ABSTRACT
A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.
Subject(s)
Acinetobacter baumannii/drug effects , Anti-Bacterial Agents/pharmacology , DNA Gyrase/metabolism , Drug Design , Escherichia coli/drug effects , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Line , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Mice , Mice, Knockout , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistryABSTRACT
A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.
Subject(s)
Anti-Bacterial Agents , DNA Cleavage , DNA Gyrase , Thiophenes , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Crystallography, X-Ray , DNA Gyrase/chemistry , DNA Gyrase/metabolism , Drug Discovery , Models, Molecular , Thiophenes/chemistry , Thiophenes/metabolismABSTRACT
A direct and specific comparison of a trifluoromethyl group with the corresponding pentafluorosulfanyl group is made in terms of primary affinity and pharmacokinetic properties.
Subject(s)
Azabicyclo Compounds/chemistry , Fluorine/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Receptors, Dopamine D3/antagonists & inhibitors , Sulfur/chemistry , Triazoles/chemistry , Animals , Azabicyclo Compounds/pharmacokinetics , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Humans , Rats , Receptors, Dopamine D3/metabolism , Triazoles/pharmacokineticsABSTRACT
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
Subject(s)
Depressive Disorder/drug therapy , Heptanes/chemistry , Heptanes/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Brain/metabolism , Depressive Disorder/metabolism , Dopamine/metabolism , Heptanes/chemical synthesis , Humans , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Microdialysis , Models, Molecular , Neurotransmitter Uptake Inhibitors/chemical synthesis , Norepinephrine/metabolism , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
Herein we report a detailed description of the structure-activity relationships for a novel series of "C-linked" 1,2,4-triazolylazabicyclo[3.1.0]hexanes. These derivatives are endowed with very high in vitro affinity and selectivity for the dopamine D(3) receptor. An optimization with respect to undesired affinity toward the hERG potassium channel is also reported. Members of this compound series also show excellent in vitro and in vivo pharmacokinetic properties.
Subject(s)
Aza Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Hexanes/chemistry , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/chemistry , Animals , Binding Sites , Computer Simulation , Hexanes/chemical synthesis , Hexanes/pharmacokinetics , Humans , Rats , Receptors, Dopamine D3/metabolism , Structure-Activity RelationshipABSTRACT
The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
Subject(s)
Azabicyclo Compounds/pharmacology , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacokinetics , Binding, Competitive , Biogenic Monoamines/metabolism , Biological Availability , Biological Transport/drug effects , Cell Line , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Humans , Male , Mice , Microdialysis , Microsomes, Liver/metabolism , Models, Chemical , Molecular Structure , Motor Activity/drug effects , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Prefrontal Cortex/metabolism , Rats , Structure-Activity RelationshipABSTRACT
The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.
Subject(s)
Hexanes/chemistry , Hexanes/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Cell Membrane/drug effects , Cell Membrane/metabolism , Computer Simulation , Drug Design , Guinea Pigs , Humans , Male , Models, Animal , Models, Chemical , Molecular Structure , Receptors, Dopamine D3/biosynthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
Subject(s)
Benzazepines/chemical synthesis , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/chemical synthesis , Acetylcholine/metabolism , Administration, Oral , Alcohol Drinking/prevention & control , Animals , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Brain/blood supply , Brain/metabolism , Cocaine/pharmacology , Conditioning, Operant/drug effects , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Guinea Pigs , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/pharmacology , Humans , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D3/agonists , Receptors, Histamine H1/metabolism , Structure-Activity Relationship , Tobacco Use Disorder/prevention & control , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
Ramoplanin is a glycolipodepsipeptide antibiotic active against Gram-positive bacteria including vancomycin-resistant enterococci. Ramoplanin inhibits bacterial cell wall biosynthesis by a mechanism different from that of glycopeptides and hence does not show cross-resistance with these antibiotics. The systemic use of ramoplanin has been so far prevented because of its low local tolerability when injected intravenously. To overcome this problem, the fatty acid side chain of ramoplanin was selectively removed and replaced with a variety of different carboxylic acids. Many of the new ramoplanin derivatives showed antimicrobial activity similar to that of the natural precursor coupled with a significantly improved local tolerability. Among them the derivative in which the 2-methylphenylacetic acid has replaced the di-unsaturated fatty acid side chain (48) was selected as the most interesting compound and submitted to further in vitro and in vivo characterization studies.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Depsipeptides/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida albicans/drug effects , Depsipeptides/chemistry , Depsipeptides/pharmacology , Enterococcus faecalis/drug effects , Hemolysis , Microbial Sensitivity Tests , Rats , Staphylococcus aureus/drug effects , Stereoisomerism , Streptococcus pyogenes/drug effects , Structure-Activity RelationshipABSTRACT
Two independent approaches resulted in the identification of a series of isoindolone derivatives as potent and selective 5-HT2C antagonists. From a Medicinal Chemistry perspective this template was considered interesting as it allowed the incorporation of the carbon-carbon double bond of an earlier dihydropyrrolone series in an aromatic system within a comparatively simple and compact motif. Additionally an in silico screening approach of the corporate database using a 5-HT2C pharmacophore model resulted in the identification of a related structure containing this template. The strategy used to optimise potency at the target receptor and to improve the pharmacokinetic profile is described, resulting in molecules combining high potency with good selectivity and oral bioavailability.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Receptor, Serotonin, 5-HT2C/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Animals , Biological Availability , Databases, Factual , Drug Design , Drug Evaluation, Preclinical , Humans , Isoindoles , Male , Rats , Structure-Activity RelationshipABSTRACT
Within the continuous quest for the discovery of novel compounds able to treat anxiety and depression, the generation of a pharmacophore model for 5-HT2C receptor antagonists and the discovery of a new class of potent and selective 5-HT2C molecules are reported.