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2.
J Enzyme Inhib Med Chem ; 34(1): 1414-1425, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401901

RESUMO

The emergence of drug-resistant pathogenic bacteria is occurring due to the global overuse and misuse of ß-lactam antibiotics. Infections caused by some bacteria which secrete metallo-ß-lactamases (enzymes that inactivate ß-lactam antibiotics) are increasingly prevalent and have become a major worldwide threat to human health. These bacteria are resistant to ß-lactam antibiotics and MBL-inhibitor/ß-lactam antibiotic combination therapy can be a strategy to overcome this problem. So far, no clinically available inhibitors of metallo-ß-lactamases (MBLs) have been reported. In this study, L-benzyl tyrosine thiol carboxylic acid analogues (2a-2k) were synthesized after the study of computational simulation by adding of methyl, chloro, bromo and nitro groups to the benzyl ring for investigation of SAR analysis. Although the synthesized molecules 2a-k shows the potent inhibitory effects against metallo-ß-lactamase (IMP-1) with the range of Kic values of 1.04-4.77 µM, they are not as potent as the candidate inhibitor.


Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Compostos de Sulfidrila/química , Tirosina/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ácidos Carboxílicos/química , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Serratia marcescens/efeitos dos fármacos , Serratia marcescens/enzimologia , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química
3.
J Enzyme Inhib Med Chem ; 34(1): 1388-1399, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392901

RESUMO

Fourteen novel dipeptide carboxamide derivatives bearing benzensulphonamoyl propanamide were synthesized and characterized using 1H NMR, 13C NMR, FTIR and MS spectroscopic techniques. In vivo antimalarial and in vitro antimicrobial studies were carried out on these synthesized compounds. Molecular docking, haematological analysis, liver and kidney function tests were also evaluated to assess the effect of the compounds on the organs. At 200 mg/kg body weight, 7i inhibited the multiplication of the parasite by 81.38% on day 12 of post-treatment exposure. This was comparable to the 82.34% reduction with artemisinin. The minimum inhibitory concentration (MIC) in µM ranged from 0.03 to 2.34 with 7h having MIC of 0.03 µM against Plasmodium falciparium. The in vitro antibacterial activity of the compounds against some clinically isolated bacteria strains showed varied activities with some of the new compounds showing better activities against the bacteria and the fungi more than the reference drug ciprofloxacin and fluconazole.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antimaláricos/síntese química , Bactérias/efeitos dos fármacos , Dipeptídeos/síntese química , Fungos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Ratos , Sulfonamidas/química
4.
J Enzyme Inhib Med Chem ; 34(1): 1259-1270, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31287341

RESUMO

Pyrazolylphthalimide derivative 4 was synthesized and reacted with different reagents to afford the target compounds imidazopyrazoles 5-7, pyrazolopyrimidines 9, 12, 14 and pyrazolotriazines 16, 17 containing phthalimide moiety. The prepared compounds were established by different spectral data and elemental analyses. Additionally, all synthesized derivatives were screened for their antibacterial activity against four types of Gram + ve and Gram-ve strains, and for antifungal activity against two fungi micro-organisms by well diffusion method. Moreover, the antiproliferative activity was tested for all compounds against human liver (HepG-2) cell line in comparison with the reference vinblastine. Moreover, drug-likeness and toxicity risk parameters of the newly synthesized compounds were calculated using in silico studies. The data from structure-actvity relationship (SAR) analysis suggested that phthalimide derivative bearing 3-aminopyrazolone moiety, 4 illustrated the best antimicrobial and antitumor activities and might be considered as a lead for further optimization. To investigate the mechanism of the antimicrobial and anticancer activities, enzymatic assay and molecular docking studies were carried out on E. coli topoisomerase II DNA gyrase B and VEGFR-2 enzymes.


Assuntos
Ftalimidas/química , Ftalimidas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Ftalimidas/síntese química , Análise Espectral/métodos , Relação Estrutura-Atividade
5.
Photochem Photobiol Sci ; 18(8): 1910-1922, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328761

RESUMO

New porphyrin/4-oxoquinoline conjugates were synthesized from the Heck coupling reaction of a ß-brominated porphyrin with 1-allyl-4-oxoquinoline derivatives, followed by demetallation and deprotection affording the promising photosensitizers 9a-e. Singlet oxygen studies have demonstrated that all the porphyrin/4-oxoquinoline conjugates 9a-e were capable of producing cytotoxic species and found to be excellent photosensitizing agents in the inactivation of S. aureus by the antimicrobial photodynamic therapy (aPDT) protocol.


Assuntos
4-Quinolonas/farmacologia , Antibacterianos/farmacologia , Fotoquimioterapia , Porfirinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , 4-Quinolonas/química , Antibacterianos/síntese química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Porfirinas/química
6.
J Photochem Photobiol B ; 197: 111541, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31272033

RESUMO

Here, we report the novel fabrication of ZnO nanoparticles using the Costus igneus leaf extract. Gas chromatography-mass spectrometry (GC-MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy to determine the bioactive components present in the plant extract. The synthesis of Ci-ZnO NPs (C. igneus- coated zinc oxide nanoparticles) was accomplished using a cost-effective and simple technique. Ci-ZnO NPs were specified using UV-visible spectroscopy, FTIR, XRD, and TEM. Ci-ZnO NPs was authenticated by UV-Vis and exhibited a peak at 365 nm. The XRD spectra proved the crystalline character of the Ci-ZnO NPs synthesized as hexagonal wurtzite. The FTIR spectrum illustrated the presence of possible functional groups present in Ci-ZnO NPs. The TEM micrograph showed evidence of the presence of a hexagonal organization with a size of 26.55 nm typical of Ci-ZnO NPs. The α-amylase and α-glucosidase inhibition assays demonstrated antidiabetic activity of Ci-ZnO NPs (74 % and 82 %, respectively), and the DPPH [2,2-diphenyl-1-picrylhydrazyl hydrate] assay demonstrated the antioxidant activity of the nanoparticles (75%) at a concentration of 100 µg/ml. The Ci-ZnO NPs exhibited promising antibacterial and biofilm inhibition activity against the pathogenic bacteria Streptococcus mutans, Lysinibacillus fusiformis, Proteus vulgaris, and Vibrio parahaemolyticus. Additionally, the Ci-ZnO NPs showed biocompatibility with mammalian RBCs with minimum hemolytic activity (0.633 % ±â€¯0.005 %) at a concentration of 200 µg/ml.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/química , Biofilmes/efeitos dos fármacos , Nanopartículas Metálicas/química , Extratos Vegetais/química , Óxido de Zinco/química , Antibacterianos/síntese química , Antibacterianos/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Costus/química , Costus/metabolismo , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/fisiologia , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/fisiologia , Química Verde , Hemólise/efeitos dos fármacos , Humanos , Insulina/química , Nanopartículas Metálicas/toxicidade , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Extratos Vegetais/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo
7.
J Photochem Photobiol B ; 197: 111548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31288120

RESUMO

The visible light combined with photosensitizers (PSs) is exploited in both antitumoral and antimicrobial fields inducing a photo-oxidative stress within the target cells. Among the different PSs, porphyrins belong to the family of the most promising compounds to be used in clinical photodynamic applications. Although in the last years many porphyrins have been synthesised and tested, only a few reports concern the in vitro effects of the 5,15-diarylporphyrins. In this work, the activity of four 5,15-diarylporphyrins (compounds 7-10), bearing alkoxy-linked pyridinium appendixes, have been tested on cancer cell lines and against bacterial cultures. Among the synthetized PSs, compounds 7 and 9 are not symmetrically substituted porphyrins showing one cationic charge tethered at the end of one 4C or 8C carbon chains, respectively. On the other hand, compounds 8 and 10 are symmetrically substituted and show two chains of C4 and C8 carbons featuring a cationic charge at the end of both chains. The dicationic 8 and 10 were more hydrophilic than monocationic 7 and 9, outlining that the presence of two pyridinium salts have a higher impact on the solubility in the aqueous phase than the lipophilic effect exerted by the length of the alkyl chains. Furthermore, these four PSs showed a similar rate of photobleaching, irrespective of the length and number of chains and the number of positive charges. Among the eukaryotic cell lines, the SKOV3 cells were particularly sensitive to the photodynamic activity of all the tested diarylporphyrins, while the HCT116 cells were found more sensitive to PSs bearing C4 chain (7 and 8), regardless the number of cationic charges. The photo-induced killing effect of these porphyrins was also tested against two different bacterial cultures. As expected, the Gram positive Bacillus subtilis was more sensitive than the Gram negative Escherichia coli, and the dicationic porphyrin 8, bearing two C4 chains, was the most efficient on both microorganisms. In conclusion, the new compound 8 seems to be an optimal candidate to deepen as versatile anticancer and antibacterial photosensitizer.


Assuntos
Antibacterianos/química , Antineoplásicos/química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cátions/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Luz , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/síntese química , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
8.
J Photochem Photobiol B ; 197: 111556, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31326842

RESUMO

Facile green synthesis of copper nanoparticles from different biological procedures has been indicated, but among all, biosynthesis of copper nanoparticles from medicinal plants is considered as the most suitable method. The use of medicinal plant material increases the therapeutical effects of copper nanoparticles. The aim of this study was green synthesis of copper nanoparticles from aqueous extract of Falcaria vulgaris leaf (CuNPs) and assessment of their cytotoxicity, antioxidant, antifungal, antibacterial, and cutaneous wound healing properties. These nanoparticles were characterized by X-ray diffraction (XRD), fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV), transmission electron microscopy (TEM), and field emission scanning electron microscopy (FE-SEM) analysis. The synthesized CuNPs had great cell viability dose-dependently (Investigating the effect of the CuNPs on human umbilical vein endothelial cell (HUVEC) line) and indicated this method was nontoxic. Also, 2,2-diphenyl-1-picrylhydrazyl (DPPH) test was done to assess the antioxidant activities, which indicated similar antioxidant potentials for CuNPs and butylated hydroxytoluene. In part of cutaneous wound healing property of CuNPs, after creating the cutaneous wound, the rats were randomly divided into six groups: treatment with 0.2% CuNPs ointment, treatment with 0.2% CuSO4 ointment, treatment with 0.2% F. vulgaris ointment, treatment with 3% tetracycline ointment, treatment with Eucerin basal ointment, and untreated control. These groups were treated for 10 days. Treatment with CuNPs ointment remarkably increased (p ≤ .01) the wound contracture, vessel, hexosamine, hydroxyl proline, hexuronic acid, fibrocyte, and fibrocytes/fibroblast rate and substantially reduced (p ≤ .01) the wound area, total cells, neutrophil, and lymphocyte compared to other groups. In antibacterial and antifungal parts of this research, the concentration of CuNPs with minimum dilution and no turbidity was considered minimum inhibitory concentration (MIC). To determine minimum fungicidal concentration (MFC) and minimum bactericidal concentration (MBC), 60 µL MIC and three preceding chambers were cultured on Sabouraud Dextrose Agar and Muller Hinton Agar, respectively. The minimum concentration with no fungal and bacterial growth were considered MFC and MBC, respectively. CuNPs inhibited the growth of all fungi at 2-4 mg/mL concentrations and removed them at 4-8 mg/mL concentrations (p ≤ .01). In case of antibacterial effects of CuNPs, they inhibited the growth of all bacteria at 2-8 mg/mL concentrations and removed them at 4-16 mg/mL concentrations (p ≤ .01). The results of XRD, FT-IR, UV, TEM, and FE-SEM confirm that the aqueous extract of F. vulgaris leaf can be used to yield copper nanoparticles with notable amount of antioxidant, antifungal, antibacterial, and cutaneous wound healing potentials without any cytotoxicity. Further clinical trials are necessary for confirmation these therapeutical effects of CuNPs in human.


Assuntos
Apiaceae/química , Cobre/química , Nanopartículas Metálicas/química , Extratos Vegetais/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antioxidantes/química , Apiaceae/metabolismo , Candida/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Química Verde , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Nanopartículas Metálicas/toxicidade , Testes de Sensibilidade Microbiana , Folhas de Planta/química , Folhas de Planta/metabolismo , Ratos , Pele/efeitos dos fármacos , Pele/patologia , Cicatrização/efeitos dos fármacos
9.
Eur J Med Chem ; 178: 214-231, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185412

RESUMO

Discovery of antimicrobial agents with a novel model of action is in urgent need for the clinical management of multidrug-resistant bacterial infections. Recently, we reported the identification of a first-in-class bacterial ribosomal RNA synthesis inhibitor, which interrupted the interaction between the bacterial transcription factor NusB and NusE. In this study, a series of diaryl derivatives were rationally designed and synthesized based on the previously established pharmacophore model. Inhibitory activity against the NusB-NusE binding, circular dichroism of compound treated NusB, antimicrobial activity, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells were measured. Structure-activity relationship and quantitative structure-activity relationship were also concluded and discussed. Some of the derivatives demonstrated improved antimicrobial activity than the hit compound against a panel of clinically important pathogens, lowering the minimum inhibition concentration to 1-2 µg/mL against Staphylococcus aureus, including clinical strains of methicillin-resistant Staphylococcus aureus at a level comparable to some of the marketed antibiotics. Given the improved antimicrobial activity, specific inhibition of target protein-protein interaction and promising pharmacokinetic properties without significant cytotoxicity, this series of diaryl compounds have high potentials and deserve for further studies towards a new class of antimicrobial agents in the future.


Assuntos
Compostos de Anilina/farmacologia , Antibacterianos/farmacologia , Benzilaminas/farmacologia , Ligação Proteica/efeitos dos fármacos , Bases de Schiff/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/toxicidade , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Proteínas de Bactérias/metabolismo , Benzilaminas/síntese química , Benzilaminas/química , Benzilaminas/toxicidade , Células CACO-2 , Desenho de Drogas , Eritrócitos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/toxicidade , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
10.
J Photochem Photobiol B ; 197: 111531, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31212244

RESUMO

Environment friendly methods for the synthesis of copper nanoparticles have become a valuable trend in the current scenario. The utilization of phytochemicals from plant extracts has become a unique technology for the synthesis of nanoparticles, as they possess dual nature of reducing and capping agents to the nanoparticles. In the present investigation we have synthesized copper nanoparticles (CuNPs) using a rare medicinal plant Cissus arnotiana and evaluated their antibacterial activity against gram negative and gram positive bacteria. The morphology and characterization of the synthesized CuNPs were studied and done using UV-Visible spectroscopy at a wavelength range of 350-380 nm. XRD studies were performed for analyzing the crystalline nature; SEM and TEM for evaluating the spherical shape within the size range of 60-90 nm and AFM was performed to check the surface roughness. The biosynthesized CuNPs showed better antibacterial activity against the gram-negative bacteria, E. coli with an inhibition zone of 22.20 ±â€¯0.16 mm at 75 µg/ml. The antioxidant property observed was comparatively equal with the standard antioxidant agent ascorbic acid at a maximum concentration of 40 µg/ ml. This is the first study reported on C. arnotiana mediated biosynthesis of copper nanoparticles, where we believe that the findings can pave way for a new direction in the field of nanotechnology and nanomedicine where there is a significant potential for antibacterial and antioxidant activities. We predict that, these could lead to an exponential increase in the field of biomedical applications, with the utilization of green synthesized CuNPs, due to its remarkable properties. The highest antibacterial property was observed with gram-negative strains mainly, E. coli, due to its thin peptidoglycan layer and electrostatic interactions between the bacterial cell wall and CuNPs surfaces. Hence, CuNPs can be potent therapeutic agents in several biomedical applications, which are yet to be explored in the near future.


Assuntos
Antibacterianos/química , Antioxidantes/química , Cissus/química , Cobre/química , Nanopartículas Metálicas/química , Extratos Vegetais/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Cissus/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Química Verde , Nanopartículas Metálicas/toxicidade , Testes de Sensibilidade Microbiana , Eletricidade Estática
11.
Future Microbiol ; 14: 587-598, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31148472

RESUMO

Aim: 17 new 4-methoxynaphthalene-N-acylhydrazones were synthesized in order to evaluate their biological action against important pathogens. Methods: In vitro susceptibility assays of compounds were performed against Paracoccidioides brasiliensis and Mycobacterium tuberculosis. Results: Compounds 4a, 4b and 4k were the most potent against P. brasiliensis, two with minimum inhibitory concentrations of ≤1 µg ml-1 and exhibited pharmacological synergy with amphotericin B. The compounds also showed activity against M. tuberculosis, with 4c and 4k being the more promising. Compound 4k showed good synergistic antimycobacterium activity with ethambutol. None of the compounds tested showed toxicity. Conclusion: We highlight the compound 4k, as a potential agent for the treatment of patients co-infected with paracoccidioidomycosis and tuberculosis.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Coinfecção/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/tratamento farmacológico , Tuberculose/tratamento farmacológico , Anfotericina B/farmacologia , Antibacterianos/síntese química , Antifúngicos/síntese química , Combinação de Medicamentos , Descoberta de Drogas , Sinergismo Farmacológico , Etambutol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/patogenicidade , Paracoccidioides/patogenicidade
12.
Eur J Med Chem ; 178: 500-514, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202995

RESUMO

Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Pirróis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 178: 515-529, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207463

RESUMO

Carvacrol (CAR), a natural monoterpene particularly abundant in plants belonging to the Lamiaceae family, has recently attracted much attention for its many biological properties (antioxidant, anti-inflammatory, neuroprotective, antitumour, antibacterial, and several others). However, CAR has poor chemical-physical properties (low water solubility and high volatility), which hamper its potential pharmacological uses. In this paper, the synthesis and antimicrobial evaluation of 23 carvacrol derivatives (WSCP1-23) against a panel of selected gram-positive and gram-negative bacteria are reported. Using the prodrug approach, CAR hydrophilic (WSCP1-17) and lipophilic prodrugs (WSCP18-23) were prepared. Notably, CAR water solubility was increased by using polar neutral groups (such as natural amino acids) with the aim of improving oral drug delivery. On the other hand, CAR lipophilic prodrugs, obtained by prenylation of CAR hydroxyl group, were designed to promote membrane permeation and oral absorption. Our results revealed that WSCP1-3, showing the highest water solubility (>1700-fold compared to that of CAR), possessed good antibacterial activity against gram-negative bacteria with MIC values comparable to those of CAR and antifungal properties against different species of Candida. WSCP18-19 were the most promising prodrugs, showing good antibacterial profiles against gram-positive bacteria by interfering with the biofilm formation of Staphylococcus aureus and Staphylococcus epidermidis. Moreover, WSCP18-19 resulted more stable in simulated fluids and human plasma than WSCP1-3. Toxicity studies performed on human erythrocytes and HaCaT cells revealed that all WSCPs were not toxic at the tested concentrations.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Monoterpenos/farmacologia , Pró-Fármacos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Candida/efeitos dos fármacos , Relação Dose-Resposta a Droga , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monoterpenos/síntese química , Monoterpenos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Solubilidade , Relação Estrutura-Atividade
14.
Chem Pharm Bull (Tokyo) ; 67(5): 481-486, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061374

RESUMO

Quinolone 006 is under development as an anti-methicillin-resistant Staphylococcus aureus quinolone antibiotic. A linear synthetic route was utilized to prepare the compound on a multi-kilogram scale with an overall yield of 71%. The process was optimized by controlling the temperature and the vacuum pressure. Examples of parameters examined in an effort to control the polymorphism of the 006 active pharmaceutical ingredient are described.


Assuntos
Antibacterianos/síntese química , Quinolonas/síntese química , Antibacterianos/química , Técnicas de Química Sintética/economia , Técnicas de Química Sintética/métodos , Cristalização , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Quinolonas/química , Infecções Estafilocócicas/tratamento farmacológico
15.
J Enzyme Inhib Med Chem ; 34(1): 1010-1017, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072165

RESUMO

The Mur ligases form a series of consecutive enzymes that participate in the intracellular steps of bacterial peptidoglycan biosynthesis. They therefore represent interesting targets for antibacterial drug discovery. MurC, D, E and F are all ATP-dependent ligases. Accordingly, with the aim being to find multiple inhibitors of these enzymes, we screened a collection of ATP-competitive kinase inhibitors, on Escherichia coli MurC, D and F, and identified five promising scaffolds that inhibited at least two of these ligases. Compounds 1, 2, 4 and 5 are multiple inhibitors of the whole MurC to MurF cascade that act in the micromolar range (IC50, 32-368 µM). NMR-assisted binding studies and steady-state kinetics studies performed on aza-stilbene derivative 1 showed, surprisingly, that it acts as a competitive inhibitor of MurD activity towards D-glutamic acid, and additionally, that its binding to the D-glutamic acid binding site is independent of the enzyme closure promoted by ATP.


Assuntos
Trifosfato de Adenosina/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Ligases/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Cinética , Ligases/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
16.
Ultrason Sonochem ; 55: 57-66, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31084791

RESUMO

The synthesis of nanoparticles often result in the generation of harmful chemical pollutants. As such, many researchers have focused on developing green processes, which include the biosynthesis. In this research, ZnO nanoparticles were prepared using the leaf extract of whortleberry (Vaccinium arctostaphylos L.) via a simple ultrasonic-assisted method. The morphology, crystal size and structure, surface, thermal, and optical properties of the bio-mediated ZnO sample (ZnOext) were analyzed and compared with that produced without incorporating the extract (ZnOchem). The ZnO samples were evaluated for their antidiabetic, antibacterial, as well as their sono- and photo-catalytic performances. Initially, the samples were intraperitoneal injected to alloxan-diabetic rats to examine their treatment efficiency in terms of effects on fasting blood glucose, insulin, cholesterol, high-density lipoprotein, and total triglyceride levels. The ZnOext showed significantly higher efficiency for improving the health status of alloxan-diabetic rats in contrast with other tested treatments, vis. ZnOchem, insulin, and only leaf extract. In addition, both the ZnO samples were assessed against gram-negative and gram-positive bacteria and through sono- and photo-catalytic processes for removing rhodamine B, respectively. The results of this study indicated that not only the ZnOext sample was pollution free, it also exhibited higher potentials for treating diabetic rats, bacterial decontamination, and also oxidative removal of organic compounds under the influences of ultrasound and UV irradiations when compared with ZnOchem sample.


Assuntos
Nanopartículas/química , Extratos Vegetais/química , Folhas de Planta/química , Ondas Ultrassônicas , Vaccinium/química , Óxido de Zinco/química , Óxido de Zinco/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Técnicas de Química Sintética , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Oxirredução/efeitos dos fármacos
17.
Carbohydr Polym ; 216: 312-321, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047071

RESUMO

In order to improve the antibacterial efficiency and spectrum of cellulose acetate reverse osmosis membrane (CA-RO), both quaternary ammonium and bromoacetyl groups were introduced into cellulose diacetate under mild conditions forming CA-RO with bi-antibacterial groups for seawater desalination. Bromoacetyl bromide and a series of tertiary amine were chosen as the modification agents respectively. The characterization results showed that both two antibacterial groups were successfully introduced with a certain density. The obtaining membrane had a less hydrophilic but more electronegative surface as well as improved mechanical property. The flux values increased firstly and decreased subsequently after twice modifications while the salt rejection rose. The membrane modified with N,N-dimethyloctylamine (DMOA) had the optimal comprehensive performance of flux and salt rejection. The antibacterial testing results indicated that the resulting RO membranes showed high antibacterial efficiency and broad-spectrum. Their bactericidal rates against gram-negative Escherichia coli (E. coli) and gram-positive Staphylococcus aureus (S. aureus) were more than 99.9%.


Assuntos
Antibacterianos/farmacologia , Celulose/análogos & derivados , Membranas Artificiais , Acetilação , Aminas/química , Antibacterianos/síntese química , Antibacterianos/química , Incrustação Biológica/prevenção & controle , Celulose/síntese química , Celulose/química , Celulose/farmacologia , Escherichia coli/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Resistência à Tração
18.
Carbohydr Polym ; 216: 54-62, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047082

RESUMO

Biodegradable, antimicrobial, and semiconducting cellulosic composite was synthesized by in-situ polymerization of polyaniline in the presence of cellulose. The cobalt ferrite nanoparticles (CFO-NPs) were added during the polymerization process to acquire this composite magnetic property. The CFO-NPs were prepared by sol-gel method with average particles size less than 50 nm. The nanocomposites were characterized by Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX). In addition, their magnetic, dielectric constant, dielectric loss, and conductivity behaviors were studied. The magnetization (Ms) and conductivity increased up to 3.7 emu/g and 3.5 × 10-3 S/cm, respectively, with increasing CFO-NPs content. The prepared electromagnetic nanocomposite exhibits highly efficient biodegradability and antimicrobial activity against Escherichia coli, Bacillus subtilis, and Candida albicans. The antimicrobial activity increased with increasing CFO-NPs while the biodegradability decreased.


Assuntos
Compostos de Anilina/farmacologia , Celulose/farmacologia , Cobalto/farmacologia , Compostos Férricos/farmacologia , Nanocompostos/química , Nanopartículas/química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacologia , Candida albicans/efeitos dos fármacos , Celulose/análogos & derivados , Celulose/síntese química , Cobalto/química , Condutividade Elétrica , Escherichia coli/efeitos dos fármacos , Compostos Férricos/síntese química , Compostos Férricos/química , Fenômenos Magnéticos , Tamanho da Partícula
19.
Carbohydr Polym ; 217: 98-109, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31079690

RESUMO

Chitin is an abundant natural polymer and its deacetylated derivative chitosan has been a focus for the development of biobased, biocompatible and antimicrobial materials. In this work, a green and scalable route to grafting polycaprolactone (PCL) to chitosan using an enzyme catalysed reactive extrusion process is described. FTIR, 1H and 13C NMR spectroscopy and HSQC analysis confirm grafting of PCL to chitosan and show differences in the grafting pattern obtained using two commercially produced lipase enzymes from Candida antarctica (CALB® and NovoCor®). The thermostable NovoCor enzyme gave a much higher grafting yield (96.3%) than the less thermostable CALB enzyme (5.90%). In the esterification reaction, CALB preferentially catalyses reaction on primary OH groups at the C-6 position of chitosan, whereas NovoCor catalyses on the secondary OH groups of chitosan at the C-3 position. This is related to the differences in the selectivity of the two lipase enzymes. The control synthesized without enzyme did not show any grafting reaction. The degree of crystallinity and thermal stability of the lipase catalysed copolymer was reduced compared to unmodified chitosan. Moreover, the PCL grafted chitosan produced by a solvent free reactive extrusion route retained antimicrobial property against E.coli. Such grafted co-polymers may have applications in the controlled release coatings and tissue culture surfaces.


Assuntos
Antibacterianos/síntese química , Quitosana/síntese química , Lipase/química , Poliésteres/síntese química , Antibacterianos/farmacologia , Quitosana/farmacologia , Escherichia coli/efeitos dos fármacos , Química Verde/métodos , Poliésteres/farmacologia , Estudo de Prova de Conceito , Staphylococcus aureus/efeitos dos fármacos , Temperatura Ambiente
20.
Molecules ; 24(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035531

RESUMO

A series of new thiazoline derivatives were synthesized. Structure analyses were accomplished employing 1H-NMR, 13C-NMR, X-ray and MS techniques. The in vitro antitumor activities were assessed against human hepatocellular carcinoma (HepG-2) and colorectal carcinoma (HCT-116) cell lines. The results revealed that the thiazolines 5b and 2c exhibited significant activity against the two cell lines. The in vitro antimicrobial screening showed that the thiazolines 2c, 5b and 5d showed promising inhibition activity against Salmonella sp. Additionally, the inhibition activity of thiazolines 2e and 5b against Escherichia coli was comparable to that of the reference compound gentamycin.


Assuntos
Técnicas de Química Sintética , Simulação de Acoplamento Molecular , Compostos Orgânicos/química , Compostos Orgânicos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Ligações de Hidrogênio , Estrutura Molecular , Compostos Orgânicos/síntese química , Análise Espectral , Relação Estrutura-Atividade
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