A5002533565- Synthesis and biological activity
- Chemical Synthesis and Analysis
- Sulfur-Based Synthesis Techniques
- Antibiotic Resistance in Bacteria
- Synthesis and Catalytic Reactions
- X-ray Diffraction in Crystallography
- Research on Leishmaniasis Studies
- Trypanosoma species research and implications
- Crystallization and Solubility Studies
- Synthesis and Biological Evaluation
- Chemical Synthesis and Reactions
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthesis of heterocyclic compounds
- Pneumocystis jirovecii pneumonia detection and treatment
- Chemical Reaction Mechanisms
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Organoselenium and organotellurium chemistry
- Synthesis and Characterization of Heterocyclic Compounds
- Organic Chemistry Cycloaddition Reactions
- Quinazolinone synthesis and applications
- Tuberculosis Research and Epidemiology
- Antibiotics Pharmacokinetics and Efficacy
- Parasites and Host Interactions
- Synthetic Organic Chemistry Methods
- Synthesis of β-Lactam Compounds
Universidad de la República de Uruguay
2015-2025
Rede de Química e Tecnologia
1998-2019
Universidad La República
2019
Universidad de Montevideo
2016
University of Bristol
2015
Centro Uruguayo de Imagenología Molecular
1999-2012
University of Pittsburgh
2005
TU Dortmund University
1997
Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, B3), complicating development of βLIs effective against enzymes. Bisthiazolidines (BTZs) carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both l- d-BTZ enantiomers micromolar competitive MBL in vitro, Kis 6-15 µM...
Pathogenic Gram-negative bacteria resistant to almost all β-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-β-lactamases (MBLs) produced by these inactivate most antibiotics, including the carbapenems, which "last line therapies" for life-threatening infections. NDM-1 is carbapenemase belonging MBL family that rapidly spreading worldwide. Regrettably, inhibitors of MBLs not yet developed. Here we present bisthiazolidine (BTZ) scaffold as structure with some...
β-Lactamase inhibitors (BLIs) restore the efficacy of otherwise obsolete β-lactams. However, commercially available BLIs are not effective against metallo-β-lactamases (MBLs), which continue to be disseminated globally. One group most clinically important MBLs is VIM family. The discovery VIM-24, a natural variant VIM-2, possessing an R228L substitution and novel phenotype, compelled us explore role this position its effects on substrate specificity. We employed mutagenesis, biochemical...
Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems among the most potent antimicrobial agents that commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need prolonging lifetime these life-saving drugs. Here we report...
Antimicrobial resistance is a global public health threat. Metallo-β-lactamases (MBLs) inactivate β-lactam antibiotics, including carbapenems, are disseminating among Gram-negative bacteria, and lack clinically useful inhibitors. The evolving bisthiazolidine (BTZ) scaffold inhibits all three MBL subclasses (B1-B3). We report design, synthesis, evaluation of BTZ analogues. Structure-activity relationships identified the thiol as essential, while carboxylate replaceable, with its removal...
Abstract Background Cefiderocol (FDC) is a novel cephalosporin with siderophore-mimicking moiety that favors uptake into the periplasm through iron transporters. FDC was reported as only refractory to hydrolysis by metallo-β-Lactamases (MBLs). However, resistance has been due substitutions in transporter coupled expression of MBLs NDM-1 and NDM-5. In contrast, emergence involving other such VIM or IMP are not known. We aimed identify interaction NDM MBLs.Table 1.Kinetic parameters different...
ABSTRACT Tebipenem pivoxil has potent in vitro activity against Enterobacterales pathogens, but requires combination with β-lactamase inhibitor to achieve carbapenemase producers, including metallo-β-lactamases (MBLs). Herein, we evaluate the potential of tebipenem pivoxil, alone and prodrug experimental MBL CS319 (CS319-piv-SAc), disrupt indigenous mice microbiota colon promote colonization by pathogens. The effect antibiotic treatment (daily for 3 days subcutaneous saline [control],...
New dynamic combinatorial libraries (DCLs) were generated using the reversible aminothiol exchange reaction of thiazolidines and aromatic aldehydes. The proceeded in aqueous buffered media at pH 4 room temperature to generate thermodynamically controlled mixtures heterocycles. synthesis an enantiomerically pure thiazolidinyloxazolidine is also reported. oxazolidine moiety could be exchanged CH2Cl2 presence catalytic p-TsOH.
A series of 18 novel 2-hydrazolyl-4-thiazolidinones-5-carboxylic acids, amides and 5,6-α,β-unsaturated esters were synthesized, their in vitro activity on cruzipain T. cruzi epimastigotes was determined. Some agents show at 37 μm concentration the enzyme assay. Computational tools docking used to correlate biological response with physicochemical parameters compounds inhibitory effects.
The cysteine protease cruzipain is an essential T. cruzienzyme and one of the few validated drug targets for Chagas disease. Thiosemicarbazones have been described as inhibitors. While searching new antichagasic drugs, we synthesized a series selenosemicarbazone analogs demonstrated that isosteric replacement sulfur atom with selenium resulted in enhancement inhibitory effect. Three selenosemicarbazones were characterized enzymatically proved to be reversible, slow-binding inhibitors...
Metallo-β-lactamase (MBL) production in Gram-negative bacteria is an important contributor to β-lactam antibiotic resistance. Combining β-lactams with β-lactamase inhibitors (BLIs) a validated route overcoming resistance, but MBL are not available the clinic. On basis of zinc utilization and sequence, MBLs divided into three subclasses, B1, B2, B3, whose differing active-site architectures hinder development BLIs capable "cross-class" inhibition. We previously described 2-mercaptomethyl...
Herein, we describe an approach toward selenazole preparation based on the cycloisomerization of propargyl selenoamides. The selenoamides were synthesized in situ using Ishihara reagent with spontaneous cyclization to form 2,5-disubstituted selenazoles. Heterocylcles 9a-j prepared readily available starting materials, and yields ranged from moderate good (20-80%). Methylselenazole 9a could be transformed into a bromomethyl derivative 13 NBS. intermediate would provide more versatile building...
Reversible metathesis reactions of pyrazolotriazinones and aliphatic aldehydes or ketones proceed in aqueous, phosphate-buffered media at pH 4 40−60 °C to generate thermodynamically controlled mixtures heterocycles.
The synthesis of fused heterocycles such as thiazolidinyl-oxazolidine 3 is described starting from Tris·HCl. mercaptomethyl bisoxazolidine 8 was found to convert the corresponding thiazolidinyloxazolidine and spiro-heterocycle 4 by a ring-chain-ring tautomerism, depending on electronic nature ring substituents well reaction conditions. This equilibration pathway absent in hydroxymethyl bisoxazolidines 2. Computational studies confirm that both kinetic thermodynamic control features play role...