/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Eritroides/efeitos dos fármacos , Células Eritroides/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Tioureia/uso terapêutico , Talassemia beta/patologia
9.
Microbiology ; 165(6): 668-682, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31091187

RESUMO

Phenotypically heterogeneous but genetically identical mycobacterial subpopulations exist in in vitro cultures, in vitro-infected macrophages, infected animal models and tuberculosis patients. In this regard, we recently reported the presence of two subpopulations of cells, which are phenotypically different in length and buoyant density, in mycobacterial cultures. These are the low-buoyant-density short-sized cells (SCs), which constitute ~10-20 % of the population, and the high-buoyant-density normal/long-sized cells (NCs), which form ~80-90 % of the population. The SCs were found to be significantly more susceptible to rifampicin (RIF), isoniazid (INH), H2O2 and acidified nitrite than the NCs. Here we report that the RIF-/INH-/H2O2-exposed SCs showed significantly higher levels of oxidative stress and therefore higher susceptibility than the equivalent number of exposed NCs. Significantly higher levels of hydroxyl radical and superoxide were found in the antibiotic-exposed SCs than in the equivalently exposed NCs. Different proportions of the subpopulation of SCs were found to have different levels of reactive oxygen species (ROS). The hydroxyl radical quencher, thiourea, and the superoxide dismutase mimic, TEMPOL, significantly reduced hydroxyl radical and superoxide levels, respectively, in the antibiotic-exposed SCs and NCs and thereby decreased their differential susceptibility to antibiotics. Thus, the present study shows that the heterogeneity of the reactive oxygen species (ROS) levels in these mycobacterial subpopulations confers differential susceptibility to antibiotics. We have discussed the possible mechanisms that can generate differential ROS levels in the antibiotic-exposed SCs and NCs. The present study advances our current understanding of the molecular mechanisms underlying antibiotic tolerance in mycobacteria.


Assuntos
Antibacterianos/metabolismo , Antibacterianos/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Óxidos N-Cíclicos/farmacologia , Peróxido de Hidrogênio/farmacologia , Radical Hidroxila/metabolismo , Isoniazida/metabolismo , Isoniazida/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Modelos Biológicos , Mycobacterium smegmatis/genética , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Rifampina/metabolismo , Rifampina/farmacologia , Marcadores de Spin , Superóxidos/metabolismo , Tioureia/farmacologia
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.
J Biochem Mol Toxicol ; 33(7): e22332, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30974023

RESUMO

Alpha-naphthylthiourea (ANTU), a rodenticide induces lung toxicity. Chrysin a flavonoid possesses antioxidant, anti-inflammatory, and antihypertensive potential. The aim of this study was to evaluate the efficacy of chrysin against ANTU-induced pulmonary edema (PE) and pulmonary arterial hypertension (PAH) in laboratory rats. Sprague-Dawley rats were used to induce PE (ANTU, 10 mg/kg, ip) and PAH (ANTU, 5 mg/kg, ip, 4 weeks). Animals were treated with chrysin (10, 20, and 40 mg/kg) and various biochemical, molecular, and histological parameters were evaluated. Acute administration of ANTU induces PE revealed by significant (P < 0.05) increase in relative lung weight, pleural effusion volume, lung edema, bronchoalveolar lavage fluid cell counts, total protein, 5-hydroxytryptamine (5-HT), lactate dehydrogenase (LDH), and γ-glutamyl transferase (GGT), whereas pretreatment with chrysin (20 and 40 mg/kg, ip) significantly (P < 0.05) attenuated these ANTU-induced biochemical and histological alterations. Repeated administration of ANTU caused induction of PAH evaluated by significant (P < 0.05) alterations in electrocardiographic, hemodynamic changes, and left ventricular function, whereas chrysin (20 and 40 mg/kg, p.o.) treatment significantly (P < 0.05) attenuated these alterations. ANTU-induced hematological and serum biochemical (aspartate transaminase, alanine transaminase, LDH, and creatinine kinase MB) alterations were significantly (P < 0.05) inhibited by chrysin. It also significantly (P < 0.05) decreased elevated levels of oxido-nitrosative stress in the right ventricle (RV) and lung. Chrysin significantly (P < 0.05) attenuated downregulated endothelial nitric oxide synthase and upregulated vascular endothelial growth factor messenger RNA and protein expressions both in the RV and pulmonary artery. Chrysin inhibited ANTU-induced PE and PAH via modulation of inflammatory responses (5-HT, LDH, and GGT), oxido-nitrosative stress, and VEGF and eNOs levels.


Assuntos
Flavonoides/farmacologia , Hipertensão Pulmonar , Óxido Nítrico Sintase Tipo III/biossíntese , Edema Pulmonar , Tioureia/análogos & derivados , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/prevenção & controle , Pulmão/metabolismo , Pulmão/patologia , Masculino , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Edema Pulmonar/prevenção & controle , Ratos , Ratos Sprague-Dawley , Tioureia/efeitos adversos , Tioureia/farmacologia
12.
In Vitro Cell Dev Biol Anim ; 55(5): 349-354, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30989449

RESUMO

In our previous study, we proved that a novel Heat shock protein 90 (HSP90) inhibitor 4-(3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzoic acid (DPB) could inhibit A549 lung cancer cell growth via inducing apoptosis. However, whether DPB affects autophagy is still unknown. Here, we investigated the effects of DPB on autophagy and the improved anti-cancer activity in A549 lung cancer cells. Aggregation of LC3-II was observed using laser scanning confocal microscopy in GFP-LC3 stably transfected U87 cells. Autophagy and apoptosis-related protein levels were examined by Western blot analysis. It is suggested that treatment with DPB (5-20 µmol/L) induced mTOR-independent autophagy in dose- and time-dependent manners. Pre-treatment A549 cells with autophagy inhibitor 3-methyladenine (3-MA, 5 mmol/L) enhanced DPB-induced apoptosis. And, DPB inhibited A549 cell growth more effectively in combination with autophagy inhibitors 3-MA (5 mmol/L) or 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO, 30 µmol/L). These results illustrated that as a potential and promising HSP90 inhibitor, DPB could be utilized in the treatment of cancer combined with the autophagy inhibitor.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Autofagia/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/genética , Tioureia/análogos & derivados , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Apoptose/efeitos dos fármacos , Autofagia/genética , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Transdução de Sinais , Tioureia/farmacologia
13.
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
14.
Eur J Med Chem ; 170: 16-27, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878829

RESUMO

A series of Flexible Heteroarotinoid (Flex-Het) analogs was synthesized and their biological activities were evaluated against the A2780 ovarian cancer cell line. The objective of this study was to establish structure-activity relationships (SARs) for new Flex-Het derivatives, which were previously inaccessible due to the limited availability of aryl isothiocyanate precursors. The current work developed a synthesis of isothiocyanate 13 and used it to prepare 14 diverse thiourea analogs of the lead compound SHetA2 (1, NSC-721689) from a range of commercial amines. Additionally, five new ureas were prepared along with nine N-benzylthioureas, five derivatives incorporating hydrazine or hydrazide linkers and four desmethyl compounds. Potencies and efficacies were determined for each derivative. Some of the new Flex-Hets displayed high activity with IC50 values ranging from 1.86 to 4.70 µM and 85.6-95.9% efficacies, which are comparable to or better than the lead compound (IC50 3.17 µM, 84.3% efficacy). Although SHetA2 is scheduled to enter clinical trials in the near future, alternative backup drug candidates have been identified in this work. The new agents possess similar pharmacological properties and retain selective activity against A2780 ovarian cancer cells. Although a mixed SAR was obtained for these analogs, diversified, highly potent molecules were identified for further investigation. In particular, agents 2c-d and 3e-f, which incorporated CF3 and OCF3 groups in place of NO2 on the pendent aryl ring, displayed high activity and excellent differentiation between normal and cancerous cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cromanos/química , Cromanos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Tionas/química , Tionas/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromanos/síntese química , Feminino , Humanos , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade , Tionas/síntese química , Tioureia/síntese química
15.
Neurobiol Learn Mem ; 161: 12-25, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851432

RESUMO

Traumatic brain injury (TBI) is a complex injury that can cause severe disabilities and even death. TBI can induce secondary injury cascades, including but not limited to endoplasmic reticulum (ER) stress, apoptosis and autophagy. Although the investigators has previously shown that salubrinal, the selective phosphatase inhibitor of p-eIF2α, ameliorated neurologic deficits in murine TBI model, the neuroprotective mechanisms of salubrinal need further research to warrant the preclinical value. This study was undertaken to characterize the effects of salubrinal on cell death and neurological outcomes following TBI in mice and the potential mechanisms. In the current study, ER stress-related proteins including p-eIF2α, GRP78 and CHOP showed peak expressions both in the cortex and hippocampus from day 2 to day 3 after TBI, indicating ER stress was activated in our TBI model. Immunofluorescence staining showed that CHOP co-located NeuN-positive neuron, GFAP-positive astrocyte, Iba-1-positive microglia, CD31-positive vascular endothelial cell and PDGFR-ß-positive pericyte in the cortex on day 2 after TBI, and these cells mentioned above constitute the neurovascular unit (NVU). We also found TBI-induced plasmalemma permeability, motor dysfunction, spatial learning and memory deficits and brain lesion volume were alleviated by continuous intraperitoneal administration of salubrinal post TBI. To investigate the underlying mechanisms further, we determined that salubrinal suppressed the expression of ER stress, autophagy and apoptosis related proteins on day 2 after TBI. In addition, salubrinal administration decreased the number of CHOP+/TUNEL+ and CHOP+/LC3+ cells on day 2 after TBI, detected by immunofluorescence. In conclusion, these data imply that salubrinal treatment improves morphological and functional outcomes caused by TBI in mice and these neuroprotective effects may be associated with inhibiting apoptosis, at least in part by suppressing ER stress-autophagy pathway.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Cinamatos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Tioureia/análogos & derivados , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR , Tioureia/farmacologia
16.
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
17.
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
18.
Chem Asian J ; 14(8): 1262-1270, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30706633

RESUMO

Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η6 -p-cymene) complexes employing benzoylthiourea derivatives as ligands. Such ligands often coordinate to metal centers through their S and O donor atoms. We isolated complexes where the ligands were mono- or bidentately coordinated to Ru involving the S donor atom and surprisingly in bidentate coordination mode a deprotonated thiourea nitrogen resulting in a 4-membered ring structure around the metal center. DFT calculations were used to explain the differences in coordination behavior. These were complemented by stability studies and biological investigations of the compounds as anticancer agents. Several of the synthesized derivatives exhibited significant cell growth inhibitory activity, with the complexes featuring bidentate ligands being more potent than their monodentate counterparts. This can be explained by the higher stability of the former under the conditions employed in cell culture assays.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Rutênio/farmacologia , Tioureia/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Rutênio/química , Relação Estrutura-Atividade , Tioureia/análogos & derivados , Tioureia/química
19.
Bioorg Med Chem ; 27(5): 805-812, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711311

RESUMO

By using a new Fragment-Based Virtual Screen strategy, two series of novel FBA-II inhibitors (thiourea derivatives) were de novo discovered based on the active site of fructose-1, 6-bisphosphate aldolase from Cyanobacterial (CyFBA). In comparison, most of the N-(2-benzoylhydrazine-1-carbonothioyl) benzamide derivatives (L14∼L22) exhibit higher CyFBA-II inhibitory activities compared to N-(phenylcarbamothioyl) benzamide derivatives (L1∼L13). Especially, compound L14 not only shows higher CyFBA-II activity (Ki = 0.65 µM), but also exhibits most potent in vivo activity against Synechocystis sp. PCC 6803 (EC50 = 0.09 ppm), higher (7-fold) than that of our previous inhibitor (EC50 = 0.6 ppm). The binding modes of compound L14 and CyFBA-II were further elucidated by jointly using DOX computational protocol, MM-PBSA and site-directed mutagenesis assays. The positive results suggest that strategy adopted in this study was promising to rapidly discovery the potent inhibitors with novel scaffolds. The satisfactory algicide activities suggest that the thiourea derivatives is very likely to be a promising lead for the development of novel specific algicides to solve Cyanobacterial harmful algal blooms (CHABs).


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Frutose-Bifosfato Aldolase/antagonistas & inibidores , Herbicidas/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Frutose-Bifosfato Aldolase/química , Frutose-Bifosfato Aldolase/genética , Herbicidas/síntese química , Herbicidas/química , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação , Synechocystis/efeitos dos fármacos , Synechocystis/enzimologia , Tioureia/síntese química
20.
Ann Pharm Fr ; 77(2): 126-135, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30709547

RESUMO

OBJECTIVES: This work aims at getting more insights into the distinct behavior of S-oxide derivatives of thiocarbonyl-containing antitubercular drugs, in order to better understand their mechanism of action and toxicity. METHODS: Computational calculation of relative free energy (ΔΔG) of S-oxide tautomers (sulfine R-C [SO]NH2), sulfenic acid (R-C [S-OH]NH) and sulfoxide (R-C [SHO]NH) derived from thioamide and thiourea antitubercular drugs and an update of the literature data with a new point of view about how the structural features of oxidized primary metabolites (S-oxide) can influence the outcome of the reactions and be determinant for the mechanisms of action and of toxicity of these drugs. RESULTS: The calculated free energy of S-oxide tautomers, derived from thioamide and thiourea-type antitubercular drugs, supported by some experimental results, revealed that S-oxide derivatives could be found under sulfine and sulfenic acid forms depending on their chemical structures. Thiocarbonyl compounds belonging to the thioamide series are firstly oxidized, in the presence of H2O2, into the corresponding S-oxide derivatives that are more stable under the sulfine tautomeric form. Otherwise, S-oxides of thiourea-type (acyclic and cyclic) compounds tend to adopt the sulfenic acid tautomeric form preferentially. While the intermediate ethionamide-SO under sulfine form can be isolated and in the presence of H2O2 can undergo further oxidation by a mechanism yielding radical species that are toxic for Mycobacterium tuberculosis and human, thioacetazone-SO, found mainly into sulfenic acid form, is unstable and sufficiently reactive in biological conditions to intercept different biochemical pathways and manifests thus its toxicity. CONCLUSION: Based on experimental and theoretical data, we propose that S-oxide derivatives of thioamide and thiourea-type antitubercular drugs have preference for distinct tautomeric forms. S-oxide of ethioamide is preferentially under sulfine form whereas S-oxide of thiourea compound as thioacetazone is mainly found under sulfenic acid form. These structural features lead to individual chemical reactivities that might explain the distinct mechanism of action and toxicity observed for the thioamide and thiourea antitubercular drugs.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Óxidos/química , Óxidos/farmacologia , Antituberculosos/toxicidade , Cromatografia Líquida de Alta Pressão , Óxidos/toxicidade , Estereoisomerismo , Ácidos Sulfênicos/química , Tioamidas/química , Tioamidas/farmacologia , Tioamidas/toxicidade , Tioureia/química , Tioureia/farmacologia , Tioureia/toxicidade
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