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1.
Anticancer Res ; 40(9): 4913-4919, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878779

RESUMO

BACKGROUND/AIM: A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease. MATERIALS AND METHODS: Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells. RESULTS: Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 µM in both cell lines growing as monolayers or as spheroids. Their antiproliferative and antimigratory activity was associated with inhibition of phospho-FAK, as detected by a specific ELISA assay in STO cells. Interestingly, these compounds potentiated the antiproliferative activity of gemcitabine, and these results might be explained by the increase in the mRNA expression of the key gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT-1). CONCLUSION: These promising results support further studies on new imidazo[2,1-b][1,3,4]thiadiazole compounds as well as on the role of both FAK and hENT-1 modulation in order to develop new drug combinations for peritoneal mesothelioma.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/genética , Quinase 1 de Adesão Focal/metabolismo , Imidazóis/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Estrutura Molecular , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Fosforilação/efeitos dos fármacos , Tiadiazóis/síntese química , Tiadiazóis/química , Células Tumorais Cultivadas
2.
PLoS One ; 15(6): e0234115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544157

RESUMO

The variation of the HOMO-LUMO band gap is explored for varying packing arrangements of the 4mod BT-4TIC donor-acceptor molecule pair, by means of a high-throughput ab-initio random structure search of packing possibilities. 350 arrangements of the dimer have been relaxed from initial random dispositions, using non-local density-functional theory. We find that the electronic band gap varies within 0.3 eV, and that this magnitude, the binding energy, and the geometry are not significantly correlated. A clearly favoured structure is found with a binding energy of 1.75±0.07 eV, with all but three other arrangements displaying values of less than one third of this highest binding one, which involves the aliphatic chain of 4TIC.


Assuntos
Compostos Orgânicos/química , Energia Solar , Teoria da Densidade Funcional , Tiadiazóis/química , Tiofenos/química
3.
Acta Pharm ; 70(3): 259-290, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32074064

RESUMO

Parasitic diseases are a serious public health problem affecting hundreds of millions of people worldwide. African trypanosomiasis, American trypanosomiasis, leishmaniasis, malaria and toxoplasmosis are the main parasitic infections caused by protozoan parasites with over one million deaths each year. Due to old medications and drug resistance worldwide, there is an urgent need for new antiparasitic drugs. 1,3,4-Thiadiazoles have been widely studied for medical applications. The chemical, physical and pharmacokinetic properties recommend 1,3,4-thiadiazole ring as a target in drug development. Many scientific papers report the antiparasitic potential of 2-amino-1,3,4-thiadiazoles. This review presents synthetic 2-amino-1,3,4-thiadiazoles exhibiting antitrypanosomal, antimalarial and antitoxoplasmal activities. Although there are insufficient results to state the quality of 2-amino-1,3,4-thiadiazoles as a new class of antiparasitic agents, many reported derivatives can be considered as lead compounds for drug synthesis and a promise for the future treatment of parasitosis and provide a valid strategy for the development of potent antiparasitic drugs.


Assuntos
Antiparasitários/farmacologia , Doenças Parasitárias/tratamento farmacológico , Tiadiazóis/farmacologia , Animais , Antiparasitários/síntese química , Antiparasitários/química , Desenvolvimento de Medicamentos , Humanos , Doenças Parasitárias/epidemiologia , Doenças Parasitárias/parasitologia , Tiadiazóis/síntese química , Tiadiazóis/química , Tripanossomíase/tratamento farmacológico , Tripanossomíase/epidemiologia , Tripanossomíase/parasitologia
4.
Eur J Med Chem ; 189: 112088, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007666

RESUMO

A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 µM, and 0.29-12.2 µM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tiadiazóis/química , Tiofenos/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose , Carcinoma Ductal Pancreático/patologia , Movimento Celular , Proliferação de Células , Desoxicitidina/farmacologia , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Pancreáticas/patologia , Tiofenos/química , Células Tumorais Cultivadas
5.
Molecules ; 25(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075199

RESUMO

Herein we report the synthesis and characterization of a novel bis-tridentate 1,3,4-thiadiazole ligand (L = 2,5-bis[(2-pyridylmethyl)thio]methyl-1,3,4-thiadiazole). Two new mononuclear complexes of the type [MII(L)2](ClO4)2 (with M = FeII (C1) and CoII (C2)) have been synthesized, containing the new ligand (L). In both complexes the metal centers are coordinated by an N4S2-donorset and each of the two ligands is donating to the metal ion with just one of the tridentate pockets. The iron(II) complex (C1) is in the low spin [LS] state below room temperature and shows an increase in the magnetic moment only above 300 K. In contrast, the cobalt(II) complex (C2) shows a gradual spin crossover (SCO) with T1/2 = 175 K. To our knowledge, this is the first cobalt(II) SCO complex with an N4S2-coordination.


Assuntos
Cobalto/química , Complexos de Coordenação/química , Ferro/química , Ligantes , Magnetismo , Marcadores de Spin , Tiadiazóis/síntese química , Tiadiazóis/química
6.
Molecules ; 25(4)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32093125

RESUMO

Viral infections have resulted in millions of victims in human history. Although great efforts have been made to find effective medication, there are still no drugs that truly cure viral infections. There are currently approximately 90 drugs approved for the treatment of human viral infections. As resistance toward available antiviral drugs has become a global threat to health, there is an intrinsic need to identify new scaffolds that are useful in discovering innovative, less toxic and highly active antiviral agents. 1,3,4-Thiadiazole derivatives have been extensively studied due to their pharmacological profile, physicochemical and pharmacokinetic properties. This review provides an overview of the various synthetic compounds containing the 2-amino-1,3,4-thiadiazole moiety that has been evaluated for antiviral activity against several viral strains and could be considered possible prototypes for the development of new antiviral drugs.


Assuntos
Antivirais/uso terapêutico , Tiadiazóis/uso terapêutico , Viroses/tratamento farmacológico , Antivirais/síntese química , Antivirais/química , Humanos , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química
7.
Eur J Med Chem ; 188: 112035, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31951850

RESUMO

Tuberculosis, caused by Mycobacterium tuberculosis, is a serious infectious disease and remains a global health problem. There is an increasing need for the discovery of novel therapeutic agents for its treatment due to the emerging multi-drug resistance. Herein, we present the rational design and the synthesis of eighteen new thiadiazolylhidrazones (TDHs) which were synthesized by intramolecular oxidative N-S bond formation reaction of 2-benzylidene-N-(phenylcarbamothioyl)hydrazine-1-carboximidamide derivatives by phenyliodine(III) bis(trifluoroacetate) (PIFA) under mild conditions. The compounds were characterized by various spectral techniques including FTIR, 1H NMR, 13C NMR and HRMS. Furthermore, the proposed structure of TDH12 was resolved by single-crystal X-ray analysis. The compounds were evaluated for their in vitro antitubercular activity against M. tuberculosis H37Rv. Among them, some compounds exhibited remarkable antimycobacterial activity, MIC = 0.78-6.25 µg/mL, with low cytotoxicity. Additionally, the most active compounds were screened for their biological activities against M. tuberculosis in the nutrient starvation model. Enzyme inhibition assays and molecular docking studies revealed enoyl acyl carrier protein reductase (InhA) as the possible target enzyme of the compounds to show their antitubercular activities.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hidrazonas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Tiadiazóis/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hidrazonas/química , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Oxirredutases/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química
8.
Chem Commun (Camb) ; 56(7): 1093-1096, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894764

RESUMO

We prepared novel conjugated polymer based NIR-II nanoparticles, which display extremely high photothermal conversion efficiency (65%). Both in vitro and in vivo investigations revealed that the as-prepared nanoparticles exhibit excellent theranostic properties including an extremely high cancer cell killing ability, admirable tumor elimination efficiency (100%) and a remarkable photoacoustic imaging contrast enhancing ability.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas/uso terapêutico , Compostos de Organossilício/uso terapêutico , Polímeros/uso terapêutico , Tiadiazóis/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Células Hep G2 , Humanos , Hipertermia Induzida/métodos , Raios Infravermelhos , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nanopartículas/química , Nanopartículas/efeitos da radiação , Compostos de Organossilício/química , Compostos de Organossilício/efeitos da radiação , Técnicas Fotoacústicas/métodos , Polímeros/química , Polímeros/efeitos da radiação , Nanomedicina Teranóstica/métodos , Tiadiazóis/química , Tiadiazóis/efeitos da radiação
9.
Arch Pharm (Weinheim) ; 353(1): e1900233, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31696959

RESUMO

Inflammation acts as an alarming signal for the progression of various biological complications. Various reports in the literature have revealed that heterocycle-containing synthetic compounds have a restorative capability against acute and chronic inflammatory stages. In the current study, we synthesized a series of 1,2,4-triazole-conjugated 1,3,4-thiadiazole hybrid scaffolds and evaluated their impacts against carrageenan-induced paw edema and proinflammatory markers in Wistar rats. Further, 3D QSAR study (three-dimensional quantitative structure-activity relationships), ADMET (absorption, distribution, metabolism, and excretion) profiling, and docking studies were performed to determine the possible mechanism of the action of the derivatives. The study shows that the most active derivatives, 13f and 13g, have optimal logP, a higher anti-inflammatory activity score, and poor metabolism at various sites of cytochrome P450. The docking studies recommended that the synthesized compounds have a similar affinity as the ligands A307, 63X, and S58 to interact with tumor necrosis factor-α, COX-1, and COX-2. So, these molecules will definitely hold a promise for the future drug development initiative.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Tiadiazóis/farmacologia , Triazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carragenina , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Inflamação/induzido quimicamente , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar , Tiadiazóis/química , Triazóis/química
10.
Eur J Med Chem ; 186: 111897, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761382

RESUMO

Diosgenin, a naturally occurring steroidal saponin, has been confirmed to possess potent anticancer properties. In the current work, two series of novel diosgenin derivatives bearing 1,3,4-oxadiazole (6a-6e and 7a-7e) or 1,3,4-thiadiazole (8a-8e and 9a-9e) moieties were designed, synthesized and evaluated for their cytotoxicities in four human cancer cell lines (HepG2, A549, MCF-7 and HCT-116) and normal human gastric epithelial cells (GES-1) using the MTT assay in vitro. The results showed that compounds 8d and 9d exhibited significant cytotoxic activities against the HepG2 and A549 cells, being more potent than their parent compound diosgenin. Furthermore, the 1,3,4-thiadiazole series of compounds generally exhibited stronger cytotoxicity compared with the 1,3,4-oxadiazole series against HepG2 and A549 cells, and the substitution of 3-pyridyl group at the C5 position of the 1,3,4-thiadiazole ring was the preferred option for these compounds to display significant cytotoxic activities. Compound 8d showed potent cytotoxic activity against A549 cell line (IC50 = 3.93 µM) and was 6.7-fold more potent than diosgenin (IC50 = 26.41 µM). Moreover, compound 8d displayed low toxicity against GES-1 cells (IC50 = 420.4 µM), showing specificity between normal and tumor cells. Further cellular mechanism studies in A549 cells indicated that compound 8d triggered the mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential, which was associated with up-regulation of Bax, down-regulation of Bcl-2 and activation levels of the caspase cascade. The above results indicated that compound 8d may be used as a promising skeleton for antitumor agents with improved efficacy.


Assuntos
Antineoplásicos/farmacologia , Diosgenina/farmacologia , Desenho de Fármacos , Oxidiazóis/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diosgenina/síntese química , Diosgenina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Oxidiazóis/química , Relação Estrutura-Atividade , Tiadiazóis/química
11.
Int J Biol Macromol ; 142: 423-431, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593734

RESUMO

Chitosan (Chit) coatings were applied on zinc substrates by the dip-coating method. Subsequently, the coatings were impregnated with a corrosion inhibitor, 2-Acetylamino-5-mercapto-1,3,4-thiadiazole (AcAMT) to obtain an increased anticorrosive effect. The coating thickness and the AcAMT accumulation were determined using UV-Vis spectroscopy on glass and quartz substrates, respectively. The surface morphology and coverage were investigated with atomic force microscopy. Electrochemical impedance spectroscopy and potentiodynamic polarization techniques were used to investigate the protective properties of the impregnated coatings. The chitosan coatings facilitated the accumulation of the corrosion inhibitor inside the polymeric matrix (a multiplication of 380 times compared to the impregnating solution concentration was calculated), channeling high amounts of AcAMT to the Zn surface, which resulted in an inhibition efficiency of >90%. This effect demonstrates the applicability of chitosan coatings as carriers for corrosion inhibitors, significantly reducing the amount of inhibitor needed to achieve good anticorrosive effects.


Assuntos
Quitosana/química , Materiais Revestidos Biocompatíveis/química , Corrosão , Tiadiazóis/química , Zinco/química , Espectroscopia Dielétrica , Teste de Materiais , Microscopia de Força Atômica , Estrutura Molecular , Análise Espectral , Propriedades de Superfície
12.
J Pharmacol Exp Ther ; 372(1): 1-10, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31619465

RESUMO

Padsevonil is an antiepileptic drug (AED) candidate synthesized in a medicinal chemistry program initiated to rationally design compounds with high affinity for synaptic vesicle 2 (SV2) proteins and low-to-moderate affinity for the benzodiazepine binding site on GABAA receptors. The pharmacological profile of padsevonil was characterized in binding and electrophysiological experiments. At recombinant SV2 proteins, padsevonil's affinity for SV2A was greater than that of levetiracetam and brivaracetam (pKi 8.5, 5.2, and 6.6, respectively). Unlike the latter AEDs, both selective SV2A ligands, padsevonil also displayed high affinity for the SV2B and SV2C isoforms (pKi 7.9 and 8.5, respectively). Padsevonil's interaction with SV2A differed from that of levetiracetam and brivaracetam; it exhibited slower binding kinetics: dissociation t 1/2 30 minutes from the human protein at 37°C compared with <0.5 minute for levetiracetam and brivaracetam. In addition, its binding was not potentiated by the allosteric modulator UCB1244283. At recombinant GABAA receptors, padsevonil displayed low to moderate affinity (pIC50≤6.1) for the benzodiazepine site, and in electrophysiological studies, its relative efficacy compared with zolpidem (full-agonist reference drug) was 40%, indicating partial agonist properties. In in vivo (mice) receptor occupancy studies, padsevonil exhibited SV2A occupancy at low ED50 (0.2 mg/kg) and benzodiazepine site occupancy at higher doses (ED50 36 mg/kg), supporting in vitro results. Padsevonil's selectivity for its intended targets was confirmed in profiling studies, where it lacked significant effects on a wide variety of ion channels, receptors, transporters, and enzymes. Padsevonil is a first-in-class AED candidate with a unique target profile allowing for presynaptic and postsynaptic activity. SIGNIFICANCE STATEMENT: Padsevonil is an antiepileptic drug candidate developed as a single molecular entity interacting with both presynaptic and postsynaptic targets. Results of in vitro and in vivo radioligand binding assays confirmed this target profile: padsevonil displayed nanomolar affinity for the three synaptic vesicle 2 protein isoforms (SV2A, B, and C) and micromolar affinity for the benzodiazepine binding site on GABAA receptors. Furthermore, padsevonil showed greater affinity for and slower binding kinetics at SV2A than the selective SV2A ligands, levetiracetam, and brivaracetam.


Assuntos
Anticonvulsivantes/farmacocinética , Agonistas GABAérgicos/farmacocinética , Imidazóis/farmacocinética , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Pirrolidinonas/farmacocinética , Receptores de GABA-A/metabolismo , Tiadiazóis/farmacocinética , Animais , Anticonvulsivantes/química , Células COS , Chlorocebus aethiops , Agonistas GABAérgicos/química , Células HEK293 , Humanos , Imidazóis/química , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Pirrolidinonas/química , Ratos , Ratos Sprague-Dawley , Tiadiazóis/química
13.
Eur J Med Chem ; 185: 111808, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683103

RESUMO

Managing the advanced glycation end-products (AGEs) concentration is a reliable approach to achieve control over the pathogenesis of diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is also an attractive way to tackle type 2 diabetes mellitus (T2DM). We showed previously that azoloazine heterocycles have the potential to prevent the formation of AGEs and in this work, we conducted docking studies with DPP-4 of 5-alkylamino-6-nitro-1,3,4-thiadiazolo[3,2-a]pyrimidines. Consequently, we have developed a synthetic approach to these structures by chlorodeoxygenation and amination reactions. Antidiabetic properties of obtained compounds were studied by evaluating DPP-4 (ex vivo/in vitro) and AGEs formation inhibition (in vitro). It was shown that the nitrothiadiazolopyrimidines exhibit a higher antiglycation activity than reference compound aminoguanidine, but only moderate inhibition of DPP-4. The most active DPP-4 inhibitor 1l had IC50 of 55.87 µM and showed the ability to inhibit serum DPP-4 activity in rats after 10 mg/kg oral administration but with the less and shorter effect than vildagliptin. At the same time, 1l was the most active antiglycating compound in the series (IC50 134.4 µM). Copper chelation properties of synthesized compounds were also investigated since the formation of AGEs is catalyzed by the transition metal cations. A noticeable correlation between antiglycation activity and metal chelation was revealed. Both activities (antiglycation and copper chelation) correlated with quantum-chemical properties (calculated with ab initio) of the tested compounds. These findings will allow us to predict both activities in the future, without the need to model multiple steps of glycation reaction.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Tiadiazóis/farmacologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química
14.
Chem Commun (Camb) ; 56(5): 707-710, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31850402

RESUMO

Visual detection of the methylglyoxal (MGO) level in the brain is critical for understanding its role in the onset and progression of AD. Herein, we disclosed a NIR fluorescent probe, DBTPP, for detecting MGO by utilizing a thiadiazole-fused o-phenylenediamine moiety as a MGO-specific sensing unit. DBTPP exhibits a series of distinct advantages, such as NIR emission, high selectivity and sensitivity, excellent acid-stability, and a huge off-on ratio. The probe could accurately monitor both exogenous and endogenous MGO variations in SH-SY5Y cells. Besides, it was able to image the endogenous MGO in a transgenic AD mouse model successfully, suggesting the great potential of MGO as a biomarker for early AD diagnosis.


Assuntos
Doença de Alzheimer/metabolismo , Corantes Fluorescentes/química , Fenilenodiaminas/química , Aldeído Pirúvico/análise , Tiadiazóis/química , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Fenilenodiaminas/síntese química , Presenilina-1/genética , Aldeído Pirúvico/metabolismo , Tiadiazóis/síntese química
15.
Org Biomol Chem ; 18(3): 495-499, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31850447

RESUMO

A robust lipophilic dye, based on the structures of the benzothiadiazole heterocycle, was shown to be a potent fluorescent stain for the selective imaging of lipid droplets (LDs) within both live and fixed human cells. Its small molecular framework, large Stokes shift, and vastly improved photostability over that of the current status quo, Nile Red, highlight its tremendous potential as a versatile chemical tool for facilitating LD imaging and research.


Assuntos
Corantes Fluorescentes/química , Gotículas Lipídicas/metabolismo , Tiadiazóis/química , Células HeLa , Humanos , Gotículas Lipídicas/química , Coloração e Rotulagem/métodos
16.
Molecules ; 24(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683688

RESUMO

The Kinesins are proteins involved in several biological processes such as mitosis, intracellular transport, and microtubule movement. The mitotic process is allowed by the correct formation of the mitotic spindle which consists of microtubules originating from the spindle poles. In recent years, kinesin Eg5 inhibitors were studied as new chemotherapeutic drugs, due to the lack of side effects and resistance mechanisms. The aim of this work was to investigate the molecular signaling underlying the administration of novel kinesis Eg5 inhibitors in an in vitro model of gastric adenocarcinoma. Data obtained from analogues of K858 led us to select compounds 2 and 41, due to their lower IC50 values. The ability of kinesin inhibitors to induce apoptosis was investigated by evaluating Bax and Caspase-3 protein expression, evidencing that compound 41 and K858 markedly raise Bax expression, while only compounds 2 and 41 co-administrated with K858 trigger Caspase-3 activation. The inhibition of mitotic spindle was measured by ß-tubulin immunofluorescence analysis revealing monopolar spindles formation in gastric cancer cells treated with compounds 2, 41, and K858. Nitric Oxide Synthase (NOS-2) and Matrix Metalloproteinase 9 (MMP-9) expression levels were measured finding a NOS-2-mediated downregulation of MMP-9 when compound 41 and K858 are co-administered. However, this is in contrast to what was reported by migration assay in which both novel compounds and K858 in monotherapy markedly reduce cell migration. This work remarks the importance of understanding and exploring the biological effects of different novel Eg5 kinesin inhibitors administered in monotherapy and in combination with K858 as potential strategy to counteract gastric cancer.


Assuntos
Antineoplásicos/uso terapêutico , Cinesina/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Cinesina/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Modelos Moleculares , Neoplasias Gástricas/patologia , Tiadiazóis/química , Tiadiazóis/farmacologia , Tubulina (Proteína)/metabolismo , Proteína X Associada a bcl-2/metabolismo
17.
Molecules ; 24(22)2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718083

RESUMO

New 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives, (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5a), 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5b)), (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6a), and 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6b)), were prepared and screened in vitro for their antimicrobial activity against various pathogenic microbes. In addition, two compounds (5a and 6a) were examined for their in vivo genotoxicity using rats and an 8-hydroxy-2'-deoxyguanosine (8-OHdG) assay. Compounds 5a and 5b were found to be highly active against Gram-positive and Gram-negative bacteria. In addition, a significant inhibition of urinary 8-OHdG level (50.2%) was observed upon treatment of animals with 500 mg/kg body weight (b.w.) of compound 6a (p < 0.0001). However, compound 5a increased urinary 8-OHdG levels. The lethal dose (LD50) values for compounds 5a and 6a were determined by an up-and-down procedure (OECD 425; OECD 1998), which showed that these compounds are safe, since the LD50 was >5000 mg/kg b.w. Thus, the tested compounds might have the potential for use as antibiotics, since they have low genotoxicity and strong antimicrobial activity.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Mutagênicos/síntese química , Mutagênicos/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Anti-Infecciosos/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos , Dose Letal Mediana , Testes de Sensibilidade Microbiana , Mutagênicos/química , Tiadiazóis/química
18.
ACS Appl Mater Interfaces ; 11(50): 46525-46535, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31746180

RESUMO

Borylated poly(fluorene-benzothiadiazoles) (PF8-BT) are π-conjugated polymers (CPs) with deep-red/near-infrared (NIR) absorption and emission profiles suitable for in vivo optical imaging. A fully borylated PF8-BT derivative (P4) was encapsulated in pegylated poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles and compared with a reference NIR-emitting CP (PCPDTBT) or indocyanine green (ICG). All formulations satisfied quality requirements for parenterally administered diagnostics. P4 nanoparticles had higher quantum yield (2.3%) than PCPCDTBT (0.01%) or ICG nanoparticles (1.1%). The signal/background ratios (SBRs) of CP systems P4 and PCPDTBT in a phantom mouse (λem = 820 nm) increased linearly with fluorophore mass (12.5-100 µg/mL), while the SBRs of ICG decreased above 25 µg/mL. P4 nanoparticles experienced <10% photobleaching over 10 irradiations (PCPDTBT: ∼25% and ICG: >44%). In a mouse tumor xenograft model, P4 nanoparticles showed a 5-fold higher SBR than PCPDTBT particles with fluorophore accumulation in the liver > spleen > tumor. Blood chemistry and tissue histology showed no abnormalities compared to untreated animals after a single administration.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Tiadiazóis/farmacologia , Animais , Fluorenos/química , Fluorenos/farmacologia , Corantes Fluorescentes/química , Xenoenxertos , Humanos , Verde de Indocianina/química , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Camundongos , Nanopartículas/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotodegradação/efeitos dos fármacos , Poliésteres/química , Polietilenoglicóis/química , Polímeros/química , Baço/diagnóstico por imagem , Baço/efeitos dos fármacos , Tiadiazóis/efeitos adversos , Tiadiazóis/química
19.
Int J Mol Sci ; 20(21)2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31690061

RESUMO

The below article presents the results of spectroscopic research, theoretical (time-dependent density functional theory (TD-DFT)), microbiological, and antioxidative calculations for three compounds from the group of 1,3,4-thiadiazoles: 2-amino-5-phenyl-1,3,4-thiadiazole (TB), 2-amino-5-(2-hydroxyphenyl)-1,3,4-thiadiazole (TS), 2-amino-5-(2-hydroxy-5-sulfobenzoyl)-1,3,4-thiadiazole (TSF). In the fluorescence emission spectra (TS) of solutions with varying concentrations of hydrogen ions, a particularly interesting effect of dual fluorescence was observed. The aforementioned effect was observed even more clearly in the environment of butan-1-ol, relative to the compound's concentration. Depending on the modification of the resorcylic substituent (TS and TSF), we observed the emergence of two separate, partially overlapping, fluorescence emission spectra or a single emission spectrum. Interpretation of the obtained spectra using stationary and time-resolved spectroscopy allowed the correlation of the effect's emergence with the phenomenon of molecular aggregation (of a particular type) as well as, above all, the structure of the substituent system. The overlap of said effects most likely induces the processes related to the phenomenon of charge transfer (in TS) and is responsible for the observed fluorescence effects. Also, the position of the -OH group (in the resorcylic ring) is significant and can facilitate the charge transfer (CT). The determinations of the changes in the dipole moment and TD-DFT calculations further corroborate the above assumption. The following paper presents the analysis (the first for this particular group of analogues) of the fluorescence effects relative to the changes in the structure of the resorcylic group combined with pH effects. The results of biological studies also indicate the highest pharmacological potential of the analogue in the case where the effects of dual fluorescence emission are observed, which predisposes this particular group of fluorophores as effective fluorescence probes or potential pharmaceuticals with antimycotic properties.


Assuntos
Antifúngicos/química , Tiadiazóis/química , Absorção de Radiação , Antifúngicos/farmacologia , Antifúngicos/efeitos da radiação , Candida/efeitos dos fármacos , Fluorescência , Tiadiazóis/farmacologia , Tiadiazóis/efeitos da radiação , Raios Ultravioleta
20.
Molecules ; 24(21)2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31690062

RESUMO

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , RNA Helicases DEAD-box/antagonistas & inibidores , Tiadiazóis/química , Antivirais/química , HIV-1/efeitos dos fármacos , Humanos , Replicação Viral/efeitos dos fármacos
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