Carbapenem‐resistant Gram‐negative bacteria (GNB) are heading the list of pathogens for which antibiotics are the most critically needed. Many antibiotics are either unable to penetrate the outer‐membrane or are excluded by efflux mechanisms. Here, we report a cationic block β‐peptide (PAS8‐b‐PDM12) that reverses intrinsic antibiotic resistance in GNB by two distinct mechanisms of action. PAS8‐b‐PDM12 does not only compromise the integrity of the bacterial outer‐membrane, it also deactivates efflux pump systems by dissipating the transmembrane electrochemical potential. As a result, PAS8‐b‐PDM12 sensitizes carbapenem‐ and colistin‐resistant GNB to multiple antibiotics in vitro and in vivo. The β‐peptide allows the perfect alternation of cationic versus hydrophobic side chains, representing a significant improvement over previous antimicrobial α‐peptides sensitizing agents. Together, our results indicate that it is technically possible for a single adjuvant to reverse innate antibiotic resistance in all pathogenic GNB of the ESKAPE group, including those resistant to last resort antibiotics. 相似文献
Incorporation of silicon‐containing amino acids in peptides is known to endow the peptide with desirable properties such as improved proteolytic stability and increased lipophilicity. In the presented study, we demonstrate that incorporation of β‐silicon‐β3‐amino acids into the antimicrobial peptide alamethicin provides the peptide with improved membrane permeabilizing properties. A robust synthetic procedure for the construction of β‐silicon‐β3‐amino acids was developed and the amino acid analogues were incorporated into alamethicin at different positions of the hydrophobic face of the amphipathic helix by using SPPS. The incorporation was shown to provide up to 20‐fold increase in calcein release as compared with wild‐type alamethicin. 相似文献
In order to explore the anticancer and antimicrobial activity associated with the thiazole framework, we synthesized the new series (Z )‐2‐((5‐(4‐nitrobenzylidene)‐4‐oxo‐4,5‐dihydrothiazol‐2‐yl)amino)‐substituted acid derivatives 6a – l . All the synthesized compounds were evaluated for anticancer and antimicrobial activity in vitro. Among these, the compounds 6a , 6b, 6c , 6e , 6f , 6g , 6h , 6i , 6j , and 6k showed highest antibacterial and antifungal activity. The compound 6a exhibited significant antibacterial activity against Bacillus subtilis , whereas compound 6j displays significant antifungal activity against fungal strains, that is, A. oryzae . The in vitro anticancer studies revealed that 6e , 6g , 6h , 6k , and 6l are the most active compounds against MCF‐7 and BT‐474 human breast cancer cell lines, which can be regarded as the promising drug candidate for development of anticancer drugs. 相似文献
A new series of 2‐aryl‐5‐((2‐arylthiazol‐4‐yl)methyl)‐1,3,4‐oxadiazole derivatives was synthesized by condensation of 2‐(2‐substituted thiazol‐4‐yl)acetohydrazide with aryl aldehydes followed by oxidative cyclocondensation using iodobenzene diacetate. The structure of synthesized compounds was characterized by IR, NMR, and mass analysis. All the newly synthesized compounds were evaluated for their in vitro antimicrobial activity. Some of the compounds showed moderate antimicrobial activity. 相似文献
A series of 1,2‐dihydroquinoxaline‐3‐yl‐3‐substitutedphenyl‐1H‐pyrazole‐4‐carbaldehyde were synthesized and evaluated for their antimicrobial activity against two Gram‐positive and two Gram‐negative organisms and two fungal organisms. The study has shown that pyrazole‐4‐carbaldehyde‐incorporated quinoxaline was essential for activity. Among the compounds, 5a , 5c , 5d had shown significant activity against all selected strains when compared with control. These compounds may prove useful as antimicrobial agents. 相似文献
A simple environmentally friendly solid‐phase microwave‐assisted method was used to synthesis of the 1,3′‐diazaflavanone ( 2 ) and 1,3′‐diazaflavone ( 3 ) from the cyclization of 2′‐amino (E)‐3″‐azachalcone ( 1 ). Ten new N‐alkyl (C5–12,14,15)‐substituted 1,3′‐diazaflavanonium bromides ( 2a–j ) were prepared from compound 2 with corresponding alkyl halides in acetonitrile under reflux. In addition, nine new N,N′‐dialkyl (C5–12,14)‐substituted 1,3′‐diazaflavonium bromides ( 3a–i ) were also synthesized from compound 3 with corresponding alkyl halides using basic silica in acetonitrile. The antimicrobial activities of compounds 1–3 , 2a–j , and 3a–i were tested against Gram‐positive (G+) (Bacillus subtilis, Staphylococcus epidermidis, Staphylococcus aureus, and Enterococcus faecalis) and Gram‐negative (G?) (Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Proteus vulgaris, Salmonella typhimirium, Yersinia pseudotuberculosis, and Enterobacter cloaceae) microorganisms. They showed good antimicrobial activity against the Gram‐positive bacteria tested with the minimal inhibitory concentration values less than 7.8 μg/mL in most cases. The optimum length of the alkyl chain for better and broader activity is situated in the range of 9–12 carbon atoms in the series of compounds 2a–j and five to six carbon atoms in the series of compounds 3a–i . The nonalkylated compounds 1–3 were not effective, as were the ones alkylated with five or six C alkyl groups ( 2a and 2b ) and 8–13 C alkyl groups for N,N′‐dialkyl compounds ( 3c–3i ). The antimicrobial activity increased as the length of the alkyl substitution increased from 8 to 12 carbons in compounds 2a–j . However, antimicrobial activity decreased as the length of the alkyl substitution increased from 7 to 13 carbons in compounds 3c–i . J. Heterocyclic Chem., (2012) 相似文献
A series of new α‐aminophosphonates containing 1,3,4‐thiadiazole moiety (4a–l) were synthesized via a simple, efficient, and one‐pot three‐component Kabachnik–Fields reaction of 2‐amino‐5‐ethyl‐1,3,4‐thiadiazole with various aryl/heteroaryl aldehydes and diethylphosphite under solvent‐free microwave irradiation conditions using phosphosulfonic acid, as a reusable and heterogeneous solid acid catalyst. All the title compounds were screened for radical scavenging activity by DPPH and H2O2 methods, and antimicrobial activity against bacteria (Gram‐positive and Gram‐negative) and fungi using the disc diffusion technique. They exhibited potent in vitro antioxidant and moderate antimicrobial activity. 相似文献
A series of novel 4‐(3,3‐dimethylspiro{bicyclo[2.2.1]heptan‐2,5′‐isoxazoline‐2}‐3′‐yl)‐2‐phenyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepines were synthesized. These molecules were screened in vitro for their antifungal and antibacterial activity, and none of the tested compounds showed promising antimicrobial or antifungal activity. J. Heterocyclic Chem., 2011. 相似文献
The cyclopropanation of the title compound (S)‐ 2 with various sulfur ylides has been examined. The reaction with methylenesulfonium ylides gave the corresponding cyclopropanes 4 with low diastereoselectivity. The formation of the second product 5 arising from the subsequent methylenation of the CO group was also observed. A clean cyclopropanation of (S)‐ 2 took place with ethyl (dimethylsulfanylidene)acetate affording the cyclopropanes 6 , with high π‐facial selectivity, but low endo/exo ratio. A high endo/exo selectivity, but low π‐facial selectivity was observed in the reaction of (S)‐ 2 with (2‐ethoxy‐2‐oxoethyl)(diphenyl)sulfonium tetrafluoroborate. The use of α‐bromoacetate carbanion as the cyclopropanation reagent resulted in the formation of 6 with very high facial and endo/exo‐selectivity. In a proposed explanation of the stereochemical outcome of the cyclopropanations investigated, the ground‐state conformation of the sulfoxide 2 and the transition‐state structure of the initial addition step were taken into account. 相似文献
The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this series of peptide derivatives identified a compound that combines effective antibacterial activity with virtually no toxicity within the same concentration range. This peptide acts against both Gram‐negative and Gram‐positive bacteria, including several MRSA strains, and represents an interesting lead for the development of a broadly applicable antibiotic. 相似文献
The scope of this study includes the synthesis of chitosan‐g‐[peptide‐poly‐ε‐caprolactone] and its self‐assembly into polymeric vesicles employing the solvent shift method. In this way, well‐defined core–shell structures suitable for encapsulation of drugs are generated. The hydrophobic polycaprolactone side‐chain and the hydrophilic chitosan backbone are linked via an enzyme‐cleavable peptide. The synthetic route involves the functionalization of chitosan with maleimide groups and the preparation of polycaprolactone with alkyne end‐groups. A peptide functionalized with a thiol group on one side and an azide group on the other side is prepared. Thiol‐ene click‐chemistry and azide–alkyne Huisgen cycloaddition are then used to link the chitosan and poly‐ε‐caprolactone chains, respectively, with this peptide. For a preliminary study, poly‐l ‐lysin is a readily available and cleavable peptide that is introduced to investigate the feasibility of the system. The size and shape of the polymersomes are studied by dynamic light scattering and cryo‐scanning electron microscopy. Furthermore, degradability is studied by incubating the polymersomes with two enzymes, trypsin and chitosanase. A dispersion of polymersomes is used to coat titanium plates and to further test the stability against enzymatic degradation. 相似文献
A new series of 1‐(5‐(benzylsulfinyl)‐3‐methyl‐1,3,4‐thiadiazol‐2(3H)‐ylidene)‐thiourea/urea derivatives ( 1a – j ) were designed and synthesized. For the first time, (i) a new process was developed for N‐methylation of 1,3,4‐thiadiazole moiety using dimethyl carbonate an environmentally benign reagent in presence of N,N,N′,N′‐tetramethylethylenediamine and (ii) the sulfide was selectively oxidized to sulfoxide in higher yield by using chlorine (g) in aqueous acetic acid media under mild reaction condition. The synthesized compounds ( 1a – j ) were investigated for their antimicrobial activities. The tested compounds ( 1a – j ) were exhibited moderate to excellent antibacterial activities against both Gram‐positive and Gram‐negative bacterial strains. The same compounds exhibited good antifungal activities against selected fungal strains. Particularly, the compounds 1b , 1d , 1h , and 1i were proved to be promising leads exhibiting both antibacterial and antifungal activities compared with standard drugs, ciprofloxacin, and fluconazole. The presence of 1,3,4‐thiadiazole moiety has a significant role in the display of antimicrobial activity. In addition, the presence of both sulfinyl and thiourea or urea functionalities has enhanced the activity as per obtained antimicrobial activity data. 相似文献
A novel 1,3‐alternate 25,27‐bis‐[cyanopropyloxy]‐26,28‐bis‐[3‐propyloxy]‐calix[4]arene‐bonded silica gel stationary phase (CalixPrCN) was prepared and its structure was confirmed by ATR‐FTIR spectroscopy and elemental analysis. The CalixPrCN phase was characterized in terms of its surface coverage, hydrophobic selectivity, aromatic selectivity, shape selectivity, hydrogen bonding capacity, residue metal content, and silanol activity based on Tanaka, Lindner, and SMR 870 test protocols. The effect of the acetonitrile content on the retention and selectivity of the selected neutral, basic, and acidic solutes was studied. The neutral and acidic analytes exhibited classical RP behavior, in which retention time decreases with increasing acetonitrile content. In contrast, basic analytes showed an increase in retention at low and high percentages of acetonitrile, forming “U‐shaped” retention profiles. The new calixarene phase was compared with previously reported 1,3‐alternate 25,27‐bis‐[propyloxy]‐26,28‐bis‐[3‐propyloxy]‐calix[4]arene stationary phase and commercial cyanopropyl column. The results indicate that the CalixPrCN stationary phase behaves like RP packing; however, inclusion complex formation, dipole–dipole, and π–π interactions seem to be involved in the separation process. The selectivity of this phase was demonstrated in separation of polynuclear aromatic hydrocarbons, non‐steroidal anti‐inflammatory drugs, and sulfonamides as analytes. 相似文献
Polymers conjugated to the exterior of a protein mediate its interactions with surroundings, enhance its processability and can be used to direct its macroscopic assemblies. Most studies to date have focused on peptide–polymer conjugates based on hydrophilic polymers. Engineering amphiphilicity into protein motifs by covalently linking hydrophobic polymers has the potential to interface peptides and proteins with synthetic polymers, organic solvents, and lipids to fabricate functional hybrid materials. Here, we synthesized amphiphilic peptide–polymer conjugates in which a hydrophobic polymer is conjugated to the exterior of a heme‐binding four‐helix bundle and systematically investigated the effects of the hydrophobicity of the conjugated polymer on the peptide structure and the integrity of the heme‐binding pocket. In aqueous solution with surfactants present, the side‐conjugated hydrophobic polymers unfold peptides and may induce an α‐helix to β‐sheet conformational transition. These effects decrease as the polymer becomes less hydrophobic and directly correlate with the polymer hydrophobicity. Upon adding organic solvent to solubilize the hydrophobic polymers, however, the deleterious effects of hydrophobic polymers on the peptide structures can be eliminated. Present studies demonstrate that protein structure is sensitive to the local environment. It is feasible to dissolve amphiphilic peptide–polymer conjugates in organic solvents to enhance their solution processability while maintaining the protein structures.
A convenient synthesis of a new series of N‐aryl‐5‐(pyridin‐3‐yl)‐1H/3H‐1,2,3‐triazole‐4‐carbonitriles and alkyl N‐aryl‐5‐(pyridin‐3‐yl)‐1H/3H‐1,2,3‐triazole‐4‐carboxylic acid esters is reported. The newly synthesized 5‐(pyridin‐3‐yl)‐1,2,3‐triazole derivatives are evaluated for their antibacterial and antifungal activity. Some of these triazole derivatives have exhibited moderate antimicrobial activity. 相似文献
A series of highly stereoselective polysubstituted cyclopropane derivatives were synthesized via one‐pot two‐step tandem reaction starting from pyridine, 4‐chloro phenacyl bromide, 1,3‐indandione and aromatic aldehydes in acetonitrile using triethylamine as catalyst. Pyridinium ylide generated from 4‐chloro phenacyl bromide undergo cyclopropanation with 2‐arylidene‐2H‐indene‐1,3‐dione in situ afford the title compounds. Structures of all the compounds were confirmed by their analytical and spectral studies. Single crystal X‐ray analysis was also performed on compound 4c in order to determine the crystal structure. All the compounds were screened for antimicrobial and nematicidal activities. Significant antimicrobial activity was shown by the compounds derived from 2‐hydroxybenzaldehyde ( 4i ) and 4‐(dimethylamino)benzaldehyde ( 4m ) against all the tested bacterial and fungal strains. Compound 4i has shown good activity (48% mortality) against Meloidogyne incognita after 48 h of exposure at 250 µg/mL concentration. 相似文献