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1.
Molecules ; 26(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34443550

RESUMO

To confirm that the ß-phenyl-α,ß-unsaturated thiocarbonyl (PUSTC) scaffold, similar to the ß-phenyl-α,ß-unsaturated carbonyl (PUSC) scaffold, acts as a core inhibitory structure for tyrosinase, twelve (Z)-5-(substituted benzylidene)-4-thioxothiazolidin-2-one ((Z)-BTTZ) derivatives were designed and synthesized. Seven of the twelve derivatives showed stronger inhibitory activity than kojic acid against mushroom tyrosinase. Compound 2b (IC50 = 0.47 ± 0.97 µM) exerted a 141-fold higher inhibitory potency than kojic acid. Kinetic studies' results confirmed that compounds 2b and 2f are competitive tyrosinase inhibitors, which was supported by high binding affinities with the active site of tyrosinase by docking simulation. Docking results using a human tyrosinase homology model indicated that 2b and 2f might potently inhibit human tyrosinase. In vitro assays of 2b and 2f were conducted using B16F10 melanoma cells. Compounds 2b and 2f significantly and concentration-dependently inhibited intracellular melanin contents, and the anti-melanogenic effects of 2b at 10 µM and 2f at 25 µM were considerably greater than the inhibitory effect of kojic acid at 25 µM. Compounds 2b and 2f similarly inhibited cellular tyrosinase activity and melanin contents, indicating that the anti-melanogenic effects of both were due to tyrosinase inhibition. A strong binding affinity with the active site of tyrosinase and potent inhibitions of mushroom tyrosinase, cellular tyrosinase activity, and melanin generation in B16F10 cells indicates the PUSTC scaffold offers an attractive platform for the development of novel tyrosinase inhibitors.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Melaninas/biossíntese , Tiazóis/química , Tiazóis/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Inibidores Enzimáticos/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/metabolismo , Conformação Proteica , Relação Estrutura-Atividade , Tiazóis/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445315

RESUMO

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing's syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11ß-HSD1. Inhibition of 11ß-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing's syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11ß-HSD isoforms. For most of them, over 50% inhibition of 11ß-HSD1 and less than 45% inhibition of 11ß-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11ß-HSD1 correctly reproduced the experimental IC50 values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC50 value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Simulação de Acoplamento Molecular , Tiazóis/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/química , Sítios de Ligação , Inibidores Enzimáticos/farmacologia , Hidrocortisona/química , Hidrocortisona/metabolismo , Ligação Proteica , Tiazóis/farmacologia
3.
Exp Parasitol ; 228: 108142, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34375652

RESUMO

We investigated the in vitro activity and selectivity, and in vivo efficacy of ravuconazole (RAV) in self-nanoemulsifying delivery system (SNEDDS) against Trypanosoma cruzi. Novel formulations of this poorly soluble C14-α-demethylase inhibitor may improve its efficacy in the experimental treatment. In vitro activity was determined in infected cardiomyocytes and efficacy in vivo evaluated in terms of parasitological cure induced in Y and Colombian strains of T. cruzi-infected mice. In vitro RAV-SNEDDS exhibited significantly higher potency of 1.9-fold at the IC50 level and 2-fold at IC90 level than free-RAV. No difference in activity with Colombian strain was observed in vitro. Oral treatment with a daily dose of 20 mg/kg for 30 days resulted in 70% of cure for RAV-SNEDDS versus 40% for free-RAV and 50% for 100 mg/kg benznidazole in acute infection (T. cruzi Y strain). Long-term treatment efficacy (40 days) was able to cure 100% of Y strain-infected animals with both RAV preparations. Longer treatment time was also efficient to increase the cure rate with benznidazole (Y and Colombian strains). RAV-SNEDDS shows greater efficacy in a shorter time treatment regimen, it is safe and could be a promising formulation to be evaluated in other pre-clinical models to treat T. cruzi and fungi infections.


Assuntos
Doença de Chagas/tratamento farmacológico , Tiazóis/administração & dosagem , Triazóis/administração & dosagem , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/parasitologia , Emulsões , Feminino , Células Hep G2 , Humanos , Concentração Inibidora 50 , Camundongos , Miócitos Cardíacos , Nanoestruturas , Ratos , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Tiazóis/toxicidade , Triazóis/farmacologia , Triazóis/uso terapêutico , Triazóis/toxicidade
4.
Science ; 373(6557): 931-936, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285133

RESUMO

There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro. Mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation. Masitinib was also effective in vitro against all tested variants of concern (B.1.1.7, B.1.351, and P.1).


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Coronavirus Humano OC43/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , SARS-CoV-2/efeitos dos fármacos , Tiazóis/farmacologia , Células A549 , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , COVID-19/virologia , Domínio Catalítico , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Coronavirus Humano OC43/fisiologia , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/metabolismo , Células HEK293 , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Transgênicos , Testes de Sensibilidade Microbiana , SARS-CoV-2/enzimologia , SARS-CoV-2/fisiologia , Tiazóis/química , Tiazóis/metabolismo , Tiazóis/uso terapêutico , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
5.
Molecules ; 26(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299452

RESUMO

In recent decades, demands for novel insecticides against mosquitoes are soaring, yet candidate chemicals with desirable properties are limited. Kathon is a broad-spectrum isothiazolinone microbicide, but other applications remain uncharacterized. First, we treated larvae of Culex quinquefasciatus and Aedes albopictus, two major mosquito vectors of human viral diseases, with Kathon at 15 mg/L (a concentration considered safe in cosmetic and body care products), and at lower concentrations, and found that Kathon treatment resulted in high mortality of larvae. Second, sublethal concentration of Kathon can cause significantly prolonged larval development of C. quinquefasciatus. Third, we explored the effects of two constituents of Kathon, chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT), on the survival of larvae, and found that CMIT was the major toxic component. Further, we explored the mechanisms of action of Kathon against insect cells and found that Kathon reduces cell viability and adenosine triphosphate production but promotes the release of lactate dehydrogenase in Drosophila melanogaster S2 cells. Our results indicate that Kathon is highly toxic to mosquito larvae, and we highlight its potential in the development of new larvicides for mosquito control.


Assuntos
Culicidae/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Aedes/efeitos dos fármacos , Animais , Anopheles/efeitos dos fármacos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Culex/efeitos dos fármacos , Culicidae/metabolismo , Inseticidas/química , Larva/efeitos dos fármacos , Controle de Mosquitos/métodos , Mosquitos Vetores
6.
J Enzyme Inhib Med Chem ; 36(1): 1694-1702, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34309466

RESUMO

A novel series of thiazole-naphthalene derivatives as tubulin polymerisation inhibitors were designed, synthesised, and evaluated for the anti-proliferative activities. The majority of the tested compounds exhibited moderate to potent antiproliferative activity on the MCF-7 and A549 cancer cell lines. Among them, compound 5b was found to be the most active compound with IC50 values of 0.48 ± 0.03 and 0.97 ± 0.13 µM. Moreover, mechanistic studies revealed that 5b significantly inhibited tubulin polymerisation with an IC50 value of 3.3 µM, as compared to the standard drug colchicine (IC50 = 9.1 µM). Further cellular mechanism studies elucidated that 5b arrested the cell cycle at G2/M phase and induced apoptosis in MCF-7 cancer cells. Molecular modelling study indicated that 5b binds well to the colchicine binding site of tubulin. In summary, these results suggest that 5b represents a promising tubulin polymerisation inhibitor worthy of further investigation as potential anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Naftalenos/farmacologia , Tiazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
7.
Chem Biol Interact ; 347: 109597, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34303695

RESUMO

In this work, 22 new compounds were obtained and evaluated for their cytotoxic activity on peripheral blood mononuclear cells (PBMC) and eight different tumor cell lines. All compounds displayed IC50 values above 100 µM when assayed against PBMCs. The cytotoxic assays in tumor cell lines revealed that sub-series of phthalimido-bis-1,3-thiazoles (5a-f) exhibited the best anti-tumor activity profile, presenting viability values below 59 %. As a result, the IC50 value was calculated for compounds 5a-f and 4c, and compounds 5b and 5e were selected for further assays due to their best IC50s. Considering the results presented by the sub-series 5a-f, the importance of the 1,3-thiazole ring in improving the anti-tumor activity was pointed out. Together, the results highlighted the anti-tumor activity of phthalimido-bis-1,3-thiazole derivatives.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HL-60 , Humanos , Células K562 , Leucócitos Mononucleares/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade
8.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281197

RESUMO

Psoriasis, a long-lasting and multifactorial skin disease, is related to comorbidities such as metabolic disease, depression, and psoriatic arthritis. Psoriasis occurs due to a variety of factors including keratinocyte hyperproliferation, inflammation, and abnormal differentiation. Proinflammatory cytokines upregulated by increased activation of keratinocytes and immune cells in the skin trigger progression of psoriasis. This study aimed to investigate the effects of anoctamin1 (ANO1) on psoriasis development in vitro and in vivo. We analyzed the proliferation of HaCaT keratinocytes and ANO1-related ERK and AKT signaling pathways after ANO1 inhibitor (T16Ainh-A01 and Ani9) treatment and knock-down of ANO1. Furthermore, after applying imiquimod (IMQ) cream or coapplying IMQ cream and T16Ainh-A01 on mouse ears, we not only observed psoriatic symptoms, including ear thickening, but also quantified the effects of treatment on ERK and AKT signaling-involved proteins and proinflammatory cytokines. Inhibition of ANO1 attenuated the proliferation of HaCaT cells and induced reduction of pERK1/2. Coapplication of IMQ and T16Ainh-A01 on ears of mice reduced not only symptoms of IMQ-induced psoriasis such as thickening and erythema, but also expression of ANO1 and pERK1/2 compared to that of application of IMQ alone. In addition, the expression levels of IL-17A, IL-17F, IL-22, IL-23, IL-6, IL-1ß, and TNF-α increased after applying IMQ and were significantly reduced by coapplying IMQ and T16Ainh-A01. These results aid in understanding the underlying mechanisms of ANO1 in epidermal layer keratinocyte hyperproliferation and suggest the potential of ANO1 as a target to treat psoriasis.


Assuntos
Anoctamina-1/farmacologia , Queratinócitos/efeitos dos fármacos , Psoríase/induzido quimicamente , Acetamidas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HaCaT , Humanos , Hidrazonas/farmacologia , Imiquimode/efeitos adversos , Imiquimode/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Interleucinas/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/metabolismo , Psoríase/patologia , Pirimidinas/farmacologia , Tiazóis/farmacologia
9.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203800

RESUMO

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor ß/δ (PPARß/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARß/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARß/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARß/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARß/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARß/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARß/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARß/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Cardiotônicos/uso terapêutico , Metabolismo Energético , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , PPAR delta/metabolismo , PPAR beta/metabolismo , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Antioxidantes/metabolismo , Caderinas/metabolismo , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Catalase/metabolismo , Metabolismo Energético/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Modelos Biológicos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , PPAR delta/agonistas , PPAR beta/agonistas , Ratos Wistar , Superóxido Dismutase/metabolismo , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Proteína Desacopladora 3/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
Molecules ; 26(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204643

RESUMO

Plant-derived protein hydrolysates have potential applications in nutrition. Rice protein hydrolysates (RPHs), an excellent source of proteins, have attracted attention for the development of cosmeceuticals. However, few studies have reported the potential application of RPH in analysis, and this study examined their antioxidant activities and the inhibitory activities of skin aging enzymes. The results indicated that the total phenolic and flavonoid concentrations were 2.06 ± 0.13 mg gallic acid equivalent/g RPHs and 25.96 ± 0.52 µg quercetin equivalent/g RPHs, respectively. RPHs demonstrated dose-dependent activity for scavenging free radicals from 1,1-diphenyl-2-picrylhydrazyl [half-maximal inhibitory concentration (IC50) = 42.58 ± 2.1 mg/g RPHs] and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (IC50 = 2.11 ± 0.88 mg/g RPHs), dose-dependent reduction capacity (6.95 ± 1.40 mg vitamin C equivalent/g RPHs) and oxygen radical absorbance capacity (473 µmol Trolox equivalent/g RPHs). The concentrations of the RPH solution required to achieve 50% inhibition of hyaluronidase and tyrosinase activities were determined to be 8.91 and 107.6 mg/mL, respectively. This study demonstrated that RPHs have antioxidant, antihyaluronidase, and antityrosinase activities for future cosmetic applications.


Assuntos
Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Clareadores/química , Clareadores/metabolismo , Flavonoides/farmacologia , Sequestradores de Radicais Livres/química , Ácido Gálico/farmacologia , Camundongos , Oryza/química , Oryza/enzimologia , Oryza/metabolismo , Oxirredução , Fenóis/farmacologia , Picratos/química , Picratos/farmacologia , Extratos Vegetais/química , Quercetina/farmacologia , Células RAW 264.7 , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , Tiazóis/química , Tiazóis/farmacologia
11.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204139

RESUMO

The prohibitin (PHB)-binding compound fluorizoline as well as PHB-downregulation activate the integrated stress response (ISR) in HEK293T and U2OS human cell lines. This activation is denoted by phosphorylation of eIF2α and increases in ATF4, ATF3, and CHOP protein levels. The blockage of the activation of the ISR by overexpression of GRP78, as well as an increase in IRE1 activity, indicate the presence of ER stress after fluorizoline treatment. The inhibition of the ER stress response in HEK293T and U2OS led to increased sensitivity to fluorizoline-induced apoptosis, indicating a pro-survival role of this pathway after fluorizoline treatment in these cell lines. Fluorizoline induced an increase in calcium concentration in the cytosol and the mitochondria. Finally, two different calcium chelators reduced fluorizoline-induced apoptosis in U2OS cells. Thus, we have found that fluorizoline causes increased ER stress and activation of the integrated stress response, which in HEK293T and U2OS cells are protective against fluorizoline-induced apoptosis.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células HEK293 , Homeostase/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298950

RESUMO

More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/ß-catenin activation. Tankyrase (TNKS) mediates the release of active ß-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized AXIN2, reduced active ß-catenin, and downregulated ß-catenin target genes in COLO320DM and DLD-1 cells. The antitumor activities of TI-12403 were confirmed by the viability of the colorectal cancer cells and its lack of visible toxicity in DLD-1 xenograft mouse model. In addition, combined 5-FU and TI-12403 treatment synergistically inhibited proliferation to a greater extent than that in a single drug treatment. Our observations suggest that TI-12403, a novel selective TNKS1 inhibitor, may be a suitable compound for anticancer drug development.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Descoberta de Drogas , Inibidores Enzimáticos , Proteínas de Neoplasias/antagonistas & inibidores , Piridinas , Tanquirases/antagonistas & inibidores , Tiazóis , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Proteínas de Neoplasias/metabolismo , Piridinas/química , Piridinas/farmacologia , Tanquirases/metabolismo , Tiazóis/química , Tiazóis/farmacologia
13.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201561

RESUMO

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (EMAC2063) was the most potent towards RNaseH (IC50 = 4.5 mM)- and RDDP (IC50 = 8.0 mM) HIV RT-associated functions.


Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/metabolismo , Ribonuclease H/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/química , HIV-1/enzimologia , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Tiazóis/síntese química
14.
Molecules ; 26(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070661

RESUMO

BACKGROUND: Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is contained in more than 18 FDA-approved drugs as well as in numerous experimental drugs. OBJECTIVE: To summarize recent literature on the biological activities of thiazole ring-containing compounds Methods: A literature survey regarding the topics from the year 2015 up to now was carried out. Older publications were not included, since they were previously analyzed in available peer reviews. RESULTS: Nearly 124 research articles were found, critically analyzed, and arranged regarding the synthesis and biological activities of thiazoles derivatives in the last 5 years.


Assuntos
Tiazóis/química , Humanos , Relação Estrutura-Atividade , Tiazóis/farmacologia
15.
Int J Lab Hematol ; 43(4): 795-801, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34092030

RESUMO

INTRODUCTION: Andexanet alfa (AnXa) was developed for anticoagulant effect reversal of direct factor Xa inhibitors (DXaI) (apixaban, rivaroxaban, edoxaban) in emergency situations. Regular anti-Xa assays are not suitable to evaluate anti-Xa activity after AnXa administration because of the high sample dilution resulting in the AnXa-DXaI dissociation which gives inaccurately high DXaI measured concentrations. This study aimed at developing dedicated STA-Liquid anti-Xa test set-ups for accurately measuring DXaI after reversal with AnXa. METHODS: Modified anti-Xa test set-ups, with reduced sample dilution, were developed to overcome regular assays limitations and to improve measured accuracy with results comparable to Portola microplate reference method used in clinical studies. Both regular and optimized assays were used to measure DXaI concentration in AnXa-containing samples. Quality controls, normal pooled plasma spiked with five DXaI and three AnXa concentrations, samples from DXaI-treated patients spiked with AnXa and ex vivo healthy volunteers having received both DXaI and AnXa were used. RESULTS: The lower limit of quantitation of optimized anti-Xa assays was <10 ng/mL with CVs ≤10%. DXaI samples containing 300 ng/mL and 1 µmol/L AnXa resulted in DXaI residual concentrations of 29-72 ng/mL depending on the DXaI (76%-90% reversal), compared to 20-28 ng/mL with reference method (92%-94% reversal) and 135-165 ng/mL with regular assays (about 50% reversal). CONCLUSION: Modified test set-ups are automated alternative to reference method with improved precision and reproducibility. They can be run in all laboratories where regular anti-Xa assays are performed using commercially available reagents.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Fator Xa/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Proteínas Recombinantes/farmacologia , Rivaroxabana/farmacologia , Tiazóis/farmacologia , Testes de Coagulação Sanguínea/métodos , Humanos
16.
Cell Death Dis ; 12(7): 641, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162831

RESUMO

A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.


Assuntos
Antivirais/farmacologia , Azocinas/farmacologia , Compostos Benzidrílicos/farmacologia , Genoma Viral , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Fígado/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Modelos Animais de Doenças , Células Hep G2 , Hepatite B/metabolismo , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/virologia , Interações Hospedeiro-Patógeno , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Organoides , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Replicação Viral/efeitos dos fármacos
17.
Eur J Med Chem ; 222: 113581, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102377

RESUMO

A series of novel acyclic nucleoside phosphonates (ANPs) was synthesized as potential adenylate cyclase inhibitors, where the adenine nucleobase of adefovir (PMEA) was replaced with a 5-substituted 2-aminothiazole moiety. The design was based on the structure of MB05032, a potent and selective inhibitor of fructose 1,6-bisphosphatase and a good mimic of adenosine monophosphate (AMP). From the series of eighteen novel ANPs, which were prepared as phosphoroamidate prodrugs, fourteen compounds were potent (single digit micromolar or submicromolar) inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT), mostly without observed cytotoxicity in J774A.1 macrophage cells. Selected phosphono diphosphates (nucleoside triphosphate analogues) were potent inhibitors of ACT (IC50 as low as 37 nM) and B. anthracis edema factor (IC50 as low as 235 nM) in enzymatic assays. Furthermore, several ANPs were found to be selective mammalian AC1 inhibitors in HEK293 cell-based assays (although with some associated cytotoxicity) and one compound exhibited selective inhibition of mammalian AC2 (only 12% of remaining adenylate cyclase activity) but no observed cytotoxicity. The mammalian AC1 inhibitors may represent potential leads in development of agents for treatment of human inflammatory and neuropathic pain.


Assuntos
Toxina Adenilato Ciclase/antagonistas & inibidores , Inibidores de Adenilil Ciclases/farmacologia , Antibacterianos/farmacologia , Organofosfonatos/farmacologia , Tiazóis/farmacologia , Toxina Adenilato Ciclase/metabolismo , Inibidores de Adenilil Ciclases/síntese química , Inibidores de Adenilil Ciclases/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Bacillus anthracis/efeitos dos fármacos , Bordetella pertussis/efeitos dos fármacos , Bordetella pertussis/enzimologia , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neuralgia/tratamento farmacológico , Organofosfonatos/química , Relação Estrutura-Atividade , Tiazóis/química
18.
Eur J Med Chem ; 222: 113628, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34139627

RESUMO

The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics has led to a growing effort to design and synthesize novel structural candidates of chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids with outstanding bacteriostatic potential. Bioactivity screening showed that hybrid 5i, which was modified with methoxybenzene, exerted a significant inhibitory activity against MRSA (MIC = 0.004 mM), which was 6 times better than the anti-MRSA activity of the reference drug norfloxacin (MIC = 0.025 mM). Compound 5i neither conferred apparent resistance onto MRSA strains even after multiple passages nor triggered evident toxicity to human hepatocyte LO2 cells and normal mammalian cells (RAW 264.7). Molecular docking showed that highly active molecule 5i might bind to DNA gyrase by forming stable hydrogen bonds. In addition, molecular electrostatic potential surfaces were developed to explain the high antibacterial activity of the target compounds. Furthermore, preliminary mechanism studies suggested that hybrid 5i could disrupt the bacterial membrane of MRSA and insert itself into MRSA DNA to impede its replication, thus possibly becoming a potential antibacterial repressor against MRSA.


Assuntos
Antibacterianos/farmacologia , Chalconas/farmacologia , Cumarínicos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Chalconas/química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química
19.
Molecules ; 26(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073584

RESUMO

PPARα is a ligand-dependent transcription factor and its activation is known to play an important role in cell defense through anti-inflammatory and antioxidant effects. MHY3200 (2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2,2-difluoroacetic acid), a novel benzothiazole-derived peroxisome proliferator-activated receptor α (PPARα) agonist, is a synthesized PPARα activator. This study examined the beneficial effects of MHY3200 on age-associated alterations in reactive oxygen species (ROS)/Akt/forkhead box (FoxO) 1 signaling in rat kidneys. Young (7-month-old) and old (22-month-old) rats were treated with MHY3200 (1 mg/kg body weight/day or 3 mg/kg body weight/day) for two weeks. MHY3200 treatment led to a notable decrease in triglyceride and insulin levels in serum from old rats. The elevated kidney ROS level, serum insulin level, and Akt phosphorylation in old rats were reduced following MHY3200 treatment; moreover, FoxO1 phosphorylation increased. MHY3200 treatment led to the increased level of FoxO1 and its target gene, MnSOD. MHY3200 suppressed cyclooxygenase-2 expression by activating PPARα and inhibiting the activation of nuclear factor-κB (NF-κB) in the kidneys of old rats. Our results suggest that MHY3200 ameliorates age-associated renal inflammation by regulating NF-κB and FoxO1 via ROS/Akt signaling.


Assuntos
Acetatos/farmacologia , Envelhecimento/efeitos dos fármacos , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , PPAR alfa/agonistas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tiazóis/farmacologia , Acetatos/uso terapêutico , Animais , Peso Corporal , Regulação da Expressão Gênica , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Rim/patologia , Masculino , PPAR alfa/metabolismo , Fosforilação , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiazóis/uso terapêutico , Fatores de Tempo , Triglicerídeos/metabolismo
20.
Eur J Med Chem ; 221: 113557, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087496

RESUMO

An unprecedented amount of fungal and fungal-like infections has recently brought about some of the most severe die-offs and extinctions due to fungal drug resistance. Aimed to alleviate the situation, new effort was made to develop novel purinylthiazolylethanone derivatives, which were expected to combat the fungal drug resistance. Some prepared purinylthiazolylethanone derivatives possessed satisfactory inhibitory action towards the tested fungi, among which compound 8c gave a MIC value of 1 µg/mL against C. albicans. The active molecule 8c was able to kill C. albicans with undetectable resistance as well as low hematotoxicity and cytotoxicity. Furthermore, it could hinder the growth of C. albicans biofilm, thus avoiding the occurrence of drug resistance. Mechanism research manifested that purinylthiazolylethanone derivative 8c led to damage of cell wall and membrane disruption, so protein leakage and the cytoplasmic membrane depolarization were observed. On this account, the activity of fungal lactate dehydrogenase was reduced and metabolism was impeded. Meanwhile, the increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) disordered redox equilibrium, giving rise to oxidative damage to fungal cells and fungicidal effect.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Etano/farmacologia , Fungicidas Industriais/farmacologia , Purinas/farmacologia , Tiazóis/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Farmacorresistência Fúngica/efeitos dos fármacos , Etano/análogos & derivados , Etano/química , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Purinas/química , Relação Estrutura-Atividade , Tiazóis/química
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