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1.
Yakugaku Zasshi ; 140(10): 1213-1224, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999200

RESUMO

In basic pharmaceutical sciences to achieve drug development, research on the efficient chemical synthesis of small molecules having cyclic skeletons is important. We have been engaged in the development of artificial catalysts for asymmetric ring formation reactions that exclusively synthesize right-handed or left-handed cyclic compounds and have achieved the construction of optically active cyclic skeletons using our original catalysts. The synthesis of biologically active compounds was facilitated through six-membered ring construction by Diels-Alder reaction of Danishefsky diene; however, no asymmetric variant of the reaction has been achieved. We approached this unresolved issue using multi-coordinated lanthanide metals. A new chiral lanthanide catalyst was developed, and the catalytic asymmetric Diels-Alder reaction of Danishefsky diene was realized for the first time. By modifying the chemical structure of Danishefsky diene, we applied the lanthanide catalyst to the syntheses of polycyclic compounds and biologically active compounds. We achieved the asymmetric synthesis of natural products, antibacterial and antimalarial compounds, and an anti-obesity drug lead compound. Moreover, the novel catalyst exhibited higher performance than the previously reported ones. The latest generation of the catalyst can be handled stably in air at room temperature. Furthermore, we succeeded in the development of new catalysts by focusing on the properties of its metal precursors, such as nickel and indium, and achieved the construction of polycyclic skeletons by using these catalysts.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos Policíclicos/síntese química , Alcenos/química , Antibacterianos/síntese química , Fármacos Antiobesidade/síntese química , Antimaláricos/síntese química , Produtos Biológicos/síntese química , Catálise , Reação de Cicloadição , Desenvolvimento de Medicamentos , Índio , Elementos da Série dos Lantanídeos/química , Níquel , Estereoisomerismo
2.
Int J Nanomedicine ; 15: 3983-3999, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606660

RESUMO

Introduction: In recent years, the use of cost-effective, multifunctional, environmentally friendly and simple prepared nanomaterials/nanoparticles have been emerged considerably. In this manner, different synthesizing methods were reported and optimized, but there is still lack of a comprehensive method with multifunctional properties. Materials and Methods: In this study, we aim to synthesis the copper oxide nanoparticles using Achillea millefolium leaf extracts for the first time. Catalytic activity was investigated by in situ azide alkyne cycloaddition click and also A3 coupling reaction, and optimized in terms of temperature, solvent, and time of the reaction. Furthermore, the photocatalytic activity of the synthesized nanoparticles was screened in terms of degradation methylene blue dye. Biological activity of the synthesized nanoparticles was evaluated in terms of antibacterial and anti-fungal assessments against Staphylococcus aureus, M. tuberculosis, E. coli, K. pneumoniae, P. mirabili, C. diphtheriae and S. pyogenes bacteria's and G. albicans, A. flavus, M. canis and G. glabrata fungus. In the next step, the biosynthesized CuO-NPs were screened by MTT and NTU assays. Results: Based on our knowledge, this is a comprehensive study on the catalytic and biological activity of copper oxide nanoparticles synthesizing from Achillea millefolium, which presents great and significant results (in both catalytic and biological activities) based on a simple and green procedure. Conclusion: Comprehensive biomedical and catalytic investigation of the biosynthesized CuO-NPs showed the mentioned method leads to synthesis of more eco-friendly nanoparticles. The in vitro studies showed promising and considerable results, and due to the great stability of these nanoparticles in a green media, effective biological activity considered as an advantageous.


Assuntos
Tecnologia Biomédica , Cobre/farmacologia , Nanopartículas Metálicas/química , Achillea/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Catálise , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Fungos/efeitos dos fármacos , Células Hep G2 , Humanos , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Solventes/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Fatores de Tempo , Difração de Raios X
3.
PLoS One ; 15(6): e0229891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497076

RESUMO

A facile method has been developed for the synthesis of Schiff bases derived from substituted and unsubstituted 3-amino- and 4-amino-1,2,4-triazoles. Condensation of the aminotrizoles with a variety of aromatic aldehydes afforded desired Schiff bases in excellent yields in 3-5 minutes of exposure to ultra-sound. The synthesized compounds were characterized by means of IR, 1HNMR and Mass spectrometry. The synthesized compounds were also screened for their antibacterial potential against Gram-negative (Escherichia coli, Shigella sonnei, Pseudomonas aeruginosa and Salmonella typhi) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) strains.


Assuntos
Amitrol (Herbicida)/síntese química , Amitrol (Herbicida)/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Ondas Ultrassônicas , Amitrol (Herbicida)/química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Triazóis/química
4.
Acta Crystallogr C Struct Chem ; 76(Pt 5): 476-482, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32367829

RESUMO

Reaction of N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide), C20H18F2N4O2, (LF), with zinc chloride and mercury(II) chloride produced different types and shapes of neutral coordination complexes, namely, dichlorido[N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide)-κ2N,O]zinc(II), [ZnCl2(C20H18F2N4O2)], (1), and dichlorido[N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide)-κ4O,N,N',O']mercury(II), [HgCl2(C20H18F2N4O2)], (2). The organic ligand and its metal complexes are characterized using various techniques: IR, UV-Vis and nuclear magnetic resonance (NMR) spectroscopies, in addition to powder X-ray diffraction (PXRD), single-crystal X-ray crystallography and microelemental analysis. Depending upon the data from these analyses and measurements, a typical tetrahedral geometry was confirmed for zinc complex (1), in which the ZnII atom is located outside the bis(benzhydrazone) core. The HgII atom in (2) is found within the core and has a common octahedral structure. The in vitro antibacterial activities of the prepared compounds were evaluated against two different bacterial strains, i.e. gram positive Bacillus subtilis and gram negative Pseudomonas aeruginosa bacteria. The prepared compounds exhibited differentiated growth-inhibitory activities against these two bacterial strains based on the difference in their lipophilic nature and structural features.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Cloretos/farmacologia , Mercúrio/química , Compostos de Zinco/farmacologia , Zinco/química , Antibacterianos/química , Cloretos/química , Complexos de Coordenação/química , Cristalografia por Raios X , Difração de Raios X , Compostos de Zinco/química
5.
Nat Commun ; 11(1): 2431, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415161

RESUMO

Chemical desymmetrization reactions of meso-diols are highly effective for the precise and efficient synthesis of chiral molecules. However, even though enzyme-catalyzed desymmetric glycosylations are frequently found in nature, there is no method for highly diastereoselective desymmetric chemical glycosylation of meso-diols. Herein, we report a highly diastereoselective desymmetric 1,2-cis-glycosylation of meso-diols found in myo-inositol 1,3,5-orthoesters using a boronic acid catalyst based on predictions of regioselectivity by density functional theory (DFT) calculations. The enantiotopic hydroxyl groups of the meso-diols are clearly differentiated by the stereochemistry at the C2 position of the glycosyl donor with excellent regioselectivities. In addition, the present method is successfully applied to the synthesis of core structures of phosphatidylinositolmannosides (PIMs) and glycosylphosphatidylinositol (GPI) anchors, and common ß-mannoside structures of the LLBM-782 series of antibiotics.


Assuntos
Antibacterianos/síntese química , Técnicas de Química Sintética , Desenho de Fármacos , Manosídeos/química , Antibacterianos/química , Carboidratos/química , Glicosilação , Espectroscopia de Ressonância Magnética , Fosfatidilinositóis/química , Estereoisomerismo
6.
Int J Nanomedicine ; 15: 2353-2362, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308387

RESUMO

Purpose: Simple methodology for preparation of metal nanoparticles such as AgNPs uses an methanolic aqueous medium at room temperature or a solvent-free procedure under microwave irradiation. The prepared AgNPs showed a significant antimicrobial effect against Gram-positive bacteria, Gram-negative bacteria, and fungi. Methods: The modified methoxypolyethylene glycol bishydrazino-s-triazine (mPEGTH2) showed remarkable activity for reducing Ag+ to Ag0 in an aqueous methanolic solution and using a solvent-free method (solid phase) under microwave irradiation. In the solid phase synthesis, the size and shape of the AgNPs can be controlled by varying the weight ratio of mPEGTH2 to AgNO3 used. In addition, the antimicrobial activity depends on the ratio of mPEGTH2 to AgNO3. The mPEGTH2-AgNPs (2:1) demonstrated higher antimicrobial activity compared to mPEGTH2-AgNPs (1:1) against Gram-positive bacteria, Gram-negative bacteria, and C.albicans. Results: This work presents simple methods for the synthesis of AgNPs using modified methoxypolyethylene glycol with bishydrazino-s-triazine (mPEGTH2); a solution method, using methanol-water medium at room temperature, and a solvent-free (solid phase) method, employing microwave irradiation or direct heating which could be used for the preparation of AgNPs on large scale. In the solid phase, ratios of mPEGTH2 to AgNO3 (1:1 or 2:1, respectively) are very important to control the size and shape of AgNPs. While in solution phase is not necessary where the molar ratio used is 10:1. Most of the experimental methods resulted in AgNPs ranging in size from 7 to 10 nm as observed from XRD and TEM characterization. The antimicrobial activity of the AgNPs was also dependent on the weight ratio of mPEGTH2 to AgNO3, with a large effect as observed when using the solvent-free method. The mPEGTH2-AgNPs (2:1) demonstrated higher antimicrobial activities compared to mPEGTH2-AgNPs (1:1) against S. aureus, S. epidermidis, E. faecalis, E. coli, P. aeruginosa, S. typhimurium, and C. albicans. In all cases, the MICs and MBCs of mPEGTH2-AgNPs (1:1) were lower than those of mPEGTH2-AgNPs (2:1). Conclusion: In summary, mPEGTH2-AgNPs (2:1) is a promising candidate to kill pathogenic microbes. In particular, the method used for the preparation of AgNPs by using polyethylene glycol polymer modified with bishydrazino-s-triazine has the most potential and would be the most cost-effective method. This method of the synthesis of nanoparticles may be suitable for the preparation of other metal nanoparticles, which would allow for numerous applications in medicinal and industrial.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Nanopartículas Metálicas/química , Polietilenoglicóis/química , Prata/química , Antibacterianos/química , Candida albicans/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Micro-Ondas , Pseudomonas aeruginosa/efeitos dos fármacos , Técnicas de Síntese em Fase Sólida/métodos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos
7.
Proc Natl Acad Sci U S A ; 117(15): 8437-8448, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32241895

RESUMO

Novel classes of antibiotics and new strategies to prevent and treat infections are urgently needed because the rapid rise in drug-resistant bacterial infections in recent decades has been accompanied by a parallel decline in development of new antibiotics. Membrane permeabilizing antimicrobial peptides (AMPs) have long been considered a potentially promising, novel class of antibiotic, especially for wound protection and treatment to prevent the development of serious infections. Yet, despite thousands of known examples, AMPs have only infrequently proceeded as far as clinical trials, especially the chemically simple, linear examples. In part, this is due to impediments that often limit their applications in vivo. These can include low solubility, residual toxicity, susceptibility to proteolysis, and loss of activity due to host cell, tissue, and protein binding. Here we show how synthetic molecular evolution can be used to evolve potentially advantageous antimicrobial peptides that lack these impediments from parent peptides that have at least some of them. As an example of how the antibiotic discovery pipeline can be populated with more promising candidates, we evolved and optimized one family of linear AMPs into a new generation with high solubility, low cytotoxicity, potent broad-spectrum sterilizing activity against a panel of gram-positive and gram-negative ESKAPE pathogens, and antibiofilm activity against gram-positive and gram-negative biofilms. The evolved peptides have these activities in vitro even in the presence of concentrated host cells and also in vivo in the complex, cell- and protein-rich environment of a purulent animal wound model infected with drug-resistant bacteria.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/síntese química , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Peptídeos Catiônicos Antimicrobianos/síntese química , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana , Animais , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/química , Bactérias/genética , Infecções Bacterianas/microbiologia , Evolução Molecular Direcionada , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana
8.
J Med Chem ; 63(7): 3737-3755, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32196336

RESUMO

The ability of 6-(aryl)methylidene penicillin-based sulfones 1-7 to repurpose ß-lactam antibiotics activity with bacterial species that carry carbapenem-hydrolyzing class D ß-lactamases (OXA-23, OXA-24/40 and OXA-48), as well as with class A (TEM-1, CTX-M-2) and class C (CMY-2, DHA-1) enzymes, is reported. The combinations imipenem/3 and imipenem/4 restored almost completely the antibiotic efficacy in OXA-23 and OXA-24/40 carbapenemase-producing A. baumannii strains (1 µg mL-1) and also provided good results for OXA-48 carbapenemase-producing K. pneumoniae strains (4 µg mL-1). Compounds 2-6 in combinations with ceftazidime and ampicillin were also efficient in restoring antibiotic efficacy in E. coli strains carrying class C (CMY-2 and DHA-1) and class A (TEM-1 and CTX-M-2) ß-lactamase enzymes, respectively. Kinetic and inhibition studies with the OXA-24/40 enzyme, protein mass spectrometry analysis and docking studies allowed us to gain an insight into the inhibition mechanism and the experimentally observed differences between the ligands.


Assuntos
Antibacterianos/farmacologia , Penicilinas/farmacologia , Sulfonas/farmacologia , Inibidores de beta-Lactamases/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/enzimologia , Ampicilina/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , Domínio Catalítico , Ceftazidima/farmacologia , Reposicionamento de Medicamentos , Escherichia coli/efeitos dos fármacos , Imipenem/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Penicilinas/síntese química , Penicilinas/metabolismo , Ligação Proteica , Sulfonas/síntese química , Sulfonas/metabolismo , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/metabolismo , beta-Lactamases/química , beta-Lactamases/metabolismo
9.
Carbohydr Polym ; 235: 115973, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32122505

RESUMO

This work was designed to develop the chitosan-based melatonin layer-by-layer assembly (CMLLA) via the inclusion method. The structural characterizations and interaction present in CMLLA were investigated by the scanning electron microscope (SEM), X-ray diffraction (XRD) and Fourier Transform-Infrared spectroscopy (FTIR). The ratio of chitosan (CH) to carboxymethylcellulose (CMC) greatly influenced the mechanical properties, including the tensile strength, moisture content and color performance. Results showed that both antioxidant and antimicrobial properties of CMLLA were enhanced with the addition of melatonin (MLT). Furthermore, it was demonstrated that the CMLLA with 1.2 % (w/v) CH, 0.8 % (w/v) CMC and 50 mg/L MLT better contributed to the delay of chlorophyll degradation and the maintenance of shelf-life quality. Results from this study might open up new insights into the approaches of quality improvement of postharvest fresh products by incorporating the natural antioxidant compounds into natural polymers.


Assuntos
Antibacterianos/química , Antioxidantes/química , Quitosana/química , Materiais Revestidos Biocompatíveis/química , Bicamadas Lipídicas/química , Melatonina/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Configuração de Carboidratos , Quitosana/farmacologia , Materiais Revestidos Biocompatíveis/síntese química , Materiais Revestidos Biocompatíveis/farmacologia , Escherichia coli/efeitos dos fármacos , Bicamadas Lipídicas/síntese química , Bicamadas Lipídicas/farmacologia , Listeria monocytogenes/efeitos dos fármacos , Melatonina/farmacologia , Tamanho da Partícula , Picratos/antagonistas & inibidores , Salmonella enteritidis/efeitos dos fármacos , Propriedades de Superfície , Resistência à Tração
10.
J Infect Public Health ; 13(4): 472-479, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32139293

RESUMO

BACKGROUND: The present work is an extension of ongoing efforts toward the development and identification of new molecules as monotherapy displaying anti-inflammatory and anti-infective activities and a wide-range of gastrointestinal selectivity. A series of novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and evaluated for their in-vitro and in-vivo anti-inflammatory activities. Synthesized trisubstituted thiazole compounds were also evaluated for their potential antibacterial activity against clinical pathogens causing infectious disease. MATERIAL AND METHOD: The structures of synthesized compounds were characterized by FTIR, 1H NMR, Mass spectroscopic techniques and evaluated for their in-vitro and in-vivo anti-inflammatory effects using the human red blood cell (HRBC) membrane stabilization method and a carrageenan-induced rat paw oedema model, respectively, Diclofenac sodium and Ibuprofen were used as standard drugs. The synthesized compounds AR-17atoAR-27a screened for their in-vitro antibacterial activity against the gram-positive bacteria Staphylococcus aureus (ATCC25923) and Enterococcus faecalis (ATCC29212) and the gram-negative bacteria Escherichia coli (ATCC8739) and Pseudomonas aeruginosa (ATCC9027) using ciprofloxacin and cefdinir as standard drugs. RESULT: Compounds AR-17a and AR-27a elicited maximum anti-inflammatory activity, providing 59% and 61% protection at 20mg/kg, respectively, in the inflamed paw model. Among the tested compounds, AR-17a (6.25), (54) and AR-27a (1.56), (52) had the least minimum inhibitory concentration values and the highest zone of inhibition, indicating their marked antibacterial activities. The lowest conc. were observed at 1.56, 6.25µg/mL for inhibition of bacteria by most of the compounds. CONCLUSION: Novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and characterized successfully. The preliminary screening revealed that these compounds possess promising anti-inflammatory and antibacterial activities. In addition, the objective of the study was achieved with few of the promising structures like AR-17a to AR-27a, which are prove to be potential monotherapy candidates for the treatment of chronic inflammatory diseases and bacterial infections.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Anti-Inflamatórios/síntese química , Edema/tratamento farmacológico , Feminino , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química
11.
J Med Chem ; 63(7): 3475-3484, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32003561

RESUMO

Tachyplesin I (TPI) is a cationic ß-hairpin antimicrobial peptide with broad-spectrum, potent antimicrobial activity. In this study, the all d-amino acid analogue of TPI (TPAD) was synthesized, and its structure and activity were determined. TPAD has comparable antibacterial activity to TPI on 14 bacterial strains, including four drug-resistant bacteria. Importantly, TPAD has significantly improved stability against enzymatic degradation and decreased hemolytic activity compared to TPI, indicating that it has better therapeutic potential. The induction of bacterial resistance using low concentrations of TPAD resulted in the activation of the QseC/B two-component system. Deletion of this system resulted in at least five-fold improvement of TPAD activity, and the combined use of TPAD with LED209, a QseC/B inhibitor, significantly enhanced the bactericidal effect against three classes of multidrug-resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Ligação a DNA/farmacologia , Peptídeos Cíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sequência de Aminoácidos , Antibacterianos/síntese química , Peptídeos Catiônicos Antimicrobianos/síntese química , Proteínas de Bactérias/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Proteínas de Ligação a DNA/síntese química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Peptídeos Cíclicos/síntese química , Estereoisomerismo , Sulfonamidas/farmacologia
12.
Carbohydr Res ; 488: 107905, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32004953

RESUMO

A series of 19 synthetic alkyl and thioalkyl glycosides derived from d-mannose, d-glucose and d-galactose and having C10-C16 aglycone were investigated for cytotoxic activity against 7 human cancer and 2 non-tumor cell lines as well as for antimicrobial potential on 12 bacterial and yeast strains. The most potent compounds were found to be tetradecyl and hexadecyl ß-d-galactopyranosides (18, 19), which showed the best cytotoxicity and therapeutic index against CCRF-CEM cancer cell line. Similar cytotoxic activity showed hexadecyl α-d-mannopyranoside (5) but it also inhibited non-tumor cell lines. Because these two galactosides (18, 19) were inactive against all tested bacteria and yeast strains, they could be a target-specific for eukaryotic cells. On the other hand, ß-D-glucopyranosides with tetradecyl (11) and hexadecyl (12) aglycone inhibited only Gram-positive bacterial strain Enterococcus faecalis. The studied glycosides induce changes in the lipid bilayer thickness and lateral phase separation at high concentration, as derived from SAXS experiments on POPC model membranes. In general, glucosides and galactosides exhibit more specific properties. Those with longer aglycone show high cytotoxicity and therefore, they are more promising candidates for cancer cell line targeted inhibition.


Assuntos
Antibacterianos/síntese química , Antineoplásicos/síntese química , Enterococcus faecalis/efeitos dos fármacos , Glicosídeos/síntese química , Bicamadas Lipídicas/química , Células A549 , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Sequência de Carboidratos , Linhagem Celular , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Galactose/síntese química , Galactose/química , Galactose/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Células HCT116 , Humanos , Células K562 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Espalhamento a Baixo Ângulo , Difração de Raios X
13.
Carbohydr Polym ; 234: 115889, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070509

RESUMO

We report a facile method to prepare a novel composite based on Fe-Cu alloy decorated cellulose nanocrystals (Fe-Cu@CNC) via simple oxidation-reduction reaction. Spherical zero-valent iron nanoparticles (NZVI) and sheet-like copper nanoparticles were serially anchored on the CNC surface, and the generated composite exhibited excellent antibacterial activities and highly efficient Pb2+ removal. The composites had high antibacterial ratios of 95.9 %-99.9 %, because superoxide radicals can cause irreversible damage to the bacteria, eventually leading to apoptosis and bacterial death. Meanwhile, the Fe-Cu@CNC composite showed quick Pb2+ ion removal, reaching a 70.76 % removal within 5 min, a total removal of 93.98 % after 1 h, and excellent reusability (retaining removal efficiency of 80.41 % after six cycles). The adsorption kinetics demonstrated that the adsorption behavior can be described by pseudo-second-order kinetic model (R2>0.99). This study offers a new strategy to prepare a promising composite with advanced antibacterial and heavy metal removal properties for wastewater treatment.


Assuntos
Ligas/farmacologia , Antibacterianos/farmacologia , Celulose/farmacologia , Chumbo/isolamento & purificação , Nanopartículas/química , Poluentes Químicos da Água/isolamento & purificação , Ligas/química , Antibacterianos/síntese química , Antibacterianos/química , Celulose/química , Cobre/química , Cobre/farmacologia , Escherichia coli/efeitos dos fármacos , Ferro/química , Ferro/farmacologia , Chumbo/química , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície , Poluentes Químicos da Água/química
14.
Carbohydr Polym ; 234: 115928, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070544

RESUMO

We developed a co-delivery system of nitric oxide (NO) and antibiotic for the antibiotic-resistant bacterial infection therapy. The NO could disperse the bacterial biofilms and convert the bacteria into an antibiotic-susceptible planktonic form. Using the chitosan-graft-poly(amidoamine) dendrimer (CS-PAMAM) as the co-delivery system, methicillin (MET) and NO were conjugated successively to form CS-PAMAM-MET/NONOate. The positive CS-PAMAM could efficiently capture the negatively charged bacteria and PAMAM provide abundant reaction points for high payloads of NO and MET. The CS-PAMAM-MET/NONOate displayed effective and combined antibacterial activity to the E. coli and S. aureus. Particularly, for the MET-resistant S. aureus (MRSA), the CS-PAMAM-MET/NONOate displayed the synergistic antibacterial activity. In vivo wound healing assays also confirmed that CS-PAMAM-MET/NONOate could heal the infection formed by MRSA and then accelerate the wound healing effectively. Moreover, CS-PAMAM-MET/NONOate showed no toxicity towards 3T3 cells in vitro and rats in vivo, providing a readily but high-efficient strategy to drug-resistant bacterial infection therapy.


Assuntos
Antibacterianos/farmacologia , Quitosana/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Meticilina/farmacologia , Óxido Nítrico/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Dendrímeros/química , Dendrímeros/farmacologia , Sistemas de Liberação de Medicamentos , Masculino , Meticilina/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Tamanho da Partícula , Poliaminas/química , Poliaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/patologia , Propriedades de Superfície
15.
Inorg Chem ; 59(5): 2978-2987, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32037809

RESUMO

We have synthesized and structurally characterized three tetra-(p-tolyl)antimony(III)-containing heteropolytungstates, [{(p-tolyl)SbIII}4(A-α-XW9O34)2]n- [X = PV (1-P), AsV (1-As), or GeIV (1-Ge)], in aqueous solution using conventional, one-pot procedures. The polyanions 1-P, 1-As, and 1-Ge were fully characterized in the solid state and in solution and were shown to be soluble and stable in aqueous medium at pH 7. Biological studies demonstrated that all three polyanions possess significant antibacterial and antitumor activities. The minimum inhibitory concentrations of 1-P, 1-As, and 1-Ge were determined against four kinds of bacteria, including the two pathogenic bacteria strains, Vibrio parahaemolyticus and Vibrio vulnificus. The three novel polyanions also showed high cytotoxic potency in the human cell lines A549 (non-small cell lung cancer), CH1/PA-1 (ovarian teratocarcinoma), and SW480 (colon carcinoma).


Assuntos
Antibacterianos/farmacologia , Antimônio/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Tungstênio/farmacologia , Células A549 , Antibacterianos/síntese química , Antibacterianos/química , Antimônio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Células Tumorais Cultivadas , Tungstênio/química , Vibrio parahaemolyticus/efeitos dos fármacos , Vibrio vulnificus/efeitos dos fármacos
16.
J Med Chem ; 63(6): 3161-3171, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32097000

RESUMO

Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin could result in significant enhancement of antibacterial activity. Termed "kynomycin," this new antibiotic exhibits higher antibacterial activity than daptomycin and is able to eradicate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains, including daptomycin-resistant strains. The improved antimicrobial activity of kynomycin was demonstrated in in vitro time-killing assay, in vivo wax worm model, and different mouse infection models. The increased antibacterial activity, improved pharmacokinetics, and lower cytotoxicity of kynomycin, compared to daptomycin, showed the promise of the future design and development of next-generation daptomycin-based antibiotics.


Assuntos
Antibacterianos/uso terapêutico , Depsipeptídeos/uso terapêutico , Lipopeptídeos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Antibacterianos/toxicidade , Permeabilidade da Membrana Celular/efeitos dos fármacos , Daptomicina/química , Daptomicina/uso terapêutico , Depsipeptídeos/síntese química , Depsipeptídeos/farmacocinética , Depsipeptídeos/toxicidade , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterococcus/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Lepidópteros/efeitos dos fármacos , Lepidópteros/microbiologia , Lipopeptídeos/síntese química , Lipopeptídeos/farmacocinética , Lipopeptídeos/toxicidade , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Metilação , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
17.
Mol Biol Rep ; 47(3): 1563-1572, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32095985

RESUMO

Two new cytotoxic 1,8-naphthalimide derivatives have been synthesized and characterized. Their biological activities as cytotoxicity and antimicrobial activities and inhibitory activities against DNA-polymerase were evaluated. The interactions of compounds with double-stranded- and quadruple-DNA have been studied by UV-Vis, fluorescent intercalator displacement, competition dialysis, circular dichroism and the findings were compared with the parent naphthalimide and the other compounds. The results show that both compounds (1 and 2) and the parent compound NI have strong cytotoxic activities against Beas-2B, MCF-7, HepG2 and MDA-MB-231 cancer cell lines, antimicrobial activities against Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 and inhibitory activities towards Taq-polymerase and transcriptase. These novel cationic compounds 1 and 2 can stabilize G-quadruplexes DNA according to thermal denaturation experiments, they change the 3D structure of the DNA (see details in CD experiments) and they exhibit different binding affinities for q-DNA and ds-DNA revealed by spectrophotometric titrations and competitive dialysis studies.


Assuntos
Antineoplásicos/farmacologia , DNA/metabolismo , Quadruplex G , Naftalimidas/farmacologia , Neoplasias/metabolismo , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , DNA/química , Escherichia coli/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Modelos Químicos , Estrutura Molecular , Naftalimidas/síntese química , Naftalimidas/metabolismo , Neoplasias/patologia , Relação Estrutura-Atividade
18.
Inorg Chem ; 59(4): 2464-2483, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31984738

RESUMO

The reactivity of the multisite (amino)cyclotriphosphazene ligands, [N3P3(NHCy)6] and [N3P3(NHCy)3(NMe2)3], has been explored in order to obtain silver(I) metallophosphazene complexes. Two series of cationic silver(I) metallophosphazenes were obtained and characterized: [N3P3(NHCy)6{AgL}n](TfO)n [n = 2, L = PPh3 (2), PPh2Me (4); n = 3, L = PPh3 (3), PPh2Me (5), TPA (TPA = 1,3,5-triaza-7-phosphaadamantane, 6)] and nongem-trans-[N3P3(NHCy)3(NMe2)3{AgL}n](TfO)n [n = 2, L = PPh3 (7), PPh2Me (9); n = 3, L = PPh3 (8), PPh2Me (10)]. 5, 7, and 9 have also been characterized by single-crystal X-ray diffraction, thereby allowing key bonding information to be obtained. Compounds 2-6, 9, and 10 were screened for in vitro cytotoxic activity against two tumor human cell lines, MCF7 (breast adenocarcinoma) and HepG2 (hepatocellular carcinoma), and for antimicrobial activity against five bacterial species including Gram-positive, Gram-negative, and Mycobacteria strains. Both the IC50 and MIC values revealed excellent biological activity for these metal complexes, compared with their precursors and cisplatin and also AgNO3 and silver sulfadiazine, respectively. Both IC50 and MIC values are among the lowest values found for any silver derivatives against the cell lines and bacterial strains used in this work. The structure-activity relationships were clear. The most cytotoxic and antimicrobial derivatives were those with the triphenylphosphane and [N3P3(NHCy)6] ligands. A significant improvement in the activity was also observed upon a rise in the number of silver atoms linked to the phosphazene ring.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Organofosforados/química , Prata/química , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organofosforados/síntese química , Relação Estrutura-Atividade
19.
Biochim Biophys Acta Gen Subj ; 1864(4): 129532, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953126

RESUMO

BACKGROUND: Hybridization is a useful strategy to bond the advantages of different peptides into novel constructions. We designed a series of AMPs based on the structures of a synthetic AMP KFA3 and a naturally-occurred host defense peptide substance P (SP) to obtain peptides retaining the high antibacterial activity of KFA3 and the immunomodulatory activity and low cytotoxicity of SP. METHODS: Two repeats of KFA and different C terminal fragments of SP were hybridized, generating a series of novel AMPs (KFSP1-8). The antibacterial activities, host cell toxicity and immunomodulation were measured. The antibacterial mechanisms were investigated. RESULTS: Hybrid peptides KFSP1-4 exerted substantial antibacterial activities against Gram-negative bacteria of standard strains and clinical drug-resistant isolates including E.coli, A.baumannii and P.aeruginosa, while showing little toxicity towards host cells. Compared with KFA3, moderate reduction in α-helix content and the interruption in α-helix continuality were indicated in CD spectra analysis and secondary-structure simulation in these peptides. Membrane permeabilization combined with time-kill studies and FITC-labeled imaging, indicated a selective membrane interaction of KFSP1 with bacteria cell membranes. By specially activating NK1 receptor, the hybrid peptides kept the ability of SP to induce intracellular calcium release and ERK1/2 phosphorylation, but unable to stimulate NF-κB phosphorylation. KFSP1 facilitated the survival of mouse macrophage RAW264.7, directly interacting with LPS and inhibiting the LPS-induced NF-κB phosphorylation and TNF-α expression. CONCLUSION: Hybridization is a useful strategy to bond the advantages of different peptides. KFSP1 and its analogs are worth of advanced efforts to explore their potential applications as novel antimicrobial agents.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Oligopeptídeos/farmacologia , Substância P/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Bactérias Gram-Negativas/química , Células Hep G2 , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Lipopolissacarídeos/antagonistas & inibidores , Camundongos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Células RAW 264.7 , Relação Estrutura-Atividade , Substância P/síntese química , Substância P/química
20.
Chemistry ; 26(32): 7219-7225, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31984562

RESUMO

Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids-a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure-activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug-target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.


Assuntos
Antibacterianos/síntese química , Asparagina/análogos & derivados , Bactérias Gram-Negativas/efeitos dos fármacos , Nitrocompostos/química , Antibacterianos/química , Antibacterianos/farmacologia , Asparagina/química , Asparagina/farmacologia , Bactérias Gram-Negativas/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Nitrocompostos/farmacologia , Relação Estrutura-Atividade
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