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Antibiotics (Basel, Switzerland) Dec 2022The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial...
The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial agents remains an important drug target. From this perspective, new derivatives of benzothiazole were synthesized and evaluated for their antimicrobial activity and ability to inhibit the DHPS enzyme. The synthesis was carried out by the reaction of benzothiazole -arylsulphonylhydrazone with -aryl-2-cyano-3-(dimethylamino)acrylamide, -aryl-3-(dimethylamino)prop-2-en-1-one, arylaldehydes or diazonium salt of arylamine derivatives, which led to the formation of -arylsulfonylpyridones (yield 60-70%) and - (yield 50-60%)-(2-(benzo[]thiazole-2-yl)-3-arylacryloyl-4-methylsulfonohydrazide - (yield 60-65%) 4-(benzo[]thiazole-2-yl)-5-aryl-1-pyrazol-3(2)-one - (yield 65-75%), and -(2-(benzo[]thiazol-2-yl)-2-(2-arylhydrazono)acetyl)-4-arylsulfonohydrazide - (yield 85-70%). The antimicrobial evaluations resulted into a variety of microbial activities against the tested strains. Most compounds showed antimicrobial activity against with an MIC range of 0.025 to 2.609 mM. The most active compound, , exhibited superior activity against the strain with an of MIC 0.025 mM among all tested compounds, outperforming both standard drugs ampicillin and sulfadiazine. The physicochemical-pharmacokinetic properties of the synthesized compounds were studied, and it was discovered that some compounds do not violate rule of five and have good bioavailability and drug-likeness scores. The five antimicrobial potent compounds with good physicochemical-pharmacokinetic properties were then examined for their inhibition of DHPS enzyme. According to the finding, three compounds, -, had IC values comparable to the standard drug and revealed that compound was the most active compound with an IC value of 7.85 μg/mL, which is comparable to that of sulfadiazine (standard drug) with an IC value of 7.13 μg/mL. A docking study was performed to better understand the interaction of potent compounds with the binding sites of the DHPS enzyme, which revealed that compounds - are linked by two arene-H interactions with Lys220 within the PABA pocket.
PubMed: 36551457
DOI: 10.3390/antibiotics11121799 -
Chemical Science Nov 2022Forging carbon-carbon (C-C) linkage in DNA-encoded combinatorial library synthesis represents a fundamental task for drug discovery, especially with broad substrate...
Forging carbon-carbon (C-C) linkage in DNA-encoded combinatorial library synthesis represents a fundamental task for drug discovery, especially with broad substrate scope and exquisite functional group tolerance. Here we reported the palladium-catalyzed Suzuki-Miyaura, Heck and Hiyama type cross-coupling DNA-conjugated aryl diazonium intermediates for DNA-encoded chemical library (DEL) synthesis. Starting from commodity arylamines, this synthetic route facilely delivers vast chemical diversity at a mild temperature and pH, thus circumventing damage to fragile functional groups. Given its orthogonality with traditional aryl halide-based cross-coupling, the aryl diazonium-centered strategy expands the compatible synthesis of complex C-C bond-connected scaffolds. In addition, DNA-tethered pharmaceutical compounds (, HDAC inhibitor) are constructed without decomposition of susceptible bioactive warheads (, hydroxamic acid), emphasizing the superiority of the aryl diazonium-based approach. Together with the convenient transformation into an aryl azide photo-crosslinker, aryl diazonium's DNA-compatible diversification synergistically demonstrated its competence to create medicinally relevant combinatorial libraries and investigate protein-ligand interactions in pharmaceutical research.
PubMed: 36425486
DOI: 10.1039/d2sc04482j -
ACS Chemical Biology Nov 2022Finding the targets of natural products is of key importance in both chemical biology and drug discovery, and deconvolution of cofactor interactomes contributes to the...
Finding the targets of natural products is of key importance in both chemical biology and drug discovery, and deconvolution of cofactor interactomes contributes to the functional annotation of the proteome. Identifying the proteins that underlie natural compound activity in phenotypic screens helps to validate the respective targets and, potentially, expand the druggable proteome. Here, we present a generally applicable protocol for the photoactivated immobilization of unmodified and microgram quantities of natural products on diazirine-decorated beads and their use for systematic affinity-based proteome profiling. We show that among 31 molecules of very diverse reported activity and biosynthetic origin, 25 could indeed be immobilized. Dose-response competition binding experiments using lysates of human or bacterial cells followed by quantitative mass spectrometry recapitulated targets of 9 molecules with <100 μM affinity. Among them, immobilization of coenzyme A produced a tool to interrogate proteins containing a HotDog domain. Surprisingly, immobilization of the cofactor flavin adenine dinucleotide (FAD) led to the identification of nanomolar interactions with dozens of RNA-binding proteins.
Topics: Humans; Proteome; Diazomethane; Biological Products; Flavin-Adenine Dinucleotide; Mass Spectrometry
PubMed: 36302507
DOI: 10.1021/acschembio.2c00500 -
Molecules (Basel, Switzerland) Sep 2022As a promising therapy, photothermal therapy (PTT) converts near-infrared (NIR) light into heat through efficient photothermal agents (PTAs), causing a rapid increase in...
As a promising therapy, photothermal therapy (PTT) converts near-infrared (NIR) light into heat through efficient photothermal agents (PTAs), causing a rapid increase in local temperature. Considering the importance of PTAs in the clinical application of PTT, the safety of PTAs should be carefully evaluated before their widespread use. As a promising PTA, mesoporous polydopamine (MPDA) was studied for its clinical applications for tumor photothermal therapy and drug delivery. Given the important role that intestinal microflora plays in health, the impacts of MPDA on the intestine and on intestinal microflora were systematically evaluated in this study. Through biological and animal experiments, it was found that MPDA exhibited excellent biocompatibility, in vitro and in vivo. Moreover, 16S rRNA analysis demonstrated that there was no obvious difference in the composition and classification of intestinal microflora between different drug delivery groups and the control group. The results provided new evidence that MPDA was safe to use in large doses via different drug delivery means, and this lays the foundation for further clinical applications.
Topics: Animals; Diazonium Compounds; Gastrointestinal Microbiome; Hyperthermia, Induced; Indoles; Intestines; Nanoparticles; Phototherapy; Polymers; Pyridines; RNA, Ribosomal, 16S
PubMed: 36234997
DOI: 10.3390/molecules27196461 -
Molecules (Basel, Switzerland) Sep 2022A strategy for the synthesis of 5-((2-cyanoethyl)-X-amino)-[1,2,3]triazolo[4,5-][1,2,5]oxadiazol-5-ium-4-ides (X = H; CHCHCN; NO (); CN (); COEt ()) starting from...
Anions Containing Tripoid Conjugated N System: Salts of 5-(Substituted Amino)-[1,2,3]triazolo[4,5-][1,2,5]oxadiazol-5-ium-4-ides, as well as Their Synthesis, Structure, and Thermal Stability.
A strategy for the synthesis of 5-((2-cyanoethyl)-X-amino)-[1,2,3]triazolo[4,5-][1,2,5]oxadiazol-5-ium-4-ides (X = H; CHCHCN; NO (); CN (); COEt ()) starting from 3-amino-4-azido-1,2,5-oxadiazole was developed. The key step in this strategy is the intramolecular thermolytic cyclization of the azido group and the bis(2-cyanoethyl)triazene group. Removal of the 2-cyanoethyl protecting group from amides - gave potassium salt of the corresponding nitramide and sodium salts of cyano- and ethoxycarbonylamide. The structure and thermal stability of the synthesized compounds were studied experimentally using multinuclear NMR spectroscopy, X-ray crystallography, thermogravimetry, and differential scanning calorimetry.
Topics: Amides; Anions; Nitrogen Dioxide; Oxadiazoles; Potassium; Salts; Sodium; Triazenes
PubMed: 36234825
DOI: 10.3390/molecules27196287 -
Frontiers in Chemistry 2022The exploration of novel nitrogen-rich heterocyclic building blocks is of importance in the field of energetic materials. A series of...
The exploration of novel nitrogen-rich heterocyclic building blocks is of importance in the field of energetic materials. A series of 2-(1,2,4-triazole-5-yl)-1,3,4-oxadiazole derivatives based on a new energetic skeleton have been first synthesized by a simple synthetic strategy. All three compounds are well-characterized by IR spectroscopy, NMR spectroscopy and thermal analysis. The compounds and are further characterized by single-crystal X-ray diffraction analysis. and its salts (-) possess relative high decomposition temperature and low sensitivity, while exhibits low decomposition temperature and high sensitivity. According to EXPLO5 calculation results of detonation performance, both and display acceptable detonation velocities () of 8450 m/s and 8130 m/s and detonation pressures () of 31.6 GPa and 29.2 GPa, respectively. Furthermore, containing a rare diazonium ylide structure shows high impact sensitivity (4.5 J), making it has a potential as a primary explosive.
PubMed: 36092665
DOI: 10.3389/fchem.2022.996812 -
ChemMedChem Oct 2022Identifying the protein targets of drugs is an important but tedious process. Existing proteomic approaches enable unbiased target identification but lack the throughput...
Identifying the protein targets of drugs is an important but tedious process. Existing proteomic approaches enable unbiased target identification but lack the throughput needed to screen larger compound libraries. Here, we present a compound interaction screen on a photoactivatable cellulose membrane (CISCM) that enables target identification of several drugs in parallel. To this end, we use diazirine-based undirected photoaffinity labeling (PAL) to immobilize compounds on cellulose membranes. Functionalized membranes are then incubated with protein extract and specific targets are identified via quantitative affinity purification and mass spectrometry. CISCM reliably identifies known targets of natural products in less than three hours of analysis time per compound. In summary, we show that combining undirected photoimmobilization of compounds on cellulose with quantitative interaction proteomics provides an efficient means to identify the targets of natural products.
Topics: Biological Products; Cellulose; Diazomethane; Mass Spectrometry; Proteins; Proteomics
PubMed: 35867055
DOI: 10.1002/cmdc.202200346 -
Journal of the American Society of... Oct 2022Barlow's mitral valve disease with late systolic mitral regurgitation provides diagnostic and therapeutic challenges. The mechanisms of the regurgitation are still...
OBJECTIVES
Barlow's mitral valve disease with late systolic mitral regurgitation provides diagnostic and therapeutic challenges. The mechanisms of the regurgitation are still unclear. We hypothesized that the onset and the severity of late systolic regurgitation are determined by annulus dynamics and the mechanical stresses imposed by the left ventricle.
METHODS
Ten patients with Barlow's mitral valve disease and mitral annulus disjunction (MAD) were compared with 10 healthy controls. Resting blood pressure was measured, and transthoracic three-dimensional echocardiography was analyzed using a holographic display that allows tracking and measurements of mitral annulus surface area (ASA) throughout the cardiac cycle. A novel annulus elastance index (dASA/dP) was calculated between aortic valve opening and onset of mitral regurgitation. Severity of MAD was quantified as the disjunction index (mm × degree). Leaflet coaptation area was calculated using a finite element model.
RESULTS
Peak systolic ASAs in controls and patients were 9.3 ± 0.6 and 21.1 ± 3.1 cm, respectively (P < .001). In patients, the ASA increased rapidly during left ventricular ejection, and onset of mitral regurgitation coincided closely with peak upslope of annulus area change (dASA/dt). The finite element model showed a close association between rapid annulus displacement and coaptation area deficit in Barlow's mitral valve disease. Systolic annulus elastance index (0.058 ± 0.036 cm/mm Hg) correlated strongly with disjunction index (r = 0.91, P < .0001). Moreover, regurgitation volume showed a positive correlation with systolic blood pressure (r = 0.80, P < .01).
CONCLUSION
The present pilot study supports the hypothesis that annulus dilatation may accentuate mitral valve regurgitation in patients with Barlow's mitral valve disease. A novel annulus elastance index may predict the severity of mitral valve regurgitation in selected patients.
Topics: Diazonium Compounds; Elasticity; Humans; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Pilot Projects; Sulfanilic Acids
PubMed: 35842077
DOI: 10.1016/j.echo.2022.07.001 -
Biochimica Et Biophysica Acta.... Oct 2022Although the incorporation of photo-activatable lipids into membranes potentially opens new avenues for studying interactions with peptides and proteins, the question of...
Although the incorporation of photo-activatable lipids into membranes potentially opens new avenues for studying interactions with peptides and proteins, the question of whether azide- or diazirine-modified lipids are suitable for such studies remains controversial. We have recently shown that diazirine-modified lipids can indeed form cross-links to membrane peptides after UV activation and that these cross-links can be precisely determined in their position by mass spectrometry (MS). However, we also observed an unexpected backfolding of the lipid's diazirine-containing stearoyl chain to the membrane interface challenging the potential application of this modified lipid for future cross-linking (XL)-MS studies of protein/lipid interactions. In this work, we compared an azide- (AzidoPC) and a diazirine-modified (DiazPC) membrane lipid regarding their self-assembly properties, their mixing behavior with saturated bilayer-forming phospholipids, and their reactivity upon UV activation using differential scanning calorimetry (DSC), dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), and MS. Mixtures of both modified lipids with DMPC were further used for photo-chemically induced XL experiments with a transmembrane model peptide (KLAW23) to elucidate similarities and differences between the azide and the diazirine moiety. We showed that both photo-reactive lipids can be used to study lipid/peptide and lipid/protein interactions. The AzidoPC proved easier to handle, whereas the DiazPC had fewer degradation products and a higher cross-linking yield. However, the problem of backfolding occurs in both lipids; thus, it seems to be a general phenomenon.
Topics: Azides; Cross-Linking Reagents; Diazomethane; Mass Spectrometry; Membrane Lipids; Peptides; Scattering, Small Angle; X-Ray Diffraction
PubMed: 35841926
DOI: 10.1016/j.bbamem.2022.184004 -
Journal of the American Chemical Society May 2022Biocatalytic carbene transfer from diazo compounds is a versatile strategy in asymmetric synthesis. However, the limited pool of stable diazo compounds constrains the...
Biocatalytic carbene transfer from diazo compounds is a versatile strategy in asymmetric synthesis. However, the limited pool of stable diazo compounds constrains the variety of accessible products. To overcome this restriction, we have engineered variants of protoglobin (Pgb) that use diazirines as carbene precursors. While the enhanced stability of diazirines relative to their diazo isomers enables access to a diverse array of carbenes, they have previously resisted catalytic activation. Our engineered Pgb variants represent the first example of catalysts for selective carbene transfer from these species at room temperature. The structure of an Pgb variant, determined by microcrystal electron diffraction (MicroED), reveals that evolution has enhanced access to the heme active site to facilitate this new-to-nature catalysis. Using readily prepared aryl diazirines as model substrates, we demonstrate the application of these highly stable carbene precursors in biocatalytic cyclopropanation, N-H insertion, and Si-H insertion reactions.
Topics: Azo Compounds; Biocatalysis; Catalysis; Diazomethane; Methane
PubMed: 35561334
DOI: 10.1021/jacs.2c02723