Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 95
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Pharmaceuticals (Basel) ; 14(11)2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34832877

RESUMO

This manuscript deals with the synthesis and computational and experimental evaluation of the antimicrobial activity of twenty-nine 4-(indol-3-yl)thiazole-2-amines and 4-ιndol-3-yl)thiazole acylamines. An evaluation of antibacterial activity against Gram (+) and Gram (-) bacteria revealed that the MIC of indole derivatives is in the range of 0.06-1.88 mg/mL, while among fourteen methylindole derivatives, only six were active, with an MIC in the range of of 0.47-1.88 mg/mL. S. aureus appeared to be the most resistant strain, while S. Typhimurium was the most sensitive. Compound 5x was the most promising, with an MIC in the range of 0.06-0.12 mg/mL, followed by 5d and 5m. An evaluation of these three compounds against resistant strains, namely MRSA P. aeruginosa and E. coli, revealed that they were more potent against MRSA than ampicillin. Furthermore, compounds 5m and 5x were superior inhibitors of biofilm formation, compared to ampicillin and streptomycin, in terms Compounds 5d, 5m, and 5x interact with streptomycin in additive manner. The antifungal activity of some compounds exceeded or was equipotent to those of the reference antifungal agents bifonazole and ketoconazole. The most potent antifungal agent was found to be compound 5g. Drug likeness scores of compounds was in a range of -0.63 to 0.29, which is moderate to good. According to docking studies, E. coli MurB inhibition is probably responsible for the antibacterial activity of compounds, whereas CYP51 inhibition was implicated in antifungal activity. Compounds appeared to be non-toxic, according to the cytotoxicity assessment in MRC-5 cells.

2.
Antioxidants (Basel) ; 10(10)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34679706

RESUMO

The impact of two extraction solvents on the phenolic composition, antioxidant, and enzymes inhibitory and antimicrobial activities of two parts (leaves and stem bark) of P. kotschyi was studied. Two different LC-DAD-MSn approaches were used to identify and quantify the bioactive compounds in the different extracts. A total of thirty-two compounds were quantified, being the procyanidin the most abundant in stem bark while catechin and flavonoids are most abundant in leaves. Overall, the stem bark extraction using methanol showed higher amounts of total phenolic (131.83 ± 1.81 mg GAE/g) and flavanol (14.14 ± 0.11 mg CE/g) while the leaves extraction using water exhibited stronger levels of total flavonoid (44.95 ± 0.38 mg RE/g) and phenolic acid (63.58 ± 2.00 mg CAE/g). As regards the antioxidant assays, methanol stem bark extracts were characterized by the highest antioxidant activities (DPPH: 1.94 ± 0.01 mmol TE/g, ABTS: 3.31 ± 0.01 mmol TE/g, FRAP: 2.86 ± 0.02 mmol TE/g, CUPRAC: 5.09 ± 0.08 mmol TE/g, phosphomolybdenum: 5.16 ± 0.23 mmol TE/g and metal chelating: 17.12 ± 0.46 mg EDTAE/g). In addition, the methanolic extracts of stem bark had highest impact on acetylcholinesterase (2.54 mg GALAE/g), butyrylcholinesterase (5.48 mg GALAE/g). In contrast, the methanolic extracts of leaves was potent against tyrosinase (77.39 ± 0.21 mg KAE/g) and α-glucosidase (0.97 ± 0.01 mmol ACAE/g), while a higher anti-α-amylase (0.97 ± 0.01 mmol ACAE/g) was observed for water extracts of the same part. All of the tested extracts showed inhibitory effects on elastase, except methanolic leaves extracts. Additionally, the extracts exhibited appreciable antifungal toward A. ochraceus, A. fumigatus, P. ochrochloron, T. viride, and P. funiculosum and promising antibacterial activity against M. flavus, S. aureus, L. monocytogenes, E. coli, P. aeruginosa, E. cloacae, and S. typhimurium. Taken together, the outcomes demonstrated P. kotschyi as a novel source of bioactive molecules of interest with an evident therapeutic value.

3.
J Fungi (Basel) ; 7(10)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34682255

RESUMO

Severe drawbacks associated with the topical use of depigmenting agents in treatments of skin hyperigmentations impose a great demand for novel, effective, and safe melanogenesis inhibitors. Edible and medicinal mushrooms, known for numerous health-promoting properties, represent a rich reservoir of anti-melanogenic compounds, with the potential to be applied in preventing excessive skin pigmentation. Herein, using zebrafish (Danio rerio) as a preclinical animal model, we have demonstrated that ethanol extract of Laetiporus sulphureus (LSE) and Agaricus silvaticus (ASE) are not toxic at high doses up to 400-500 µg/mL while effectively inhibit melanogenesis in a dose-dependent manner. At depigmenting doses, the explored extracts showed no adverse effects on zebrafish embryos melanocytes. Even more, they did not provoke inflammation or neutropenia when applied at the highest dose ensuring almost complete the cells depigmentation. Since LSE and ASE have demonstrated significantly higher the therapeutic potential than kojic acid and hydroquinone, two well-known depigmenting agents, overall results of this study strongly suggest that the explored mushrooms extracts could be used as efficient and safe topical agents in treatments of skin hyperpigmentation disorders.

4.
Molecules ; 26(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299579

RESUMO

Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a-3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1-184.2 and 71.3-199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays.


Assuntos
Antifúngicos , Cromonas , Hypocreales/crescimento & desenvolvimento , Fungos Mitospóricos/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Cromonas/síntese química , Cromonas/química , Cromonas/farmacologia , Avaliação Pré-Clínica de Medicamentos
5.
Food Funct ; 12(15): 6780-6792, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34109332

RESUMO

Lentinus crinitus (L.) Fr. (Basidiomycota: Polyporales) is a wild mushroom with several biotechnological applications; however, there are few studies on its chemical composition and antimicrobial activity. Therefore, this study aims to evaluate the chemical composition, cytotoxicity, and antimicrobial activity of L. crinitus basidiocarp. For that, its nutritional value (AOAC procedures) and its composition in some hydrophilic and lipophilic compounds (chromatographic techniques) were assessed. Moreover, the potential hepatotoxic effects were evaluated using a primary cell culture obtained from porcine liver, and its growth inhibitory capacity was also evaluated against four human tumour cell lines (spectrophotometric assays). The antimicrobial activity was evaluated by microdilution against eight bacteria and fungi. The basidiocarp has a high content of carbohydrates and, therefore, a relatively high energetic value. It is also rich in soluble sugars, ß-tocopherol, phenolic acids, mainly p-hydroxybenzoic acid, and organic acids, mainly malic acid. L. crinitus did not show cytotoxicity in non-tumour cells, but it did not inhibit the growth of human tumour cell lines either. The basidiocarp has a wide antimicrobial activity, inhibiting the growth of different species of bacteria and fungi. It showed minimum bactericidal and fungicidal concentration values similar to or lower than those verified by commercial antibiotics or food additives used as preservatives. The antimicrobial activity was more evident against Listeria monocytogenes, Salmonella enterica, and Penicillium ochrochloron, followed by Aspergillus ochraceus and Trichoderma viride, when compared to the controls. The results obtained in this study showed that L. crinitus basidiocarp has great potential to be used by the industry without toxicity risks.

6.
J Fungi (Basel) ; 7(5)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947042

RESUMO

This study aims to fill the gaps in ethnomycological knowledge in Serbia by identifying various fungal species that have been used due to their medicinal or nutritional properties. Ethnomycological information was gathered using semi-structured interviews with participants from different mycological associations in Serbia. A total of 62 participants were involved in this study. Eighty-five species belonging to 28 families were identified. All of the reported fungal species were pointed out as edible, and only 15 of them were declared as medicinal. The family Boletaceae was represented by the highest number of species, followed by Russulaceae, Agaricaceae and Polyporaceae. We also performed detailed analysis of the literature in order to provide scientific evidence for the recorded medicinal use of fungi in Serbia. The male participants reported a higher level of ethnomycological knowledge compared to women, whereas the highest number of used fungi species was mentioned by participants within the age group of 61-80 years. In addition to preserving ethnomycological knowledge in Serbia, this study can present a good starting point for further pharmacological investigations of fungi.

7.
Food Chem ; 351: 129263, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33631614

RESUMO

Nowadays, the use of carob (Ceratonia siliqua L.) is reduced to its seeds. In fact, the food additive E410, locust bean gum, is obtained from its endosperm. However, the available information regarding the bioactive potential of carob seeds is limited and, often, with poorly established terminologies, not allowing the reader to know if the studied samples included seedless or seeded samples. So, the present study intended to carry out a chemical characterization of carob seeds focused on their bioactive compounds and test their bioactive properties. Carob seeds proved to be a source of tocopherols and organic acids, including phenolic compounds. Its antioxidant potential was demonstrated in vitro, as well as its antimicrobial capacity. This work proves that carob seeds have other functions in addition to those associated with E410. Thus, another potential can be given to the locust bean seed, namely the function of food preservative.


Assuntos
Fracionamento Químico/métodos , Fabaceae/química , Sementes/química , Antioxidantes/análise , Antioxidantes/isolamento & purificação , Fenóis/análise , Fenóis/isolamento & purificação
8.
Int J Mol Sci ; 22(2)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33418931

RESUMO

Candidaalbicans represents one of the most common fungal pathogens. Due to its increasing incidence and the poor efficacy of available antifungals, finding novel antifungal molecules is of great importance. Camphor and eucalyptol are bioactive terpenoid plant constituents and their antifungal properties have been explored previously. In this study, we examined their ability to inhibit the growth of different Candida species in suspension and biofilm, to block hyphal transition along with their impact on genes encoding for efflux pumps (CDR1 and CDR2), ergosterol biosynthesis (ERG11), and cytotoxicity to primary liver cells. Camphor showed excellent antifungal activity with a minimal inhibitory concentration of 0.125-0.35 mg/mL while eucalyptol was active in the range of 2-23 mg/mL. The results showed camphor's potential to reduce fungal virulence traits, that is, biofilm establishment and hyphae formation. On the other hand, camphor and eucalyptol treatments upregulated CDR1;CDR2 was positively regulated after eucalyptol application while camphor downregulated it. Neither had an impact on ERG11 expression. The beneficial antifungal activities of camphor were achieved with an amount that was non-toxic to porcine liver cells, making it a promising antifungal compound for future development. The antifungal concentration of eucalyptol caused cytotoxic effects and increased expression of efflux pump genes, which suggests that it is an unsuitable antifungal candidate.


Assuntos
Antifúngicos/farmacologia , Cânfora/farmacologia , Candida albicans/patogenicidade , Eucaliptol/farmacologia , Virulência/efeitos dos fármacos , Animais , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candida albicans/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Proteínas Fúngicas/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , Suínos
9.
Food Chem ; 342: 128526, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33223300

RESUMO

Aqueous extracts from seven coloured potato varieties (three red-fleshed, three-purple fleshed, and one marble-fleshed) were studied for their anthocyanin content, in vitro biological activities, colouring properties and their potential application in the food industry. Acylated glycosides or pelargonidin and petunidin aglycones were identified as the main anthocyanin forms in the red and purple varieties, respectively. The total anthocyanin content among varieties ranged from 478.3 to 886.2 mg/100 g extract. All the extracts presented in vitro antioxidant, antibacterial and antifungal activities, whereas no toxic effects were detected. Finally, two selected extracts were tested as colourants in a soft drink formulation and presented suitable sensory profiles as well as high colour stability during a 30-day shelf-life when compared with the commercial colourant E163. Therefore, the tested extracts could be used as natural food colourants and considered for substituting the existing synthetic colouring agents.


Assuntos
Antocianinas/química , Bebidas Gaseificadas/análise , Extratos Vegetais/química , Solanum tuberosum/química , Antocianinas/análise , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Antioxidantes/química , Aspergillus/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Corantes de Alimentos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Solanum tuberosum/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Paladar
10.
Toxicology ; 447: 152634, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33197509

RESUMO

Cadmium (Cd) is one of the most toxic environmental heavy metals to which the general population is exposed mainly via the oral route. Owing to its immunomodulatory potential, orally acquired Cd affects antimicrobial immune defense in several organs, including the lungs. While there are data concerning Cd and viral and bacterial pulmonary infections, effects on fungal infections are not studied yet. In the present study, the effect of the Cd (5 mg/L for 30 days, in drinking water, the average daily Cd intake 0.641 ± 0.089 mg/kg) on the immune response of rats to pulmonary A. fumigatus infection was examined. Data obtained showed that orally acquired cadmium does not affect the elimination of the fungus in immunocompetent rats owing to the preservation of some aspects of innate immune responses (lung leukocyte infiltration and NBT reduction) and an increase in other (increased numbers of mucus-producing goblet cells, MPO release). Cd does not affect an IFN-γ response in lung leukocytes during the infection (despite suppression of cytokine production in cells of lung-draining lymph nodes), while it stimulates IL-17 and suppresses IL-10 response to the fungus. As a result, the elimination of the fungus occurs in a milieu with the prevailing proinflammatory response in Cd-exposed animals that preserved fungal elimination from the lungs, though with more intense injury to the lung tissue. Therefore, the proinflammatory microenvironment in the lungs created by Cd that sustains inflammatory/immune response to the fungus to which humans are exposed for a lifetime, raises a concern of orally acquired Cd as a risk factor for the development of chronic low-grade pulmonary inflammation.


Assuntos
Aspergilose/prevenção & controle , Aspergillus fumigatus/efeitos dos fármacos , Cádmio/administração & dosagem , Imunidade Inata/efeitos dos fármacos , Infecções Oportunistas/prevenção & controle , Pneumonia/induzido quimicamente , Animais , Aspergilose/imunologia , Aspergillus fumigatus/imunologia , Cádmio/toxicidade , Exposição Ambiental , Imunidade Inata/imunologia , Hospedeiro Imunocomprometido/efeitos dos fármacos , Hospedeiro Imunocomprometido/imunologia , Masculino , Infecções Oportunistas/imunologia , Pneumonia/imunologia , Pneumonia/prevenção & controle , Ratos
11.
Arch Pharm (Weinheim) ; 354(1): e2000208, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33029832

RESUMO

In this study, we report the synthesis and antimicrobial activity of some new disubstituted piperazines. Thus, 3-chlorocyclopenta[c]pyridines and 6-chloropyrano[3,4-c]pyridine 1 under mild reaction conditions with piperazine gave the 3(6)-piperazine-substituted cyclopenta[c]pyridines and pyrano[3,4-c]pyridine 2. Furthermore, the latter, by alkylation with 2-chloro-N-1,3-thiazol-2-ylacetamide, led to the formation of the target compounds. The evaluation of the antibacterial activity revealed that 3k was the most potent compound. The most sensitive bacterium was found to be Listeria monocytogenes, whereas Staphylococcus aureus was the most resistant one. Three compounds, 3d, 3g, and 3k, were tested also against the following resistant strains: methicillin-resistant S. aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa. All three compounds appeared to be more potent than ampicillin against MRSA. Moreover, compound 3d showed a better activity than the reference drug ampicillin against P. aeruginosa, whereas 3g was more efficient against E. coli. The best antifungal activity was observed again for compound 3k. The most resistant fungi appeared to be Aspergillus fumigatus, whereas Trichoderma viride seemed the most sensitive one toward the compounds tested. Molecular docking studies on E. coli MurB, as well as on Candida albicans CYP51 and dihydrofolate reductase, were used for the prediction of the mechanisms of the antibacterial and antifungal activities, confirming the experimental results.


Assuntos
Acetamidas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Piperazinas/síntese química , Piperazinas/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
12.
EXCLI J ; 19: 1436-1445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33312106

RESUMO

Due to limited arsenal of systemically available antifungal agents, infections caused by Candida albicans are difficult to treat and the emergence of drug-resistant strains present a major challenge to the clinicians worldwide. Hence further exploration of potential novel and effective antifungal drugs is required. In this study we have explored the potential of a flavonoid, astragalin, in controlling the growth of C. albicans, in both planktonic and biofilm forms by microdilution method; and in regulating the morphological switch between yeast and hyphal growth. Astragalin ability to interfere with membrane integrity, ergosterol synthesis and its role in the regulation of genes encoding for efflux pumps has been addressed. In our study, astragalin treatment produced good antimicrobial and significant antibiofilm activity. Anticandidal activity of astragalin was not related to ERG11 downregulation, neither to direct binding to CYP51 enzyme nor was linked to membrane ergosterol assembly. Instead, astragalin treatment resulted in reduced expression of CDR1 and also affected cell membrane integrity without causing cytotoxic effect on human gingival fibroblast cells. Considering that astragalin-mediated decreased expression of efflux pumps increases the concentration of antifungal drug inside the fungal cells, a combinatorial treatment with this agent could be explored as a novel therapeutic option for candidiasis.

13.
Molecules ; 25(18)2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32971797

RESUMO

This study explored the biological properties of three wild growing Russula species (R. integra, R. rosea, R. nigricans) from Serbia. Compositional features and antioxidant, antibacterial, antibiofilm, and cytotoxic activities were analyzed. The studied mushroom species were identified as being rich sources of carbohydrates and of low caloric value. Mannitol was the most abundant free sugar and quinic and malic acids the major organic acids detected. The four tocopherol isoforms were found, and polyunsaturated fatty acids were the predominant fat constituents. Regarding phenolic compounds, P-hydroxybenzoic and cinnamic acids were identified in the prepared methanolic and ethanolic extracts, which displayed antioxidant activity through the inhibition of thiobarbituric acid reactive substances (TBARS) formation and oxidative hemolysis; the highest activity was attributed to the R. nigricans ethanolic extract. This is the first report on the antibacterial and antibiofilm potential of the studied species, with the most promising activity observed towards Streptococcus spp. (0.20-0.78 mg/mL as the minimal inhibitory concentration, MIC). The most promising cytotoxic effect was caused by the R. integra methanolic extract on non-small cell lung cancer cells (NCI-H460). Therefore, due to the observed in vitro bioactive properties, the studied mushrooms arise as a source of functional ingredients with potential to be used in novel nutraceutical and drug formulations, which can be used in the treatment of various diseases and health conditions.


Assuntos
Antibacterianos/isolamento & purificação , Antioxidantes/química , Antioxidantes/farmacologia , Basidiomycota/química , Extratos Vegetais/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antioxidantes/isolamento & purificação , Biofilmes/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
14.
Curr Top Med Chem ; 20(29): 2681-2691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32962619

RESUMO

BACKGROUND: Although a great number of the targets of antimicrobial therapy have been achieved, it remains among the first fields of pharmaceutical research, mainly because of the development of resistant strains. Docking analysis may be an important tool in the research for the development of more effective agents against specific drug targets or multi-target agents 1-3. METHODS: In the present study, based on docking analysis, ten tetrahydrothiazolo[2,3-a]isoindole derivatives were chosen for the evaluation of the antimicrobial activity. RESULTS: All compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species being, in some cases, more potent than ampicillin and streptomycin against all species. The most sensitive bacteria appeared to be S. aureus and En. Cloacae, while M. flavus, E. coli and P. aeruginosa were the most resistant ones. The compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited good antifungal activity better than reference drugs bifonazole (1.4 - 41 folds) and ketoconazole (1.1 - 406 folds) against all fungal species. In order to elucidate the mechanism of action, docking studies on different antimicrobial targets were performed. CONCLUSION: According to docking analysis, the antifungal activity can be explained by the inhibition of the CYP51 enzyme for most compounds with a better correlation of the results obtained for the P.v.c. strain (linear regression between estimated binding Energy and log(1/MIC) with R 2 =0.867 and p=0.000091 or R 2 = 0.924, p= 0.000036, when compound 3 is excluded.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Isoindóis/farmacologia , Simulação de Acoplamento Molecular , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Isoindóis/síntese química , Isoindóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular
15.
Bioorg Med Chem Lett ; 30(17): 127368, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738986

RESUMO

1,2,4-Triazole is a very important scaffold in medicinal chemistry due to the wide spectrum of biological activities and mainly antifungal activity of 1,2,4-triazole derivatives. The main mechanism of antifungal action of the latter is inhibition of 14-alpha-demethylase enzyme (CYP51). The current study presents synthesis and evaluation of eight triazole derivatives for their antimicrobial activity. Docking studies to elucidate the mechanism of action were also performed. The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. All tested compounds showed good antibacterial activity with MIC and MBC values ranging from 0.0002 to 0.0069 mM. Compound 2 h appeared to be the most active among all tested with MIC at 0.0002-0.0033 mM and MBC at 0.0004-0.0033 mM followed by compounds 2f and 2g. The most sensitive bacterium appeared to be Xanthomonas campestris while Erwinia amylovora was the most resistant. The evaluation of antifungal activity revealed that all compounds showed good antifungal activity with MIC values ranging from 0.02 mM to 0.52 mM and MFC from 0.03 mM to 0.52 mM better than reference drugs ketoconazole (MIC and MFC values at 0.28-1.88 mM and 0.38 mM to 2.82 mM respectively) and bifonazole (MIC and MFC values at 0.32-0.64 mM and 0.64-0.81 mM). The best antifungal activity is displayed by compound 2 h with MIC at 0.02-0.04 mM and MFC at 0.03-0.06 mM while compound 2a showed the lowest activity. The results showed that these compounds could be lead compounds in search for new potent antimicrobial agents. Docking studies confirmed experimental results.


Assuntos
Anti-Infecciosos/síntese química , Triazóis/química , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Sítios de Ligação , DNA Girase/química , DNA Girase/metabolismo , Desenho de Fármacos , Erwinia amylovora/efeitos dos fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Núcleosídeo-Fosfato Quinase/química , Núcleosídeo-Fosfato Quinase/metabolismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacologia , Xanthomonas campestris/efeitos dos fármacos
16.
Curr Top Med Chem ; 20(24): 2192-2209, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32598259

RESUMO

BACKGROUND: From the literature it is known that many derivatives of fused thienopyrimidines and furopyrimidines possess broad spectrum of biological activity. OBJECTIVES: The current studies describe the synthesis and evaluation of antimicrobial activity of some new N-1,3-thiazol-2-ylacetamides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines. METHODS: By cyclocondensation of ethyl 1-aminofuro(thieno)[2,3-b]pyridine-2-carboxylates 1with formamide were converted to the pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidin-7(8)-ones 2.Alkylation of compound 2 with 2-chloro-N-1,3-thiazol-2-ylacetamide led to the aimed N-1,3-thiazol-2-ylaceta-mides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 3. Starting from compound 2 the relevant S-alkylated derivatives of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 6 were also synthesized. RESULTS: All the compounds showed antibacterial activity to non-resistant strains. Compounds 3a-3m showed antibacterial activity with MIC/MBC at 0.08-2.31 mg/mL/0.11-3.75 mg/mL .The two most active compounds, 3j and 6b, appeared to be more active towards MRSA than the reference drugs. Half of the tested compounds appeared to be equipotent/more potent than ketoconazole and more potent than bifonazole. The docking analysis provided useful information about the interactions occurring between the tested compounds and the different enzymes. CONCLUSION: Gram-negative and Gram-positive bacteria and fungi showed different response towards tested compounds, indicating that different substituents may lead to different modes of action or that the metabolism of some bacteria/fungi was better able to overcome the effect of the compounds or adapt to it.


Assuntos
Antibacterianos/química , Antifúngicos/síntese química , Pirimidinas/química , Triazóis/química , Alquilação , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Desenho de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Acoplamento Molecular , Ligação Proteica , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologia
17.
Antibiotics (Basel) ; 9(5)2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32365907

RESUMO

We evaluated the antimicrobial activity of thirty-one nitrogen-containing 5-alpha-androstane derivatives in silico using computer program PASS (Prediction of Activity Spectra for Substances) and freely available PASS-based web applications (www.way2drug.com). Antibacterial activity was predicted for 27 out of 31 molecules; antifungal activity was predicted for 25 out of 31 compounds. The results of experiments, which we conducted to study the antimicrobial activity, are in agreement with the predictions. All compounds were found to be active with MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration) values in the range of 0.0005-0.6 mg/mL. The activity of all studied 5-alpha-androstane derivatives exceeded or was equal to those of Streptomycin and, except for the 3ß-hydroxy-17α-aza-d-homo-5α-androstane-17-one, all molecules were more active than Ampicillin. Activity against the resistant strains of E. coli, P. aeruginosa, and methicillin-resistant Staphylococcus aureus was also shown in experiments. Antifungal activity was determined with MIC and MFC (Minimum Fungicidal Concentration) values varying from 0.007 to 0.6 mg/mL. Most of the compounds were found to be more potent than the reference drugs Bifonazole and Ketoconazole. According to the results of docking studies, the putative targets for antibacterial and antifungal activity are UDP-N-acetylenolpyruvoylglucosamine reductase and 14-alpha demethylase, respectively. In silico assessments of the acute rodent toxicity and cytotoxicity obtained using GUSAR (General Unrestricted Structure-Activity Relationships) and CLC-Pred (Cell Line Cytotoxicity Predictor) web-services were low for the majority of compounds under study, which contributes to the chances for those compounds to advance in the development.

18.
Curr Pharm Des ; 26(16): 1799-1815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32264808

RESUMO

BACKGROUND: Heavy metals are elements that are naturally found in the earth. They are used in many modern-day applications in agriculture, medicine, and industry. Heavy metal poisoning occurs when the body's soft tissues absorb too much of a particular metal. The heavy metals of interest for this review paper were cadmium, arsenic, mercury, and lead since these are the most common metals that the human body can absorb in toxic amounts. Different plant species were investigated in recent years for their effect on oxidative stress parameters after intoxication with heavy metals. OBJECTIVES: This review paper is focused on the current update to research on heavy metals induced oxidative stress in animal models and improvement of the oxidative stress parameters upon/co-/after treatment with different plant extracts and isolated compounds. METHODS: The available literature was screened for the novel data regarding the influence of plant extracts and compounds on heavy metals induced oxidative stress. For that purposes Scopus database was used, looking for the publications in the last 5-10 years with the key terms: plant extracts, oxidative stress, in vivo, cadmium, lead, mercury and arcenic. RESULTS: Various parameters of oxidative stress were investigated, and their improvement with plant extracts/ compounds was observed in the brain, lungs, kidneys, liver, uterus, testis, thymus, spleen, heart, skin and blood of experimental animals. Common parameters used to determine oxidative stress in animals were: superoxide dismutase; catalase; reduced glutathione; glutathione reductase; glutathione-S-transferase; glutathione peroxidase; lipid peroxidation; oxidized glutathione; malondialdehyde; xanthine oxidase; nonprotein-soluble thiol; thioredoxin reductase; total sulphydryl group; nitric oxide; γ-glutamyl cysteine synthetase. CONCLUSION: The most investigated species for antioxidant effects upon intoxication with heavy metals seem to be Allium sp., Bacopa monniera, Camellia sinensis, Moringa oleifera, Vitis vinifera and Zingiber officinale. According to literature data, the most promising effect to alleviate symptoms of intoxication was achieved with proanthocyanidins obtained from Vitis vinifera.


Assuntos
Metais Pesados , Extratos Vegetais , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Catalase/metabolismo , Glutationa/metabolismo , Glutationa Redutase/química , Glutationa Redutase/metabolismo , Humanos , Masculino , Metais Pesados/toxicidade , Estresse Oxidativo , Extratos Vegetais/farmacologia
19.
Molecules ; 25(8)2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32340255

RESUMO

BACKGROUND: Infectious diseases symbolize a global consequential strain on public health security and impact on the socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in crucial need for the discovery and development of novel entity for the infectious treatment with different modes of action that could target both sensitive and resistant strains. METHODS: Compounds were synthesized using classical methods of organic synthesis. RESULTS: All 20 synthesized compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species. It should be mentioned that all compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Furthermore, 18 compounds appeared to be more potent than streptomycin against Staphylococcus aureus, Enterobacter cloacae, Pseudomonas aeruginosa, Listeria monocytogenes, and Escherichia coli. Three the most active compounds 4h, 5b, and 5g appeared to be more potent against MRSA than ampicillin, while streptomycin did not show any bactericidal activity. All three compounds displayed better activity also against resistant strains P. aeruginosa and E. coli than ampicillin. Furthermore, all compounds were able to inhibit biofilm formation 2- to 4-times more than both reference drugs. Compounds were evaluated also for their antifungal activity against eight species. The evaluation revealed that all compounds exhibited antifungal activity better than the reference drugs bifonazole and ketoconazole. Molecular docking studies on antibacterial and antifungal targets were performed in order to elucidate the mechanism of antibacterial activity of synthesized compounds. CONCLUSION: All tested compounds showed good antibacterial and antifungal activity better than that of reference drugs and three the most active compounds could consider as lead compounds for the development of new more potent agents.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Anti-Infecciosos/síntese química , Técnicas de Química Sintética , Compostos Heterocíclicos/síntese química , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
20.
Int J Biol Macromol ; 148: 129-139, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31935408

RESUMO

In spite of extensive usage of Laetiporus sulphureus (sulphur polypore) in traditional European and Asian ethno-medicine for centuries, its anticancer therapeutic potential and toxicity profile remained explored in animal models. Herein, using zebrafish (Danio rerio), as a preclinical animal model, we demonstrated that L. sulphureus lectin (LSL) and ethanol extract (LSE) are non-toxic at high doses up to 400-500 µg/mL, while they effectively inhibited angiogenesis and cancer development at much lower doses. Lectin showed 74-fold higher anti-angiogenic potency than the extract, and even 378-fold higher therapeutic potential than sunitinib-malate, cardiotoxic and myelosupressive anti-angiogenic drug of clinical relevance. Using wound healing and MTT assays, we proved LSL's strong antimigratory effect and selective endothelial cytotoxicity in relation to lung fibroblasts. In addition, employing the zebrafish xenograft models, we demonstrated that LSL almost completely reduced growth, neovascularization and metastasis of human colorectal carcinoma and mouse melanoma. Even more, LSL exerted 8-fold higher potency towards colorectal carcinoma than melanoma, showing markedly higher activity than cisplatin, while LSE failed to express any anticancer activity. Accompanied with non-toxic response, including neutropenia and inflammation, the results of this study strongly imply that LSL could be used as safe adjuvant in chemotherapy against colorectal carcinoma and melanoma.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Lectinas/farmacologia , Melanoma/tratamento farmacológico , Polyporales/química , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Neoplasias Colorretais/patologia , Humanos , Melanoma/patologia , Camundongos , Neovascularização Patológica/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...