ABSTRACT
The continued emergence of bacteria resistant to current standard of care antibiotics presents a rapidly growing threat to public health. New chemical entities (NCEs) to treat these serious infections are desperately needed. Herein we report the discovery, synthesis, SAR and in vivo efficacy of a novel series of 4-hydroxy-2-pyridones exhibiting activity against Gram-negative pathogens. Compound 1c, derived from the N-debenzylation of 1b, preferentially inhibits bacterial DNA synthesis as determined by standard macromolecular synthesis assays. The structural features of the 4-hydroxy-2-pyridone scaffold required for antibacterial activity were explored and compound 6q, identified through further optimization of the series, had an MIC90 value of 8⯵g/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8â¯mg/kg in mice infected with a lethal dose of E. coli. This novel series of 4-hydroxy-2-pyridones serves as an excellent starting point for the identification of NCEs treating Gram-negative infections.
Subject(s)
Anti-Bacterial Agents/metabolism , Azabicyclo Compounds/chemistry , DNA/metabolism , Niacin/analogs & derivatives , Pyridines/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds/metabolism , Azabicyclo Compounds/pharmacology , Azabicyclo Compounds/therapeutic use , DNA/chemistry , Drug Evaluation, Preclinical , Escherichia coli/drug effects , Escherichia coli/pathogenicity , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/microbiology , Gram-Negative Bacterial Infections/veterinary , Half-Life , Mice , Microbial Sensitivity Tests , Niacin/metabolism , Niacin/pharmacology , Niacin/therapeutic use , Pyridines/metabolism , Pyridines/pharmacology , Pyridines/therapeutic use , Structure-Activity RelationshipABSTRACT
A successful enone version of an intramolecular aza-[3 + 3] annulation reaction is described here. Use of piperidinium trifluoroacetate salt as the catalyst and toluene as the solvent appears to be critical for a successful annulation. We also demonstrated for the first time that microwave irradiation can accelerate aza-[3 + 3] annulation reactions. An attempt to expand the scope of the enone aza-[3 + 3] annulation was made in the form of propyleine synthesis as a proof of concept. While synthesis of the enone annulation precursor was successfully accomplished, the annulation proved to be challenging and was only modestly successful.
ABSTRACT
There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure-activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds 6o and 6v showed improved MIC90 values against Escherichia coli (0.5-1 µg/mL) and Acinetobacter baumannii (8-16 µg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of E. coli.
Subject(s)
Anti-Bacterial Agents/pharmacology , DNA Topoisomerases, Type II/chemistry , Drug Discovery , Drug Resistance, Multiple, Bacterial/drug effects , Gram-Negative Bacteria/drug effects , Sepsis/drug therapy , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Female , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Protein Conformation , Pyridines/chemistry , Sepsis/microbiology , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemistryABSTRACT
[structure: see text] A stereodivergent approach toward total syntheses of Coccinellidae defensive alkaloids is described. These syntheses feature a highly diastereoselective intramolecular aza-[3 + 3] annulation strategy, which represents a de novo approach to this family of natural products.
Subject(s)
Alkaloids/chemical synthesis , Cyclic N-Oxides/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Quinazolines/chemical synthesis , Alkaloids/chemistry , Animals , Coleoptera/chemistry , Cyclic N-Oxides/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Molecular Structure , Quinazolines/chemistry , StereoisomerismABSTRACT
Complex piperidinyl heterocycles (for example, 2) were accessed by using a novel intramolecular formal [3+3] cycloaddition reaction of vinylogous amides tethered with enals (for example, 1). This method has been applied to a formal total synthesis of (+)-gephyrotoxin (3).
ABSTRACT
An enantioselective and diastereoselective aza-[3+3] annulation of pyrrolidine-based exo-cyclic vinylogous amides and urethanes with chiral vinyl iminium salts is described. This asymmetric annulation manifold is possible because of an unexpected regiochemical reversal whereby head-to-tail annulations dominated over the predicted head-to-head. It should find prevalent synthetic applications in the enantioselective synthesis of indolizidines.
Subject(s)
Aza Compounds/chemistry , Indolizidines/chemical synthesis , Molecular Structure , StereoisomerismABSTRACT
The first success in constructing a member of quinolizidine family of alkaloids employing an intramolecular aza-[3 + 3] annulation strategy is described here. The key feature is the usage of vinylogous urethane tethered to a vinyl iminium intermediate with trifluoroacetate serving as the counter anion. The proof-of-concept is illustrated with the synthesis of 2-deoxy-lasubine II.
ABSTRACT
A detailed account on the stereoselective total syntheses of azaphenalene alkaloids via an intramolecular aza-[3+3] annulation strategy is described here. All five members of the Coccinellidae family of defensive alkaloids were prepared from the same common intermediate, which was derived from a stereoselective aza-[3+3] annulation reaction.
Subject(s)
Alkaloids/chemistry , Aza Compounds/chemistry , Carmine/analogs & derivatives , Carmine/chemical synthesis , Carmine/chemistry , Lactams/chemistry , Models, Molecular , Molecular Structure , Oxidation-Reduction , Propanols/chemistry , Quinazolines/chemistry , Water/chemistryABSTRACT
Total syntheses of indoloquinolizidine alkaloid (+/-)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids.
Subject(s)
Indole Alkaloids/chemical synthesis , Indole Alkaloids/chemistry , Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
A detailed account on chiral secondary amine salt promoted enantioselective intramolecular formal aza-[3 + 3] cycloadditions is described here for the first time. The dependence of enantioselectivity on the structural feature of these chiral amines is thoroughly investigated. This study also reveals a very interesting reversal of the stereochemistry in the respective cycloadducts obtained using C(1)- and C(2)-symmetric amine salts. In addition, the influence of solvents, counteranions, and temperatures on the enantioselectivity is described, and a unified mechanistic model based on experimental results as well as semiempirical calculations is proposed.
Subject(s)
Amines/chemistry , Heterocyclic Compounds/chemical synthesis , Models, Chemical , Catalysis , Crystallography, X-Ray , Cyclization , Molecular Conformation , Molecular Structure , Salts/chemistry , StereoisomerismABSTRACT
Evidence is described here to support that a highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes is a key step in formal [3 + 3] cycloaddition or annulation reactions of chiral vinylogous amides with alpha,beta-unsaturated iminium salts. This would represent the first highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes. We have also unambiguously demonstrated that these specific ring closures are reversible, leading to the major diastereomer that is also thermodynamically more stable, and that a rotation preference likely also plays a role. A synthetic application is illustrated here to stereoselectively transform the resulting dihydropyridines to cis-1-azadecalins with unique anti relative stereochemistry at C2 and C2a, leading to synthesis of epi isomers of (-)-pumiliotoxin C.
Subject(s)
Alkaloids/chemical synthesis , Amphibian Venoms/chemical synthesis , Naphthalenes/chemical synthesis , Quinolines , Alkaloids/chemistry , Alkenes/chemistry , Amphibian Venoms/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Cyclization , Naphthalenes/chemistry , StereoisomerismABSTRACT
A detailed account regarding a formal [3 + 3] cycloaddition method using 4-hydroxy-2-pyrones and 1,3-diketones is described here. This formal cycloaddition reaction or annulation reaction is synthetically useful for constructing 2H-pyranyl heterocycles. The usage of alpha,beta-unsaturated iminium salts is significant in controlling competing reaction pathways to give exclusively 2H-pyrans. Most significantly, experimental evidence is provided to support the mechanism of this reaction that involves a sequential Knoevenagel condensation and a reversible 6pi-electron electrocyclic ring-closure of 1-oxatrienes.