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Molecules (Basel, Switzerland) May 2024An efficient access to the novel 5-(aryl)amino-1,2,3-triazole-containing 2,1,3-benzothiadiazole derivatives has been developed. The method is based on 1,3-dipolar...
An efficient access to the novel 5-(aryl)amino-1,2,3-triazole-containing 2,1,3-benzothiadiazole derivatives has been developed. The method is based on 1,3-dipolar azide-nitrile cycloaddition followed by Buchwald-Hartwig cross-coupling to afford the corresponding -aryl and ,-diaryl substituted 5-amino-1,2,3-triazolyl 2,1,3-benzothiadiazoles under NHC-Pd catalysis. The one-pot diarylative Pd-catalyzed heterocyclization opens the straightforward route to triazole-linked carbazole-benzothiadiazole D-A systems. The optical and electrochemical properties of the compound obtained were investigated to estimate their potential application as emissive layers in OLED devises. The quantum yield of photoluminescence (PLQY) of the synthesized D-A derivatives depends to a large extent on electron-donating strengths of donor (D) component, reaching in some cases the values closed to 100%. Based on the most photoactive derivative and wide bandgap host material mCP, a light-emitting layer of OLED was made. The device showed a maximum brightness of 8000 cd/m at an applied voltage of 18 V. The maximum current efficiency of the device reaches a value of 3.29 cd/A.
PubMed: 38731642
DOI: 10.3390/molecules29092151 -
Molecules (Basel, Switzerland) May 2024Copper-catalyzed azide-alkyne cycloaddition click (CuAAC) reaction is widely used to synthesize drug candidates and other biomolecule classes. Homogeneous catalysts,...
Copper-catalyzed azide-alkyne cycloaddition click (CuAAC) reaction is widely used to synthesize drug candidates and other biomolecule classes. Homogeneous catalysts, which consist of copper coordinated to a ligand framework, have been optimized for high yield and specificity of the CuAAC reaction, but CuAAC reaction with these catalysts requires the addition of a reducing agent and basic conditions, which can complicate some of the desired syntheses. Additionally, removing copper from the synthesized CuAAC-containing biomolecule is necessary for biological applications but inconvenient and requires additional purification steps. We describe here the design and synthesis of a PNN-type pincer ligand complex with copper (I) that stabilizes the copper (I) and, therefore, can act as a CuAAC catalyst without a reducing agent and base under physiologically relevant conditions. This complex was immobilized on two types of resin, and one of the immobilized catalyst forms worked well under aqueous physiological conditions. Minimal copper leaching was observed from the immobilized catalyst, which allowed its use in multiple reaction cycles without the addition of any reducing agent or base and without recharging with copper ion. The mechanism of the catalytic cycle was rationalized by density functional theory (DFT). This catalyst's utility was demonstrated by synthesizing coumarin derivatives of small molecules such as ferrocene and sugar.
Topics: Copper; Click Chemistry; Ligands; Catalysis; Azides; Cycloaddition Reaction; Alkynes; Coumarins; Ferrous Compounds; Metallocenes; Molecular Structure
PubMed: 38731638
DOI: 10.3390/molecules29092148 -
Chemical Science May 2024Ferrocene and its derivatives have fascinated chemists for more than 70 years, not least due to the analogies with the properties of benzene. Despite these similarities,...
Ferrocene and its derivatives have fascinated chemists for more than 70 years, not least due to the analogies with the properties of benzene. Despite these similarities, the obvious difference between benzene and ferrocene is the presence of an iron ion and hence the availability of d-orbitals for properties and reactivity. Phenylnitrene with its rich photochemistry can be considered an analogue of nitrenoferrocene. As with most organic and inorganic nitrenes, nitrenoferrocene can be obtained by irradiating the azide precursor. We study the photophysical and photochemical processes of dinitrogen release from 1,1'-diazidoferrocene to form 1-azido-1'-nitrenoferrocene with UV-pump-mid-IR-probe transient absorption spectroscopy and time-dependent density functional theory calculations including spin-orbit coupling. An intermediate with a bent azide moiety is identified that is pre-organised for dinitrogen release a low-lying transition state. The photochemical decay paths on the singlet and triplet surfaces including the importance of spin-orbit coupling are discussed. We compare our findings with the processes discussed for photochemical dinitrogen activation and highlight implications for the photochemistry of azides more generally.
PubMed: 38725494
DOI: 10.1039/d4sc00883a -
Journal of the American Chemical Society May 2024The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC,...
The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.
PubMed: 38712910
DOI: 10.1021/jacs.4c03348 -
Beilstein Journal of Organic Chemistry 2024A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide and Heck...
A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE).
PubMed: 38711586
DOI: 10.3762/bjoc.20.81 -
Acta Biomaterialia Jun 2024Cascade-reaction containers generating reactive oxygen species (ROS) as an alternative for antibiotic-based strategies for bacterial infection control, require...
Cetyltrimethylammonium-chloride assisted in situ metabolic incorporation of nano-sized ROS-generating cascade-reaction containers in Gram-positive and Gram-negative peptidoglycan layers for the control of bacterially-induced sepsis.
Cascade-reaction containers generating reactive oxygen species (ROS) as an alternative for antibiotic-based strategies for bacterial infection control, require endogenous oxygen-sources and ROS-generation close to or preferably inside target bacteria. Here, this is achieved by cetyltrimethylammonium-chloride (CTAC) assisted in situ metabolic labeling and incorporation of mesoporous SiO-nanoparticles, dual-loaded with glucose-oxidase and FeO-nanoparticles as cascade-reaction containers, inside bacterial cell walls. First, azide-functionalized d-alanine (D-Ala-N) was inserted in cell wall peptidoglycan layers of growing Gram-positive pathogens. In Gram-negatives, this could only be achieved after outer lipid-membrane permeabilization, using a low concentration of CTAC. Low concentrations of CTAC had no adverse effect on in vitro blood clotting or hemolysis nor on the health of mice when blood-injected. Next, dibenzocyclooctyne-polyethylene-glycol modified, SiO-nanoparticles were in situ click-reacted with d-Ala-N in bacterial cell wall peptidoglycan layers. Herewith, a two-step cascade-reaction is facilitated inside bacteria, in which glucose-oxidase generates HO at endogenously-available glucose concentrations, while subsequently FeO-nanoparticles catalyze generation of •OH from the HO generated. Generation of •OH inside bacterial cell walls by dual-loaded mesoporous SiO-nanoparticles yielded more effective in vitro killing of both planktonic Gram-positive and Gram-negative bacteria suspended in 10 % plasma than SiO-nanoparticles solely loaded with glucose-oxidase. Gram-positive or Gram-negative bacterially induced sepsis in mice could be effectively treated by in situ pre-treatment with tail-vein injected CTAC and d-Ala-N, followed by injection of dual-loaded cascade-reaction containers without using antibiotics. This makes in situ metabolic incorporation of cascade-reaction containers as described attractive for further investigation with respect to the control of other types of infections comprising planktonic bacteria. STATEMENT OF SIGNIFICANCE: In situ metabolic-incorporation of cascade-reaction-containers loaded with glucose-oxidase and FeO nanoparticles into bacterial cell-wall peptidoglycan is described, yielding ROS-generation from endogenous glucose, non-antibiotically killing bacteria before ROS inactivates. Hitherto, only Gram-positives could be metabolically-labeled, because Gram-negatives possess two lipid-membranes. The outer membrane impedes direct access to the peptidoglycan. This problem was solved by outer-membrane permeabilization using a quaternary-ammonium compound. Several studies on metabolic-labeling perform crucial labeling steps during bacterial-culturing that in real-life should be part of a treatment. In situ metabolic-incorporation as described, can be applied in well-plates during in vitro experiments or in the body as during in vivo animal experiments. Surprisingly, metabolic-incorporation proceeded unhampered in blood and a murine, bacterially-induced sepsis could be well treated.
Topics: Animals; Peptidoglycan; Reactive Oxygen Species; Sepsis; Mice; Nanoparticles; Silicon Dioxide; Gram-Positive Bacteria; Gram-Negative Bacteria
PubMed: 38702010
DOI: 10.1016/j.actbio.2024.04.045 -
NAR Molecular Medicine Apr 2024Antibiotic resistance poses a significant global health threat, necessitating innovative strategies to combat multidrug-resistant bacterial infections. , a pathogen...
Antibiotic resistance poses a significant global health threat, necessitating innovative strategies to combat multidrug-resistant bacterial infections. , a pathogen responsible for various infections, harbors highly conserved DNA quadruplexes in genes linked to its pathogenesis. In this study, we introduce a novel approach to counter antibiotic resistance by stabilizing G-quadruplex structures within the open reading frames of key resistance-associated genes (, and ). We synthesized , a bis-anthracene derivative, using Cu(I)-catalyzed azide-alkyne cycloaddition, which exhibited remarkable binding and stabilization of the G-quadruplex in the gene responsible for drug efflux. effectively permeated multidrug-resistant strains, leading to a substantial 12.5-fold reduction in ciprofloxacin resistance. Furthermore, downregulated gene expression, enhancing drug retention within bacterial cells. Remarkably, the G-quadruplex cloned into the pET28a(+) plasmid transformed into BL21 cells can template Cu-free bio-orthogonal synthesis of from its corresponding alkyne and azide fragments. This study presents a pioneering strategy to combat antibiotic resistance by genetically reducing drug efflux pump expression through G-quadruplex stabilization, offering promising avenues for addressing antibiotic resistance.
PubMed: 38694210
DOI: 10.1093/narmme/ugae005 -
RSC Advances Apr 2024The copper-free azide-alkyne click reaction has shown to be a successful alternative to immobilize covalently a fluorescente compound onto poly(-l-lactic) acid (PLLA)...
The copper-free azide-alkyne click reaction has shown to be a successful alternative to immobilize covalently a fluorescente compound onto poly(-l-lactic) acid (PLLA) surfaces. Proceded by basic hydrolysis and amidation reaction, typical surface characterization techniques have validated each functionaliztion step and the success of the conjugation. This method offers a catalyst-free option for various surface conjugations, extremely demanded in biomedical and biosensory fields.
PubMed: 38690116
DOI: 10.1039/d4ra01776e -
Journal of the American Chemical Society May 2024An ongoing challenge to chemists is the analysis of pathways and kinetics for chemical reactions in solution, including transient structures between the reactants and...
An ongoing challenge to chemists is the analysis of pathways and kinetics for chemical reactions in solution, including transient structures between the reactants and products that are difficult to resolve using laboratory experiments. Here, we enabled direct molecular dynamics simulations of a textbook series of chemical reactions on the hundreds of ns to μs time scale using the weighted ensemble (WE) path sampling strategy with hybrid quantum mechanical/molecular mechanical (QM/MM) models. We focused on azide-clock reactions involving addition of an azide anion to each of three long-lived trityl cations in an acetonitrile-water solvent mixture. Results reveal a two-step mechanism: (1) diffusional collision of reactants to form an ion-pair intermediate; (2) "activation" or rearrangement of the intermediate to the product. Our simulations yield not only reaction rates that are within error of experiment but also rates for individual steps, indicating the activation step as rate-limiting for all three cations. Further, the trend in reaction rates is due to dynamical effects, i.e., differing extents of the azide anion "crawling" along the cation's phenyl-ring "propellers" during the activation step. Our study demonstrates the power of analyzing pathways and kinetics to gain insights on reaction mechanisms, underscoring the value of including WE and other related path sampling strategies in the modern toolbox for chemists.
PubMed: 38687173
DOI: 10.1021/jacs.4c03360 -
RSC Advances Apr 2024Thiosemicarbazones of isatin have been found to exhibit versatile bioactivities. In this study, two distinct types of isatin-triazole hybrids 3a and 3b were accessed...
Thiosemicarbazones of isatin have been found to exhibit versatile bioactivities. In this study, two distinct types of isatin-triazole hybrids 3a and 3b were accessed copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC), together with their mono and bis-thiosemicarbazone derivatives 4a-h and 5a-h. In addition to the characterization by physical, spectral and analytical data, a DFT study was carried out to obtain the optimized geometries of all thiosemicarbazones. The global reactivity values showed that among the synthesized derivatives, 4c, 4g and 5c having nitro substituents are the most soft compounds, with compound 5c having the highest electronegativity and electrophilicity index values among the synthesized series, thus possessing strong binding ability with biomolecules. Molecular docking studies were performed to explore the inhibitory ability of the selected compounds against the active sites of the anticancer protein of phosphoinositide 3-kinase (PI3K). Among the synthesized derivatives, 4-nitro substituted bisthiosemicarbazone 5c showed the highest binding energy of -10.3 kcal mol. These findings demonstrated that compound 5c could be used as a favored anticancer scaffold the mechanism of inhibition against the PI3K signaling pathways.
PubMed: 38686286
DOI: 10.1039/d4ra01937g