Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Bioorg Med Chem Lett ; 27(22): 5014-5021, 2017 11 15.
Article in English | MEDLINE | ID: mdl-29032026

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 µg/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8 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 Relationship
2.
ACS Chem Biol ; 4(6): 473-83, 2009 Jun 19.
Article in English | MEDLINE | ID: mdl-19413326

ABSTRACT

As part of our effort to inhibit bacterial fatty acid biosynthesis through the recently validated target biotin carboxylase, we employed a unique combination of two emergent lead discovery strategies. We used both de novo fragment-based drug discovery and virtual screening, which employs 3D shape and electrostatic property similarity searching. We screened a collection of unbiased low-molecular-weight molecules and identified a structurally diverse collection of weak-binding but ligand-efficient fragments as potential building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment costructures, we improved the potency of the initial hits by up to 3000-fold while maintaining their ligand-efficiency and desirable physicochemical properties. In one example, hit-expansion efforts resulted in a series of amino-oxazoles with antibacterial activity. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents.


Subject(s)
Anti-Bacterial Agents/pharmacology , Carbon-Nitrogen Ligases/antagonists & inhibitors , Drug Discovery/methods , Enzyme Inhibitors/pharmacology , Anti-Bacterial Agents/chemistry , Binding Sites , Carbon-Nitrogen Ligases/metabolism , Combinatorial Chemistry Techniques , Enzyme Inhibitors/chemistry , Ligands , Microbial Sensitivity Tests , Molecular Weight , Structure-Activity Relationship
3.
Proc Natl Acad Sci U S A ; 106(6): 1737-42, 2009 Feb 10.
Article in English | MEDLINE | ID: mdl-19164768

ABSTRACT

As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.


Subject(s)
Anti-Bacterial Agents/chemistry , Carbon-Nitrogen Ligases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Discovery , Drug Evaluation, Preclinical , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Haemophilus influenzae/drug effects , Haemophilus influenzae/enzymology , Moraxella catarrhalis/drug effects , Moraxella catarrhalis/enzymology , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Small Molecule Libraries
4.
J Med Chem ; 50(24): 5886-9, 2007 Nov 29.
Article in English | MEDLINE | ID: mdl-17988109

ABSTRACT

Oxazolidinones possessing a C-5 carboxamide functionality (reverse amides) represent a new series of compounds that block bacterial protein synthesis. These reverse amides also exhibited less potency against monoamine oxidase (MAO) enzymes and thus possess less potential for the side effects associated with MAO inhibition. The title compound (14) showed reduced in vivo myelotoxicity compared to linezolid in a 14-day safety study in rats, potent in vivo efficacy in murine systemic infection models, and excellent pharmacokinetic properties.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Cyclic S-Oxides/chemical synthesis , Oxazolidinones/chemical synthesis , Acetamides/pharmacology , Administration, Oral , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Biological Availability , Cyclic S-Oxides/pharmacology , Cyclic S-Oxides/toxicity , Dogs , Drug Resistance, Bacterial , Female , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Injections, Intravenous , Linezolid , Male , Mice , Microbial Sensitivity Tests , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/toxicity , Oxazolidinones/pharmacology , Oxazolidinones/toxicity , Rats , Rats, Sprague-Dawley , Staphylococcal Infections/drug therapy , Staphylococcus aureus , Streptococcal Infections/drug therapy , Streptococcus pyogenes , Structure-Activity Relationship
5.
J Pharm Sci ; 93(5): 1131-41, 2004 May.
Article in English | MEDLINE | ID: mdl-15067690

ABSTRACT

The pharmaceutical industry has large investments in compound library enrichment, high throughput biological screening, and biopharmaceutical (ADME) screening. As the number of compounds submitted for in vitro ADME screens increases, data analysis, interpretation, and reporting will become rate limiting in providing ADME-structure-activity relationship information to guide the synthetic strategy for chemical series. To meet these challenges, a software tool was developed and implemented that enables scientists to explore in vitro and in silico ADME and chemistry data in a multidimensional framework. The present work integrates physicochemical and ADME data, encompassing results for Caco-2 permeability, human liver microsomal half-life, rat liver microsomal half-life, kinetic solubility, measured log P, rule of 5 descriptors (molecular weight, hydrogen bond acceptors, hydrogen bond donors, calculated log P), polar surface area, chemical stability, and CYP450 3A4 inhibition. To facilitate interpretation of this data, a semicustomized software solution using Spotfire was designed that allows for multidimensional data analysis and visualization. The solution also enables simultaneous viewing and export of chemical structures with the corresponding ADME properties, enabling a more facile analysis of ADME-structure-activity relationship. In vitro and in silico ADME data were generated for 358 compounds from a series of human immunodeficiency virus protease inhibitors, resulting in a data set of 5370 experimental values which were subsequently analyzed and visualized using the customized Spotfire application. Implementation of this analysis and visualization tool has accelerated the selection of molecules for further development based on optimum ADME characteristics, and provided medicinal chemistry with specific, data driven structural recommendations for improvements in the ADME profile.


Subject(s)
Chemistry, Pharmaceutical/methods , Drug Design , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , Absorption , Animals , Caco-2 Cells , Humans , Microsomes, Liver/metabolism , Rats , Software , Solubility , Tissue Distribution
SELECTION OF CITATIONS
SEARCH DETAIL
...