Fluorinated captopril analogues inhibit metallo-β-lactamases and facilitate structure determination of NDM-1 binding pose.

Bacterial resistance to the majority of clinically used β-lactam antibiotics is a global health threat and, consequently, the driving force for the development of metallo-β-lactamase (MBL) inhibitors. The rapid evolution of new MBLs calls for new strategies and tools for inhibitor development. In this study, we designed and developed a series of trifluoromethylated captopril analogues as probes for structural studies of enzyme-inhibitor binding.

Polymyxin B stabilized DNA micelles for sustained antibacterial and antibiofilm activity against .

Nucleic acid-based materials showcase an increasing potential for antimicrobial drug delivery. Although numerous reports on drug-loaded DNA nanoparticles outline their pivotal antibacterial activities, their potential as drug delivery systems against bacterial biofilms awaits further studies. Among different oligonucleotide structures, micellar nanocarriers derived from amphiphilic DNA strands are of particular interest due to their spontaneous self-assembly and high biocompatibility.

Amphipathic barbiturates as marine product mimics with cytolytic and immunogenic effects on head and neck squamous cell carcinoma cell lines.

The incidence of head and neck squamous cell carcinoma (HNSCC) is increasing and the conventional treatments for this form of cancer can be tough. Despite the success of existing immunotherapies in some HNSCC patients, many do not respond to this type of treatment. Thus, the development of novel anti-cancer therapies should be prioritized.

Investigation of tetrasubstituted heterocycles reveals hydantoins as a promising scaffold for development of novel antimicrobials with membranolytic properties.

Mimics of antimicrobial peptides (AMPs) have been proposed as a promising class of antimicrobial agents. We report the analysis of five tetrasubstituted, cationic, amphipathic heterocycles as potential AMP mimics. The analysis showed that the heterocyclic scaffold had a strong influence on the haemolytic activity of the compounds, and the hydantoin scaffold was identified as a promising template for drug lead development.

Tailored anti-biofilm activity - Liposomal delivery for mimic of small antimicrobial peptide.

The eradication of bacteria embedded in biofilms is among the most challenging obstacles in the management of chronic wounds. These biofilms are found in most chronic wounds; moreover, the biofilm-embedded bacteria are considerably less susceptible to conventional antimicrobial treatment than the planktonic bacteria. Antimicrobial peptides and their mimics are considered attractive candidates in the pursuit of novel therapeutic options for the treatment of chronic wounds and general bacterial eradication.

The marine natural product mimic MPM-1 is cytolytic and induces DAMP release from human cancer cell lines.

Bioprospecting contributes to the discovery of new molecules with anticancer properties. Compounds with cytolytic activity and the ability to induce immunogenic cell death can be administered as intratumoral injections with the aim to activate anti-tumor immune responses by causing the release of tumor antigens as well as damage-associated molecular patterns (DAMPs) from dying cancer cells. In the present study, we report the cytolytic and DAMP-releasing effects of a new natural product mimic termed MPM-1 that was inspired by the marine Eusynstyelamides.

A concise SAR-analysis of antimicrobial cationic amphipathic barbiturates for an improved activity-toxicity profile.

An amphipathic barbiturate mimic of the marine eusynstyelamides is reported as a promising class of antimicrobial agents. We hereby report a detailed analysis of the structure-activity relationship for cationic amphipathic N,N'-dialkylated-5,5-disubstituted barbiturates. The influence of various cationic groups, hydrocarbon linkers and lipophilic side chains on the compounds' antimicrobial potency and haemolytic activity was studied.

Amphipathic Barbiturates as Mimics of Antimicrobial Peptides and the Marine Natural Products Eusynstyelamides with Activity against Multi-resistant Clinical Isolates.

We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These ,'-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2-8 μg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase-carbapenemase production.

Unequivocal structure confirmation of a breitfussin analog by anisotropic NMR measurements.

Structural features of proton-deficient heteroaromatic natural products, such as the breitfussins, can severely complicate their characterization by NMR spectroscopy. For the breitfussins in particular, the constitution of the five-membered oxazole central ring cannot be unequivocally established conventional NMR methods when the 4'-position is halogenated. The level of difficulty is exacerbated by 4'-iodination, as the accuracy with which theoretical NMR parameters are determined relies extensively on computational treatment of the relativistic effects of the iodine atom.

Total Synthesis of Phorbazole B.

Phorbazoles are polychlorinated heterocyclic secondary metabolites isolated from a marine sponge and several of these natural products have shown inhibitory activity against cancer cells. In this work, a synthesis of the trichlorinated phorbazole B using late stage electrophilic chlorination was developed. The synthesis relied on the use of an oxazole precursor, which was protected with an iodine in the reactive 4-position, followed by complete chlorination of all pyrrole positions.

Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-β-lactamases.

Metallo-β-lactamases (MBLs) are an emerging cause of bacterial antibiotic resistance by hydrolysing all classes of β-lactams except monobactams, and the MBLs are not inhibited by clinically available serine-β-lactamase inhibitors. Two of the most commonly encountered MBLs in clinical isolates worldwide - the New Delhi metallo-β-lactamase (NDM-1) and the Verona integron-encoded metallo-β-lactamase (VIM-2) - are included in this study. A series of several NH-1,2,3-triazoles was prepared by a three-step protocol utilizing Banert cascade reaction as the key step.

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens .

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options.

Carbonylative Suzuki-Miyaura couplings of sterically hindered aryl halides: synthesis of 2-aroylbenzoate derivatives.

We have developed a carbonylative approach to the synthesis of diversely substituted 2-aroylbenzoate esters featuring a new protocol for the carbonylative coupling of aryl bromides with boronic acids and a new strategy to favour carbonylative over non-carbonylative reactions. Two different synthetic pathways - (i) the alkoxycarbonylation of 2-bromo benzophenones and (ii) the carbonylative Suzuki-Miyaura coupling of 2-bromobenzoate esters - were evaluated. The latter approach provided a broader substrate tolerance, and thus was the preferred pathway.

Caesium fluoride-mediated hydrocarboxylation of alkenes and allenes: scope and mechanistic insights.

A caesium fluoride-mediated hydrocarboxylation of olefins is disclosed that does not rely on precious transition metal catalysts and ligands. The reaction occurs at atmospheric pressures of CO in the presence of 9-BBN as a stoichiometric reductant. Stilbenes, β-substituted styrenes and allenes could be carboxylated in good yields.

Formal C-H Carboxylation of Unactivated Arenes.

A formal C-H carboxylation of unactivated arenes using CO in green solvents is described. The present strategy combines a sterically controlled Ir-catalyzed C-H borylation followed by a Cu-catalyzed carboxylation of the in situ generated organoboronates. The reaction is highly regioselective for the C-H carboxylation of 1,3-disubstituted and 1,2,3-trisubstituted benzenes, 1,2- or 1,4-symmetrically substituted benzenes, fluorinated benzenes and different heterocycles.

Exploration of New Biomass-Derived Solvents: Application to Carboxylation Reactions.

A range of hitherto unexplored biomass-derived chemicals have been evaluated as new sustainable solvents for a large variety of CO -based carboxylation reactions. Known biomass-derived solvents (biosolvents) are also included in the study and the results are compared with commonly used solvents for the reactions. Biosolvents can be efficiently applied in a variety of carboxylation reactions, such as Cu-catalyzed carboxylation of organoboranes and organoboronates, metal-catalyzed hydrocarboxylation, borocarboxylation, and other related reactions.

Iron-Catalyzed Carbenoid-Transfer Reactions of Vinyl Sulfoxonium Ylides: An Experimental and Computational Study.

A method for the generation of unprecedented vinyl carbenoids from sulfoxonium ylides has been developed and applied in the synthesis of a diverse array of heterocycles such as indolizines, pyrroles, 3-pyrrolin-2-ones, and furans. The reactions proceed by FeBr catalysis under mild reaction conditions with a broad substrate scope. A reaction pathway involving iron carbenoids is proposed based on a series of control experiments and DFT calculations.

An amphipathic cyclic tetrapeptide scaffold containing halogenated β -amino acids with activity against multiresistant bacteria.

The present study describes the synthesis and biological studies of a small series of head-to-tail cyclic tetrapeptides of the general structure c(Lys-β -Xaa-Lys) containing one lipophilic β -amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram-positive and gram-negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β-lactamase-carbapenemase (ESBL-CARBA) production. Toxicity was determined against human red blood cells.

A focused fragment library targeting the antibiotic resistance enzyme - Oxacillinase-48: Synthesis, structural evaluation and inhibitor design.

β-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of β-lactam resistance. The most prevalent resistance mechanism to β-lactam antibiotics is expression of β-lactamase enzymes.

Securamine Derivatives from the Arctic Bryozoan Securiflustra securifrons.

Bryozoans belonging to the Flustridae family have proven to be a rich source of structurally unique secondary metabolites. As part of our continuing search for bioactive secondary metabolites from Arctic marine invertebrates, the organic extract of Securiflustra securifrons was examined. This resulted in the isolation of three new halogenated, hexacyclic indole-imidazole alkaloids, securamines H-J (1-3), together with the previously reported compounds securamines C (4) and E (5).

Rhodium-Catalyzed Synthesis of Sulfur Ylides via in Situ Generated Iodonium Ylides.

A convenient strategy for the synthesis of sulfur ylides via rhodium-catalyzed coupling of in situ generated iodonium ylides with sulfides or sulfoxides has been developed. A wide range of sulfur ylides were obtained in moderate to good yields from inexpensive sulfur compounds and active methylene compounds with a short reaction time (MW, 5-10 min) or 12-16 h at rt. Furthermore, these sulfoxonium ylides were used as novel acceptor/acceptor carbenes for N-H insertion reactions.

Structural Insights into TMB-1 and the Role of Residues 119 and 228 in Substrate and Inhibitor Binding.

Metallo-β-lactamases (MBLs) threaten the effectiveness of β-lactam antibiotics, including carbapenems, and are a concern for global public health. β-Lactam/β-lactamase inhibitor combinations active against class A and class D carbapenemases are used, but no clinically useful MBL inhibitor is currently available. Tripoli metallo-β-lactamase-1 (TMB-1) and TMB-2 are members of MBL subclass B1a, where TMB-2 is an S228P variant of TMB-1.

Metallo-β-lactamase inhibitors by bioisosteric replacement: Preparation, activity and binding.

Bacterial resistance is compromising the use of β-lactam antibiotics including carbapenems. The main resistance mechanism against β-lactams is hydrolysis of the β-lactam ring mediated by serine- or metallo-β-lactamases (MBLs). Although several inhibitors of MBLs have been reported, none has been developed into a clinically useful inhibitor.