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1.
Antibiotic discovery and development is challenging as chemical scaffolds of synthetic origin often lack the required pharmaceutical properties, and the discovery of novel ones from natural sources is tedious. Herein, we report the discovery of new cystobactamids with a significantly improved antibacterial profile in a detailed screening of myxobacterial producer strains. Some of these new derivatives display antibacterial activities in the low‐μg mL−1 range against Gram‐negative pathogens, including clinical isolates of Klebsiella oxytoca, Pseudomonas aeruginosa, and fluoroquinolone‐resistant Enterobacteriaceae, which were not observed for previously reported cystobactamids. Our findings provide structure–activity relationships and show how pathogen resistance can be overcome by natural scaffold diversity. The most promising derivative 861‐2 was prepared by total synthesis, enabling further chemical optimization of this privileged scaffold.  相似文献   

2.
The rise of antibiotic resistance causes a serious health care problem, and its counterfeit demands novel, innovative concepts. The combination of photopharmacology, enabling a light-controlled reversible modulation of drug activity, with antibiotic drug design has led to first photoswitchable antibiotic compounds derived from established scaffolds. In this study, we converted cystobactamids, gyrase-inhibiting natural products with an oligoaryl scaffold and highly potent antibacterial activities, into photoswitchable agents by inserting azobenzene in the N-terminal part and/or an acylhydrazone moiety near the C-terminus, yielding twenty analogs that contain mono- as well as double-switches. Antibiotic and gyrase inhibition properties could be modulated 3.4-fold and 5-fold by light, respectively. Notably, the sensitivity of photoswitchable cystobactamids towards two known resistance factors, the peptidase AlbD and the scavenger protein AlbA, was light-dependent. While irradiation of an analog with an N-terminal azobenzene with 365 nm light led to less degradation by AlbD, the AlbA-mediated inactivation was induced. This provides a proof-of-principle that resistance towards photoswitchable antibiotics can be optically controlled.  相似文献   

3.
In the past 20 years, peptide‐based antibiotics, such as vancomycin, teicoplanin, and daptomycin, have often been considered as second‐line antibiotics. However, in recent years, an increasing number of reports on vancomycin resistance in pathogens appeared, which forces researchers to find novel lead structures for potent new antibiotics. Herein, we report the total synthesis of a defined endo‐type B PPAP library and their antibiotic activity against multiresistant S. aureus and various vancomycin‐resistant Enterococci . Four new compounds that combine high activities and low cytotoxicity were identified, indicating that the PPAP core might become a new non‐peptide‐based lead structure in antibiotic research.  相似文献   

4.
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.  相似文献   

5.
A series of 20 novel pyrazole derivatives were designed and prepared, characterized by 1H‐NMR, mass spectra (ES‐MS), 13C‐NMR, and elemental analysis. The synthesized compounds were then evaluated for their growth inhibitory activity against Mycobacterium smegmatis mc2 155 initially. Rifampicin was used as standard reference. In this screening, derivatives 9 , 10 , and 11 presented superior inhibition compared with standard. Later, these three compounds were exposed for their Mycobacterium tuberculosis H37Rv inhibitory assay using rifampicin as standard reference. Encouraging M. smegmatis mc2 155 inhibition (9 μg/mL), M. tuberculosis H37Rv inhibition (1.9 μg/mL), and synergism with the first‐line and second‐line antibiotics made compound 10 as lead and safe antitubercular agent among the series.  相似文献   

6.
Two new perulactone‐type withanolides, named perulactone C ( 1 ) and perulactone D ( 2 ), together with four known compounds, perulactone ( 3 ), perulactone B ( 4 ), blumenol A, and (+)‐(S)‐dehydrovomifoliol, were isolated from the aerial parts of Physalis peruviana. The structures of the new compounds were elucidated on the basis of 1D‐ and 2D‐NMR experiments, including HMBC, HSQC, 1H,1H‐COSY, and ROESY, as well as HR‐MS.  相似文献   

7.
A series of novel N‐glycosyl‐N′‐pyrazolylmethylene aminothioureas ( 4a‐4e, 5a‐5e ) were synthesized from N‐glycosyl‐N′‐aminothioureas ( 2a‐2d ) and 4‐formylpyrazole ( 3a‐3e ). Activated 4Å molecular sieves were adopted for dehydrated reagent to improve the reaction rate and yield. The structures of the new compounds were identified on the basis of IR, 1H NMR and MS spectra. Simultaneously, the compounds were detected by fluorescence spectrophotometer and had preferable fluorescence activity, so they can be selected as a kind of novel fluorescence labeled derivative of sugar.  相似文献   

8.
This paper describes the development of novel aromatic platforms for supramolecular construction. By the Suzuki cross‐coupling protocol, a variety of functionalized m‐terphenyl derivatives were prepared (Schemes 1–4). Macrolactamization of bis(ammonium salt) (S,S)‐ 6 with bis(acyl halide) 7 afforded the macrocyclic receptor (S,S)‐ 2 (Scheme 1), which was shown by 1H‐NMR titration studies to form ‘nesting' complexes of moderate stability (Ka between 130 and 290 M ?1, 300 K) with octyl glucosides 13 – 15 (Fig. 2) in the noncompetitive solvent CDCl3. Suzuki cross‐coupling starting from 3,3′,5,5′‐tetrabromo‐1,1′‐biphenyl provided access to a novel series of extended aromatic platforms (Scheme 5) for cleft‐type (Fig. 1) and macrotricyclic receptors such as (S,S,S,S)‐ 1 . Although mass‐spectral evidence for the formation of (S,S,S,S)‐ 1 by macrolactamization between the two functionalized 3,3′,5,5′‐tetraaryl‐1,1′‐biphenyl derivatives (S,S)‐ 33 and 36 was obtained, the 1H‐ and 13C‐NMR spectra of purified material remained rather inconclusive with respect to both purity and constitution. The versatile access to the novel, differentially functionalized 3,3′,5,5′‐tetrabromo‐1,1′‐biphenyl platforms should ensure their wide use in future supramolecular construction.  相似文献   

9.
In this work, the construction and performance evaluation of PVC membranes ion‐selective electrodes for the determination of tetracycline type antibiotics is described. Electrodes with the best responses were based on plastic membranes containing 31% (w/w) PVC, 68% (w/w) of dibutylphthalate as plasticizer and 1% (w/w) of β‐cyclodextrin as ionophore. The electrodes were responsive over 6 months to tetracycline, oxytetracycline, doxycycline and chlortetracycline in glycine buffer solution (pH 2), in the dynamic range 2×10?5–10?2 mol L?1 with a constant slope of about 55 mV/dec To enable large scale analysis reducing wastes as associated costs tubular shape electrodes were coupled to a sequential‐injection analysis system and its performance evaluated using pharmaceutical samples and waste waters from a treatment facility. The sample throughput of 51 samples h?1 was enabled by the system as well as results that favorably agree with those provided by chromatographic analysis.  相似文献   

10.
A novel lupane‐type triterpenoid, 3,4‐seco‐lupa‐4(23), 20(29)‐dien‐24‐hydroxy‐3‐oic acid (1) and a new cycloartane‐type triterpenoid, 23(E)‐cycloart‐23‐en‐25‐ethoxy‐3β‐ol (7), as well as eighteen known compounds, were isolated from the hot ethanol extract of the whole plant of Euphorbia humifusa Willd. The new structures were characterized by means of spectroscopic methods including 1D, 2D NMR and HRESIMS, and the known ones were established on the basis of comparing their NMR data with those of the corresponding compounds in the literature. In addition, cytotoxicity against selected cancer cell human gastric carcinoma (SGC‐7901) of compounds 1,3,4,6 were measured in vitro.  相似文献   

11.
A new megastigmane palmitate, 9‐oxomegastigm‐5(13)‐ene‐2β‐palmitate ( 1 ), and a new oleanane triterpenoid, (3β)‐3,23,28‐trihydroxyolean‐12‐en‐11‐one ( 2 ), together with three known oleanane‐type triterpenoids, β‐amyrin ( 3 ), erythrodiol ( 4 ), and (3β)‐olean‐12‐ene‐3,23,28‐triol ( 5 ), were isolated from the aerial parts of Aster yomena (Asteraceae). Their structures were identified based on 1D‐ and 2D‐NMR analysis, including 1H,1H‐COSY, HSQC, HMBC, and NOESY techniques.  相似文献   

12.
A novel N‐hydroxy succinimide‐based carbonate monomer that allows direct synthesis of polymers incorporating a reactive carbonate group in the side chain was synthesized. This new monomer was copolymerized with methyl methacrylate and poly(ethylene glycol) methylether methacrylate using free‐radical polymerization to obtain organo‐ and water‐soluble reactive copolymers. Copolymerization of the activated carbonate monomer with an azide‐containing monomer and N‐hydroxy succinimide‐containing activated ester monomer provided orthogonally functionalizable copolymers. The pendant reactive carbonate groups of the copolymers were functionalized with amines to obtain carbamates. Polymers capable of orthogonal functionalization could be selectively functionalized as desired using subsequent 1,3‐dipolar cycloaddition or amidation reactions. The novel monomer and the copolymers were characterized by 1H‐NMR, 13C‐NMR, and infrared spectroscopy. The efficient stepwise orthogonal functionalization of the copolymers were examined via 1H‐NMR spectroscopy. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010  相似文献   

13.
To combat multidrug‐resistant Gram‐positive bacteria, new antimicrobials particularly those with novel mechanism of action are badly needed. Different with conventional antibiotics which are typical inhibitors, small‐molecule activators of bacterial ClpP represent a new class of antibiotics. No ClpP activator has been developed for clinical trial. Herein, we conducted a screening on our library of bengamide‐like ring‐opened analogues and found that L472‐2 possesses a low minimum inhibitory concentration (MIC) against S.aureus and shows no activity for ClpP activation in vitro, but it displayed reduced antibacterial activity against S. aureus with clpP deletion. In order to obtain bengamide analogues that activate ClpP in vitro as well as possess antibacterial activity, we perform further structural modifications starting from L472‐2 . Compound 37 remains the antimicrobial activity and activation of ClpP protein in vitro, which could be viewed as a new chemical scaffold for ClpP activators and worthy of further investigation.  相似文献   

14.
Conformationally constrained non‐racemizing trifluoromethyl‐substituted lysine isosteres [(E)‐ and (Z)‐TCBLys] with charged side chains are presented as a new type of 19F‐NMR labels for peptide studies. Design of the labels, their synthesis, incorporation into peptides and experimental demonstration of their application for solid state NMR studies of membrane‐active peptides are described. A series of fluorine‐labeled analogues of the helical amphipathic antimicrobial peptide PGLa(Nle) was obtained, in which different lysine residues in the original peptide sequence were replaced, one at a time, by either (E)‐ or (Z)‐TCBLys. Antimicrobial activities of the synthesized analogues were practically the same as those of the parent peptide. The structural and orientational parameters of the helical PGLa(Nle) peptide in model bilayers, as determined using the novel labels confirmed and refined the previously known structure. (E)‐ and (Z)‐TCBLys, as a set of cationic 19F‐NMR labels, were shown to deliver structural information about the charged face of amphipathic peptides by solid state 19F‐NMR, previously inaccessible by this method.  相似文献   

15.
This paper describes a method of preparation of new 3,5′‐dioxo‐2′‐phenyl‐1,3‐dihydrospiro[indene‐2,4′‐[1,3]oxazol]‐1‐yl acetate and its 5‐chloro‐ and bromoderivatives as products of interaction of N‐benzoylglycine (hippuric acid) with corresponding ortho‐formylbenzoic acids. The reaction carried out in acetic anhydride media in the presence of piperidine as catalyst. The novel spirocompounds were purified by column chromatography from multicomponent reaction mixtures. The composition of the spiro‐products was confirmed by C, H, N element analysis. The structure was established by IR, MS, 1H‐ and 13C‐NMR analysis including COSY 1H‐13C experiments.  相似文献   

16.
Sijia Xue  Xubo Ma  Hongfei Bu  Li Liu  Xiao Xu 《中国化学》2011,29(10):2153-2156
A new series of 1,3,5‐trisubstituted‐1,3,5‐hexahydrotriazine‐2‐N‐nitroimines ( 3a – 3j ) were designed and synthesized as novel neonicotinoid analogues, and their structures were characterized by 1H NMR, IR, elemental analysis and MS. The preliminary bioassay tests showed that most of the target compounds had good insecticidal activities against Nilaparvata lugens as well as Aphis medicaginis at 500 mg/L, while compound 3i had 100% mortality against Nilaparvata lugens at 20 mg/L.  相似文献   

17.
Effective detection of organic/inorganic pollutants, such as antibiotics, nitro‐compounds, excessive Fe3+ and MnO4?, is crucial for human health and environmental protection. Here, a new terbium(III)–organic framework, namely [Tb(TATAB)(H2O)]?2H2O ( Tb‐MOF , H3TATAB=4,4′,4′′‐s‐triazine‐1,3,5‐triyltri‐m‐aminobenzoic acid), was assembled and characterized. The Tb‐MOF exhibits a water‐stable 3D bnn framework. Due to the existence of competitive absorption, Tb‐MOF has a high selectivity for detecting Fe3+, MnO4?, 4‐nirophenol and nitroimidazole (ronidazole, metronidazole, dimetridazole, ornidazole) in aqueous through luminescent quenching. The results suggest that Tb‐MOF is a simple and reliable reagent with multiple sensor responses in practical applications. To the best of our knowledge, this work represents the first TbIII‐based MOF as an efficient fluorescent sensor for detecting metal ions, inorganic anions, nitro‐compounds, and antibiotics simultaneously.  相似文献   

18.
Several (multiply) iodinated squarylium cyanine dyes of type 1 and 8 (see Scheme and Table), derived from 1,3‐benzothiazole and 6‐iodo‐1,3‐benzothiazole, were synthesized as potential new photosensitizers, with absorptions in the 700‐nm region. Their ability to generate singlet oxygen (1O2) was assessed by luminescence‐decay measurement in the near‐IR. Some of these new dyes show interesting photophysical properties, and may be potentially used in photodynamic therapy (PDT).  相似文献   

19.
A novel type of polymeric beads with high oil absorbency was prepared via suspension polymerization technique. For this purpose, β‐cyclodextrin with vinyl groups (β‐CD‐MA) was first synthesized from β‐cyclodextrin (β‐CD) and glycidyl methacrylate, and identified by FT‐IR and 1H‐NMR spectroscopy analyses. Suspension polymerizations were carried out with styrene and stearyl acrylate as co‐monomers, β‐CD‐MA as cross‐linking agent, poly(vinylalcohol) as stabilizer and azoisobutyronitrile as initiator, providing polymeric beads in a quantitative yield. The oil‐absorbent beads had a porous structure and exhibited high oil absorbency: 55 times the dry weight in toluene, 52 times in xylene, 75 times in CHCl3 and 102 times in CCl4. The novel beads also showed high absorbency toward toluene from a toluene/water mixture, demonstrating the potential applications of such novel oil‐absorbent beads for cleaning organic contaminations from water. Copyright © 2011 John Wiley & Sons, Ltd.  相似文献   

20.
The 1H‐pyrazole‐3‐carboxylic acid 1 was converted via reactions of its acid chloride 3 with various asymmetrical disubstituted urea and alcohol derivatives into the corresponding novel 4‐benzoyl‐N‐(N′,N′‐dialkylcarbamyl)‐1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxamide 4a , b and alkyl 4‐benzoyl‐1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxylate 7a‐c , respectively, in good yields (57%‐78%). Friedel‐Crafts reactions of 3 with aromatic compouns for 15 min.‐2 h led to the formation of the 4‐3‐diaroyl‐1‐(4‐hydroxyphenyl)‐5‐phenyl‐1H‐pyrazoles 9a‐c , 4‐benzoyl‐1‐(4‐methoxyphenyl)‐3‐aroyl‐5‐phenyl‐1H‐pyrazoles 10a , b and than from the acylation reactions of 9a‐c were obtained the 3,4‐diaroyl‐1‐(4‐acyloxyphenyl)‐5‐phenyl‐1H‐pyrazoles 13a‐d . The structures of all new synthesized compounds were established by NMR experiments such as 1H, and 13C, as well as 2D COSY and IR spectroscopic data, and elemental analyses. All the compounds were evaluated for their antimicrobial activities (agar diffusion method) against eight bacteria and two yeasts.  相似文献   

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