59 research outputs found
Indium-mediated allylation and Reformatsky reaction on glyoxylic oximes under ultrasound irradiation
A novel and more convenient method for the indium-promoted allylation of glyoxylic oximes based on the use of ultrasonic waves is reported. A similar procedure was used to develop the first example reported in the literature of an indium-mediated Reformatsky reaction on oxime ethersThis work was supported by the Spanish Ministry of Science and Innovation (CTQ2008-06493 and CTQ2009-08490). A.M.E. thanks the Spanish Ministry of Science and Innovation for an FPU grantS
Iron(III) complexation by Vanchrobactin, a siderophore of the bacterial fish pathogen Vibrio anguillarum
The bacterial fish pathogen Vibrio anguillarum serotype O2 strain RV22 produces the mono catecholate siderophore Vanchrobactin (Vb) under conditions of iron deficiency. Vb contains two potential bidentate coordination sites: catecholate and salicylate groups. The iron(iii) coordination properties of Vb is investigated in aqueous solutions using spectrophotometric and potentiometric methods. The stepwise equilibrium constants (logK) for successive addition of Vb dianion to a ferric ion are 19.9; 13.3, and 9.5, respectively, for an overall association constant of 42.7. Based on the previous results, we estimated the equilibrium concentration of free iron(iii) under physiological conditions for pH 7.4 solution containing 10-6 M total iron and 10-5 M total Vb as pFe = 20 (=-log[Fe3+]). The Vb model compounds catechol (Cat) and 2,4-dihydroxy-N-(2-hydroxyethyl)benzamide (Dhb) have also been examined, and the obtained results show that the interaction of the whole system of Vb that contains the ferric-chelating groups of both Dhb and Cat, is synergically greater than the separate parts; i.e. Vb is the best chelating agent either in acid or basic media. In summary, bacteria employing Vb-mediated iron transport thus are able to compete effectively for iron with other microorganisms within which they live.Ministerio de Educación y Ciencia; CTQ2008-04429Ministerio de Educación y Ciencia; CTQ2005-00793Galicia. Consellería de Economía e Industria; 10PXIB103157P
Ethyl 1-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-5-[(2′S)-tetrahydropyran-2-yloxy]-d-glycero-α-d-manno-heptofuronate
The title compound {systematic name: (2S,3R)-ethyl 3-[(3aS,4R,6S,6aS)-6-tert-butyldimethylsilyloxy-2,2-dimethylperhydrofuro[3,4-d][1,3]dioxol-4-yl]-2-nitro-3-[(S)-tetrahydro-2H-pyran-2-yloxy]propanoate}, C23H41NO10Si, is the product of the Henry reaction of 1-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-α-d-lyxo-pentadialdo-1,4-furanose with ethyl nitroacetate and the subsequent protection of its C-5 hydroxy group as tetrahydropyranyl, in order to avoid the retro-Henry reaction. The tetrahydropyranyl group adopts a chair conformation. The absolute configuration, assumed from the synthesis, was confirmed from the diffraction data
A C˄S-cyclometallated gold(III) complex as novel antibacterial candidate against drug-resistant bacteria
The worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed for antibacterial applications. Among them, gold(III) complexes have received increasing attention as metal-based anticancer agents. However, reports on their antibacterial activity are scarce due to stability issues. The present work demonstrates the antibacterial activity of the gold(III) complex 2 stabilized as C∧S-cycloaurated containing a diphenylphosphinothioic amide moiety, showing minimum inhibitory concentration (MIC) values that ranged from 4 to 8 and from 16 to 32 mg/L among Gram-positive and Gram-negative multidrug-resistant (MDR) pathogens, respectively. Complex 2 has a biofilm inhibitory activity of only two to four times than its MIC. We also describe for the first time a potent antibacterial synergistic effect of a gold(III) complex combined with colistin, showing a bactericidal effect in less than 2 h; confirming the role of the outer membrane as a permeability barrier. Complex 2 shows a low rate of internalization in Staphylococcus aureus and Acinetobacter baumannii; it does not interact with replication enzymes or efflux pumps, causes ultrastructural damages in both membrane and cytoplasmic levels, and permeabilizes the bacterial membrane. Unlike control antibiotics, complex 2 did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC50 = 25.5 μM) and no acute toxicity signs in vivo after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex 2 as a new chemical class of antimicrobial agents
New Morphiceptin Peptidomimetic Incorporating (1S,2R,3S,4S,5R)-2-Amino-3,4,5-trihydroxycyclopen-tane-1-carboxylic acid: Synthesis and Structural Study
We present the synthesis and structural study of a new peptidomimetic of morphiceptin, which can formally be considered as the result of the replacement of the central proline residue of this natural analgesic drug with a subunit of (1S,2R,3S,4S,5R)-2-amino-3,4,5-trihydroxycyclopentane-1-carboxylic acid, previously obtained from L-idose. An optimized synthesis of this trihydroxylated cispentacin derivative is also reported. Molecular docking calculations on the target receptor support a favorable role of the hydroxy substituents of the non-natural β-amino acid incorporated into the peptidomimeticThis work has received financial support from the Spanish Ministry of Science and Innovation (CTQ2009-08490), the Xunta de Galicia (Centro Singular de Investigación de Galicia, Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03; Project CN2011/037, project ED431C 2018/04 and Project GRC2014/040), the Principado de Asturias (FICYT IDI/2018/000181) and the European Union (European Regional Development Fund-ERDF). Partial financial support by Arcelor Mittal (R&D-Principado de Asturias; FUO-286-18). Conicyt research fellowship to ML (PFCHA/Doctorado Nacional/2018-21180427)S
Stereoselective Synthesis of Orthogonally Protected 1,2-Diaminoinositols from D-Mannose
We present herein a promising novel strategy for the transformation of sugar aldehydes into 1,2-diaminoinositols. This process, based on the sequential intermolecular aza-Henry reaction and intermolecular Henry reaction allowed the total synthesis of a 1,2-diaminoinositols with total stereochemical control. The new route constitutes a simpler and more efficient approach than those previously described routes to 1,2-diaminoinositols and it has the additional advantage of offering the possibility of orthogonal protection of the amino groups
Gold(III) Complexes Activity Against Multidrug-Resistant Bacteria Of Veterinary Significance
The emergence and spread of multidrug-resistant bacteria are a global concern. The lack of new antibiotics in the pipeline points to the need for developing new strategies. In this sense, gold(III) complexes (G3Cs) could be a promising alternative due to their recently described antibacterial activity. The aim of this study was to evaluate the antimicrobial activity of G3Cs alone and in combination with colistin against pathogenic bacteria from veterinary sources. Minimal inhibitory concentration (MIC) values were determined by broth microdilution and compared with clinically relevant antibiotics. Antibiofilm activity was determined by crystal violet staining. Combinations of selected G3Cs with colistin and cytotoxicity in commercial human cell lines were evaluated. Four and seven G3Cs showed antibacterial effect against Gram-negative and Gram-positive strains, respectively, with this activity being higher among Gram-positive strains. The G3Cs showed antibiofilm activity against Gram-negative species at concentrations similar or one to four folds higher than the corresponding MICs. Combination of G3Cs with colistin showed a potential synergistic antibacterial effect reducing concentrations and toxicity of both agents. The antimicrobial and antibiofilm activity, the synergistic effect when combined with colistin and the in vitro toxicity suggest that G3Cs would provide a new therapeutic alternative against multidrug-resistant bacteria from veterinary origin
Novel gold(III)-dithiocarbamate complex targeting bacterial thioredoxin reductase: antimicrobial activity, synergy, toxicity, and mechanistic insights
IntroductionAntimicrobial resistance is a pressing global concern that has led to the search for new antibacterial agents with novel targets or non-traditional approaches. Recently, organogold compounds have emerged as a promising class of antibacterial agents. In this study, we present and characterize a (C^S)-cyclometallated Au(III) dithiocarbamate complex as a potential drug candidate.Methods and resultsThe Au(III) complex was found to be stable in the presence of effective biological reductants, and showed potent antibacterial and antibiofilm activity against a wide range of multidrug-resistant strains, particularly gram-positive strains, and gram-negative strains when used in combination with a permeabilizing antibiotic. No resistant mutants were detected after exposing bacterial cultures to strong selective pressure, indicating that the complex may have a low propensity for resistance development. Mechanistic studies indicate that the Au(III) complex exerts its antibacterial activity through a multimodal mechanism of action. Ultrastructural membrane damage and rapid bacterial uptake suggest direct interactions with the bacterial membrane, while transcriptomic analysis identified altered pathways related to energy metabolism and membrane stability including enzymes of the TCA cycle and fatty acid biosynthesis. Enzymatic studies further revealed a strong reversible inhibition of the bacterial thioredoxin reductase. Importantly, the Au(III) complex demonstrated low cytotoxicity at therapeutic concentrations in mammalian cell lines, and showed no acute in vivo toxicity in mice at the doses tested, with no signs of organ toxicity.DiscussionOverall, these findings highlight the potential of the Au(III)-dithiocarbamate scaffold as a basis for developing novel antimicrobial agents, given its potent antibacterial activity, synergy, redox stability, inability to produce resistant mutants, low toxicity to mammalian cells both in vitro and in vivo, and non-conventional mechanism of action
New Morphiceptin Peptidomimetic Incorporating (1S,2R,3S,4S,5R)-2-Amino-3,4,5-trihydroxycyclopen-tane-1-carboxylic acid: Synthesis and Structural Study
We present the synthesis and structural study of a new peptidomimetic of morphiceptin, which can formally be considered as the result of the replacement of the central proline residue of this natural analgesic drug with a subunit of (1S,2R,3S,4S,5R)-2-amino-3,4,5-trihydroxycyclopentane-1-carboxylic acid, previously obtained from L-idose. An optimized synthesis of this trihydroxylated cispentacin derivative is also reported. Molecular docking calculations on the target receptor support a favorable role of the hydroxy substituents of the non-natural β-amino acid incorporated into the peptidomimetic
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