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1.
Total Synthesis of Albicidin: A Lead Structure from Xanthomonas albilineans for Potent Antibacterial Gyrase Inhibitors
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Julian Kretz Dennis Kerwat Vivien Schubert Stefan Grätz Alexander Pesic Siamak Semsary Stéphane Cociancich Monique Royer Prof. Dr. Roderich D. Süssmuth 《Angewandte Chemie (International ed. in English)》2015,54(6):1969-1973
The peptide antibiotic albicidin, which is synthesized by the plant pathogenic bacterium Xanthomonas albilineans, displays remarkable antibacterial activity against various Gram‐positive and Gram‐negative microorganisms. The low amounts of albicidin obtainable from the producing organism or through heterologous expression are limiting factors in providing sufficient material for bioactivity profiling and structure–activity studies. Therefore, we developed a convergent total synthesis route toward albicidin. The unexpectedly difficult formation of amide bonds between the aromatic amino acids was achieved through a triphosgene‐mediated coupling strategy. The herein presented synthesis of albicidin confirms the previously determined chemical structure and underlines the extraordinary antibacterial activity of this compound. The synthetic protocol will provide multigram amounts of albicidin for further profiling of its drug properties. 相似文献
2.
Lieby Zborovsky Leonardo Kleebauer Maria Seidel Arseni Kostenko Leonard von Eckardstein Frank Otto Gombert John Weston Roderich D. Süssmuth 《Chemical science》2021,12(43):14606
The worrisome development and spread of multidrug-resistant bacteria demands new antibacterial agents with strong bioactivities particularly against Gram-negative bacteria. Albicidins were recently structurally characterized as highly active antibacterial natural products from the bacterium Xanthomonas albilineans. Albicidin, which effectively targets the bacterial DNA-gyrase, is a lipophilic hexapeptide mostly consisting of para amino benzoic acid units and only one α-amino acid. In this study, we report on the design and synthesis of new albicidins, containing N-atoms on each of the 5 different phenyl rings. We systematically introduced N-atoms into the aromatic backbone to monitor intramolecular H-bonds and for one derivative correlated them with a significant enhancement of the antibacterial activity and activity spectrum, particularly also towards Gram-positive bacteria. In parallel we conducted DFT calculations to find the most stable conformation of each derivative. A drastic angle-change was observed for the lead compound and shows a preferred planarity through H-bonding with the introduced N-atom at the D-fragment of albicidin. Finally, we went to the next level and conducted the first in vivo experiments with an albicidin analogue. Our lead compound was evaluated in two different mouse experiments: In the first we show a promising PK profile and the absence of toxicity and in the second very good efficiency and reduction of the bacterial titre in an E. coli infection model with FQ-resistant clinically relevant strains. These results qualify albicidins as active antibacterial substances with the potential to be developed as a drug for treatment of infections caused by Gram-negative and Gram-positive bacteria.A systematic pyridine-scan of the albicidin molecule provides a new lead structure with improved antimicrobial properties. 相似文献
3.
Angshuman Ghosh Soumen Kumar Dubey Dr. Maxcimilan Patra Jishu Mandal Narendra Nath Ghosh Priyanka Das Arpita Bhowmick Dr. Keka Sarkar Dr. Suprabhat Mukherjee Rajat Saha Dr. Subham Bhattacharjee 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(63):e202201621
We have shown solvent- and substrate-dependent chiral inversion of a few glycoconjugate supramolecules. (Z)-F-Gluco, in which d -glucosamine has been attached chemically to Cbz-protected l -phenylalanine at the C terminus, forms a self-healing hydrogel through intertwining of the nanofibers wherein the gelators undergo lamellar packing in the β-sheet secondary structures with a single chiral handedness. Dihybrid (Z)-F-gluco nanocomposite gel was prepared by in-situ formation of silver nanoparticles AgNPs in the gel; this enhances the mechanical properties of the composite gel through physical crosslinking without altering the packing pattern. In contrast, (Z)-L-gluco bearing an l -leucine moiety does not form a hydrogel but an organogel. Interestingly, the chiral handedness of the aggregates of (Z)-L-gluco can be reversed by choosing suitable solvents. In addition to self-healing behavior, (Z)-L-gluco gel revealed shape persistency. Further, (Z)-F-gluco hydrogel is benign, nontoxic, non-immunogenic, and non-allergenic in animal cells. AgNP-loaded (Z)-F-gluco hydrogel showed antibacterial activity against both Gram-positive and Gram-negative bacteria. 相似文献
4.
Karol Al Ayed Ross D. Ballantine Michael Hoekstra Samantha J. Bann Charlotte M. J. Wesseling Alexander T. Bakker Zheng Zhong Yong-Xin Li Nora C. Brüchle Mario van der Stelt Stephen A. Cochrane Nathaniel I. Martin 《Chemical science》2022,13(12):3563
Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assays and in vivo infection models.Convenient solid-phase approaches are described for the synthesis of brevicidine and laterocidine. Also reported are novel analogues including a laterocidine variant with enhanced hydrolytic stability and potent in vivo antibacterial activity. 相似文献
5.
Xue‐Qing Kong Bing‐Yan Wei Chen‐Xi Yu Xiang‐Na Guan Wei‐Ping Ma Gang Liu Cai‐Guang Yang Fa‐Jun Nan 《中国化学》2020,38(10):1111-1115
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
6.
Synthetically Tuning the 2‐Position of Halogenated Quinolines: Optimizing Antibacterial and Biofilm Eradication Activities via Alkylation and Reductive Amination Pathways
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Akash Basak Yasmeen Abouelhassan Verrill M. Norwood IV Dr. Fang Bai Minh Thu Nguyen Prof. Shouguang Jin Prof. Robert W. Huigens III 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(27):9181-9189
Agents capable of eradicating bacterial biofilms are of great importance to human health as biofilm‐associated infections are tolerant to our current antibiotic therapies. We have recently discovered that halogenated quinoline (HQ) small molecules are: 1) capable of eradicating methicillin‐resistant Staphylococcus aureus (MRSA), methicillin‐resistant Staphylococcus epidermidis (MRSE) and vancomycin‐resistant Enterococcus faecium (VRE) biofilms, and 2) synthetic tuning of the 2‐position of the HQ scaffold has a significant impact on antibacterial and antibiofilm activities. Here, we report the chemical synthesis and biological evaluation of 39 HQ analogues that have a high degree of structural diversity at the 2‐position. We identified diverse analogues that are alkylated and aminated at the 2‐position of the HQ scaffold and demonstrate potent antibacterial (MIC≤0.39 μm ) and biofilm eradication (MBEC 1.0–93.8 μm ) activities against drug‐resistant Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium strains while demonstrating <5 % haemolysis activity against human red blood cells (RBCs) at 200 μm . In addition, these HQs demonstrated low cytotoxicity against HeLa cells. Halogenated quinolines are a promising class of antibiofilm agents against Gram‐positive pathogens that could lead to useful treatments against persistent bacterial infections. 相似文献
7.
Graziano Guella Ines Mancini Giuseppe Chiasera Francesco Pietra 《Helvetica chimica acta》1989,72(2):237-246
It is shown that an unidentified nudibranch of Hawaiian waters contains a 26-membered macrolide, sphinxolide ((?)- 1 ) with potent activity against the KB cell line. The structure of sphinxolide, a 2:1 mixture of (E/Z)-isomers at the formamide moiety, is established to be (–)- 1 on the basis of extensive NMR and FAB-MS analysis, in combination with data for the products of mono- (→(?)- 2 ) and diacetylation (→(+)-3). 相似文献
8.
Prof. Dr. Lena Keller Dr. Emilia Oueis Dr. Amninder Kaur Dr. Nasim Safaei Dr. Susanne H. Kirsch Dr. Antonia P. Gunesch Dr. Sibylle Haid Dr. Ulfert Rand Prof. Dr. Luka Čičin-Šain Dr. Chengzhang Fu PD Dr. Joachim Wink Prof. Dr. Thomas Pietschmann Prof. Dr. Rolf Müller 《Angewandte Chemie (International ed. in English)》2023,62(6):e202214595
A new family of highly unusual sesquarterpenoids (persicamidines A–E) exhibiting significant antiviral activity was isolated from a newly discovered actinobacterial strain, Kibdelosporangium persicum sp. nov., collected from a hot desert in Iran. Extensive NMR analysis unraveled a hexacyclic terpenoid molecule with a modified sugar moiety on one side and a highly unusual isourea moiety fused to the terpenoid structure. The structures of the five analogues differed only in the aminoalkyl side chain attached to the isourea moiety. Persicamidines A–E showed potent activity against hCoV-229E and SARS-CoV-2 viruses in the nanomolar range together with very good selectivity indices, making persicamidines promising as starting points for drug development. 相似文献
9.
Shuji Ioka Dr. Tsuyoshi Saitoh Dr. Satoshi Iwano Prof. Dr. Koji Suzuki Dr. Shojiro A. Maki Prof. Dr. Atsushi Miyawaki Prof. Dr. Masaya Imoto Prof. Dr. Shigeru Nishiyama 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(27):9330-9337
Five new firefly luciferin ( 1 ) analogues were synthesized and their light emission properties were examined. Modifications of the thiazoline moiety in 1 were employed to produce analogues containing acyclic amino acid side chains ( 2 – 4 ) and heterocyclic rings derived from amino acids ( 5 and 6 ) linked to the benzothiazole moiety. Although methyl esters of all of the synthetic derivatives exhibited chemiluminescence activity, only carboluciferin ( 6 ), possessing a pyrroline‐substituted benzothiazole structure, had bioluminescence (BL) activity (λmax=547 nm). Results of bioluminescence studies with AMP‐carboluciferin (AMP=adenosine monophosphate) and AMP‐firefly luciferin showed that the nature of the thiazoline mimicking moiety affected the adenylation step of the luciferin–luciferase reaction required for production of potent BL. In addition, BL of 6 in living mice differed from that of 1 in that its luminescence decay rate was slower. 相似文献
10.
《Journal of heterocyclic chemistry》2017,54(1):524-530
A new class of azolyl pyrimidines linked by diamino sulfone moiety was prepared and studied their antimicrobial activity. Chloro‐substituted and nitro‐substituted thiazolyl pyrimidines ( 9c and 9e ) showed excellent antibacterial activity against Bacillus subtilis , while imidazolyl pyrimidines ( 10c and 10e ) exhibited promising antifungal activity against Aspergillus niger . 相似文献
11.
Total Synthesis and Biological Evaluation of the Antibiotic Lysocin E and Its Enantiomeric,Epimeric, and N‐Demethylated Analogues
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Dr. Motoki Murai Takuya Kaji Dr. Takefumi Kuranaga Dr. Hiroshi Hamamoto Prof. Dr. Kazuhisa Sekimizu Prof. Dr. Masayuki Inoue 《Angewandte Chemie (International ed. in English)》2015,54(5):1556-1560
Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid‐phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N‐demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action. 相似文献
12.
Hogantharanni Govender Chunderika Mocktar Hezekiel M. Kumalo 《Phosphorus, sulfur, and silicon and the related elements》2013,188(11):1074-1081
AbstractFifteen 2-quinolone thiosemicarbazone derivatives of which eleven were new, were synthesized at room temperature. The key intermediate was the quinolone carbaldehyde, from which thiosemicarbazones were formed by the reaction of thiosemicarbazides with the aldehyde moiety. The structures of the synthesized compounds were elucidated by 1D and 2D-NMR spectroscopy and mass spectrometry. The synthesized compounds showed antibacterial activity with MBCs in the range 0.80 to 36.49?mM against Staphylococcus aureus, Staphylococcus aureus Rosenbach (MRSA), Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Salmonella typhimurium. The best activity was seen when a larger halogen such as chlorine and bromine were substituted at C-6 on the quinolone scaffold and when a planar phenyl group was present on the thiosemicarbazone moiety. Activity was reduced when a smaller fluorine atom was present at C-6 or when a methyl group was attached to the thiosemicarbazone. This group of compounds showed a high negative binding affinity, which suggested promising antimcrobial activity. The 6-chloro derivative with a phenyl group on the thiosemicarbazone had the greatest negative binding affinity. 相似文献
13.
Motoki Murai Takuya Kaji Takefumi Kuranaga Hiroshi Hamamoto Kazuhisa Sekimizu Masayuki Inoue 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2015,127(5):1576-1580
Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid‐phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N‐demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action. 相似文献
14.
Richiro Ushimaru Zhang Chen Houyuan Zhao Po-hsun Fan Prof. Dr. Hung-wen Liu 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(9):3586-3590
Albomycin δ2 is a sulfur-containing sideromycin natural product that shows potent antibacterial activity against clinically important pathogens. The l -serine-thioheptose dipeptide partial structure, known as SB-217452, has been found to be the active seryl-tRNA synthetase inhibitor component of albomycin δ2. Herein, it is demonstrated that AbmF catalyzes condensation between the 6′-amino-4′-thionucleoside with the d -ribo configuration and seryl-adenylate supplied by the serine adenylation activity of AbmK. Formation of the dipeptide is followed by C3′-epimerization to produce SB-217452 with the d -xylo configuration, which is catalyzed by the radical S-adenosyl-l -methionine enzyme AbmJ. Gene deletion suggests that AbmC is involved in peptide assembly linking SB-217452 with the siderophore moiety. This study establishes how the albomycin biosynthetic machinery generates its antimicrobial component SB-217452. 相似文献
15.
Haiyin He HuiY. Yang ScottW. Luckman ValerieS. Bernan Gordon Tsai DeborahM. Roll GuyT. Carter 《Helvetica chimica acta》2004,87(6):1385-1391
Echinosporamicin ( 1 ), a novel antibiotic containing an aromatic polycyclic system and a piperazinone moiety, was isolated from the fermentation broth of a new strain of Micromonospora echinospora subspecies echinospora, LL‐P175. The structure of this compound was determined by spectroscopic analysis by using variable‐temperature NMR techniques. Compound 1 exhibited potent activity against methicillin‐resistant Staphylococci and vancomycin‐resistant Enterococci strains. The methyl, ethyl, and benzyl esters showed improved antibacterial activity against Streptococci. 相似文献
16.
Dr. Cecilia C. Russell Dr. Andrew Stevens Kelly A. Young Jennifer R. Baker Siobhann N. McCluskey Dr. Manouchehr Khazandi Hongfei Pi Dr. Abiodun Ogunniyi Dr. Stephen W. Page Prof. Darren J. Trott Prof. Adam McCluskey 《ChemistryOpen》2019,8(7):896-907
Robenidine (E)-N′-((E)-1-(4-chlorophenyl)ethylidene)-2-(1-(4-chlorophenyl)ethylidene)hydrazine-1-carboximidhydrazide displays methicillin-resistant Staphyoccoccus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) MICs of 2 μg mL−1. Herein we describe the structure-activity relationship development of a novel series of guanidine to 2-aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2-NH2 pyrimidine moiety renders these analogues inactive. Introduction of a central 2-NH2 triazine moiety saw a 10-fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4-BrPh and 4-CH3Ph with MIC values of 2 and 4 μg mL−1, against MRSA and VRE respectively, are promising candidates for future development. 相似文献
17.
Cecily Eldridge Gracia Quek Michael Sako John H. Ryan Simon Saubern Mary Chebib James M. Macdonald 《Tetrahedron》2018,74(12):1245-1252
Four histrionicotoxin analogues were prepared in an efficient manner utilizing a nitrone dipolar cycloaddition reaction as the key step in forming tricyclic intermediate 13. The nitrile in intermediate 13 was reduced with DIBAL to an aldehyde which then underwent Z-selective Wittig reactions to produce intermediates containing the Z-alkene side-chain. Hydrogenation of the Z-alkenes produced saturated histrionicotoxin analogues whereas reduction with SmI2 afforded the unsaturated histrionicotoxin analogues. The histrionicotoxin analogues were shown to be potent non-competitive antagonists of the α4β2 and α7 nAChR's with the most potent analogue 3 displaying IC50's of 0.10 μM and 0.45 μM against the α4β2 and α7 nAChR's, respectively. The unsaturated analogues 15 and 18 displayed Hill slope (nH) of approximately 1 whilst the saturated analogues 16 and 3 had a nH of approximately 0.5, which may indicate that the saturated analogues are binding to more than one binding site. 相似文献
18.
Total Synthesis and Conformational Study of Callyaerin A: Anti‐Tubercular Cyclic Peptide Bearing a Rare Rigidifying (Z)‐2,3‐ Diaminoacrylamide Moiety
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Shengping Zhang Luis M. De Leon Rodriguez Ivanhoe K. H. Leung Gregory M. Cook Paul W. R. Harris Margaret A. Brimble 《Angewandte Chemie (International ed. in English)》2018,57(14):3631-3635
The first synthesis of the anti‐TB cyclic peptide callyaerin A ( 1 ), containing a rare (Z)‐2,3‐diaminoacrylamide bridging motif, is reported. Fmoc‐formylglycine‐diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor to 1 . Intramolecular cyclization between the formylglycine residue and the N‐terminal amine in the linear peptide precursor afforded the macrocyclic natural product 1 . Synthetic 1 possessed potent anti‐TB activity (MIC100=32 μm ) while its all‐amide congener was inactive. Variable‐temperature NMR studies of both the natural product and its all‐amide analogue revealed the extraordinary rigidity imposed by this diaminoacrylamide unit on peptide conformation. The work reported herein pinpoints the intrinsic role that the (Z)‐2,3‐diaminoacrylamide moiety confers on peptide bioactivity. 相似文献
19.
Madhava Rao Mannam Srimurugan S. Pramod Kumar R. S. Prasad K 《Journal of heterocyclic chemistry》2019,56(8):2179-2191
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
20.
Jhonsee Rani Telu Naveen Kuntala Kavitha Kankanala Venkanna Banothu Sarbani Pal Jaya Shree Anireddy 《Journal of heterocyclic chemistry》2021,58(4):969-982
We describe the synthesis, characterization, and in vitro antibacterial evaluation of a library of novel compounds based on 1,2,3-triazolo phosphonate framework along with the evaluation of DNA gyrase inhibitory potential of a promising molecule in silico. Preparation of these compounds was carried out via a multistep sequence comprising of the Abramov reaction followed by the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) as the key steps. Various α-hydroxyphosphonate derivatives containing either a secondary or tertiary alcohol at the α position were prepared. When screened for their antibacterial activities in vitro using a Gram-positive (Staphylococcus aureus) and three Gram-negative (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa) strains, majority of these derivatives exhibited reasonable to good effects with the analogue 5k being active against all the strains. The SAR analysis indicated that the activity was influenced by the position of the α-hydroxyphosphonate moiety as well as the substituent present on the benzene ring attached to the 1,2,3-triazole ring. Moreover, the compound 5k showed strong interactions with the DNA active site when docked into the DNA gyrase in silico. Thus, the 1,2,3-triazolo phosphonate derivative 5k appeared to be a novel and promising hit molecule that deserves further study as a potential antibacterial agent. 相似文献