ABSTRACT
DNA gyrase is an essential enzyme in bacteria, and its inhibition results in the disruption of DNA synthesis and, subsequently, cell death. The pyrrolamides are a novel class of antibacterial agents targeting DNA gyrase. These compounds were identified by a fragment-based lead generation (FBLG) approach using nuclear magnetic resonance (NMR) screening to identify low-molecular-weight compounds that bind to the ATP pocket of DNA gyrase. A pyrrole hit with a binding constant of 1 mM formed the basis of the design and synthesis of a focused library of compounds that resulted in the rapid identification of a lead compound that inhibited DNA gyrase with a 50% inhibitory concentration (IC(50)) of 3 µM. The potency of the lead compound was further optimized by utilizing iterative X-ray crystallography to yield DNA gyrase inhibitors that also displayed antibacterial activity. Spontaneous mutants were isolated in Staphylococcus aureus by plating on agar plates containing pyrrolamide 4 at the MIC. The resistant variants displayed 4- to 8-fold-increased MIC values relative to the parent strain. DNA sequencing revealed two independent point mutations in the pyrrolamide binding region of the gyrB genes from these variants, supporting the hypothesis that the mode of action of these compounds was inhibition of DNA gyrase. Efficacy of a representative pyrrolamide was demonstrated against Streptococcus pneumoniae in a mouse lung infection model. These data demonstrate that the pyrrolamides are a novel class of DNA gyrase inhibitors with the potential to deliver future antibacterial agents targeting multiple clinical indications.
Subject(s)
Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Pyrroles/pharmacology , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Topoisomerase II Inhibitors , Amides/chemistry , Animals , Anti-Bacterial Agents/chemistry , Binding Sites , Crystallography, X-Ray , DNA Gyrase/chemistry , DNA Gyrase/metabolism , Drug Resistance, Bacterial , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Microbial Sensitivity Tests , Models, Molecular , Mutation , Protein Binding , Pyrroles/chemistry , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/genetics , Staphylococcus aureus/growth & development , Streptococcus pneumoniae/growth & developmentABSTRACT
Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.
Subject(s)
Prostatic Neoplasms/drug therapy , Pyridazines/pharmacology , Receptors, Androgen/metabolism , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Humans , Ligands , Male , Models, Molecular , Molecular Structure , Molecular Weight , Prostatic Neoplasms/metabolism , Pyridazines/chemical synthesis , Pyridazines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Substitution of phenyl oxazolidinones with carbon-linked azoles resulted in the discovery of a new class of potent oxazolidinones that have excellent Gram-positive activity. In addition, replacement of the C-5 acetamide side chains with a 4-methyl triazole diminished monoamine oxidase activity. The synthesis and biological evaluation of these compounds are reported.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Animals , Anti-Bacterial Agents/pharmacokinetics , Biological Availability , Colony Count, Microbial , Female , Gram-Positive Bacteria/drug effects , Half-Life , Humans , Liver/enzymology , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/pharmacology , Pneumococcal Infections/drug therapy , Pneumococcal Infections/microbiology , Rats , Streptococcus pneumoniae/drug effects , Structure-Activity RelationshipABSTRACT
Oxazolidinones represent a new and promising class of antibacterial agents. Current research in this area is mainly concentrated on improving the safety profile and the antibacterial spectrum. Many oxazolidinones, including linezolid (marketed as Zyvox), are inhibitors of monoamine oxidase A (MAO-A), which presents an undesired side effect. Recently, it was found that the 1,2,3-triazole is a good replacement for the conventional acetamide functionality found in oxazolidinones. We now disclose the finding that 1,2,3-triazoles bearing a substituent like methyl, small substituted methyl, bromo, or a linear (sp-hybridized) group at the 4 position (compounds such as 5, 16, 19, and 21) are good antibacterials with reduced or no activity, within the detection limit of the assay, against MAO-A. The results are especially promising for the development of oxazolidinones with an improved safety profile. The MAO-A SAR can be rationalized on the basis of docking studies to a MAO-A/MAO-B homology model.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase/metabolism , Oxazolidinones/chemical synthesis , Triazoles/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Haemophilus influenzae/drug effects , Microbial Sensitivity Tests , Models, Molecular , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
Carbonylcobalt(0) species have been used as linkers between alkynes and a polymer support for the first time. The alkynes may be loaded indirectly onto a phosphine functionalised polymer via their hexacarbonyldicobalt(0) complex, or directly onto a cobalt coated polymer. The alkynes have been released either as alkynes, thus providing a traceless method of immobilising alkynes, or by reaction with an alkene to generate a cyclopentenone via the Pauson-Khand reaction. The cobalt coated polymers produced during this study were shown to catalyse the Pauson-Khand reaction.
