ABSTRACT
During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
Subject(s)
Anti-Bacterial Agents/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Chemistry Techniques, Synthetic , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , Dogs , Drug Evaluation, Preclinical/methods , ERG1 Potassium Channel/metabolism , Gram-Negative Anaerobic Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Pneumococcal Infections/drug therapy , Rats , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/microbiology , Topoisomerase II Inhibitors/pharmacokineticsABSTRACT
During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
Subject(s)
Bacteria/enzymology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Dogs , Enzyme Activation/drug effects , Haplorhini , Humans , Microbial Sensitivity Tests , Molecular Structure , RatsABSTRACT
(1R,2S)-Norephedrine has been employed in the synthesis of a novel 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one via reductive alkylation with acetone, N-nitrosation, reduction, and cyclization. The oxadiazinone was treated with either propionyl chloride or 3-thiophenylpropionyl chloride to afford the corresponding N(3)-acylated oxadiazinones 9a and 9b, respectively. X-ray crystallographic analysis of the N(3)-thiophenylpropionyl oxadiazinone 9b revealed that the C(2)-urethane carbonyl and the N(3)-carbonyl are arranged in an anti-periplanar conformation. The oxadiazinones were subsequently applied in the titanium-mediated asymmetric aldol addition reaction by treatment with titanium tetrachloride, triethylamine, and a variety of aldehydes at 0 degrees C. The aldol adducts 10a-i and 11a,b were found to have diastereoselectivities ranging from 8:1 to >99:1 favoring the formation of the non-Evans syn configuration. The absolute stereochemistry of the adduct 10a was determined by acid hydrolysis. This process afforded the N(4)-isopropyloxadiazinone 8 and (2S,3S)-3-hydroxy-2-methyl-3-phenylpropanoic acid 14 in >/=95% enantiomeric excess.
Subject(s)
Acetone/chemistry , Nitrogen/chemistry , Oxadiazoles/chemical synthesis , Phenylpropanolamine/chemistry , Acylation , Aldehydes/chemistry , Alkylation , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Oxadiazoles/chemistry , Oxidation-Reduction , StereoisomerismABSTRACT
Pseudoephedrine-based [1,3,4]-oxadiazinan-2-ones acylated at the N(3)-position with either acetyl (2a), propionyl (2b), or phenylacetyl (2c) substituents are known to undergo conformational changes that are observable by (13)C NMR spectroscopy. The conformational properties of new [1,3,4]-oxadiazinan-2-one derivatives 2d-k are examined by X-ray crystallography and variable-temperature (13)C NMR spectroscopy and further evaluated by semiempirical AM1 calculations. The collected data reveal that the conformational changes of the overall ring system are dependent upon the stereoelectronic factors of the N(3)-substituent.
ABSTRACT
[reaction: see text] Asymmetric aldol addition reactions have been conducted with (1R,2S)-ephedrine-derived 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (2). Diastereoselectivities range from 75:25 to 99:1 for the formation of the crude non-Evans syn adducts 8a-h. The facial selectivity of the enolate is directed by the stereogenic N(4)-methyl substituent. Aldol adduct 8a is readily cleaved by acid hydrolysis to afford (2S,3S)-3-hydroxy-2-methyl-3-phenylpropionic acid (9) in >95% ee.