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 series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Subject(s)
Indenes/chemical synthesis , Pyridines/chemical synthesis , Receptors, AMPA/physiology , Sulfonamides/chemical synthesis , Administration, Oral , Allosteric Regulation , Animals , Biological Availability , Blood Proteins/metabolism , Blood-Brain Barrier/metabolism , Callithrix , Cell Line , Crystallography, X-Ray , Dogs , Humans , Indenes/pharmacokinetics , Indenes/pharmacology , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Models, Molecular , Protein Binding , Protein Structure, Tertiary , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Species Specificity , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
Metal enolates and functionalized allylzinc reagents react with optically active alpha-amidoalkylphenyl sulfones to give N-carbamoylamino derivatives with variable levels of anti diastereoselectivity. Zinc enolates provide comparable results with respect to lithium enolates in terms of diastereoselectivity but afford beta-amino ester derivatives in lower yield. The synthetic utility of the obtained chiral N-carbamoylamino esters is demonstrated by the first enantioselective synthesis of (-)-1-aminopyrrolizidine a central intermediate for the preparation of various biologically active substances.
Subject(s)
Anions/chemistry , Carbon/chemistry , Pyrrolizidine Alkaloids/chemical synthesis , Sulfones/chemistry , Molecular Conformation , StereoisomerismABSTRACT
Optically active syn-alpha-amidoalkylphenyl sulfones can be prepared from chiral aldehydes in anhydrous conditions using benzenesulfinic acid. These sulfones in basic conditions give N-acylimines that react with sodium methanenitronate to afford the corresponding nitro adducts with high anti diastereoselectivity. PM3 semiempirical calculations provide a rationale for the observed opposite stereoselectivity. The obtained nitro derivatives undergo a Nef reaction followed by a methylation giving optically active beta-hydroxy-alpha-amino acid and alpha,beta-diamino acid esters in good yield. These amino acid derivatives are important building blocks for the preparation of biologically active compounds.
Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Anions/chemistry , Methane/analogs & derivatives , Methane/chemistry , Nitroparaffins/chemistry , Sulfones/chemistry , Aldehydes/chemistry , Alkylation , Amination , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Stereoisomerism , ThermodynamicsABSTRACT
Alpha-amidoalkylphenyl sulfones behave as N-acylimino equivalents in the reaction with functionalized allylzinc reagents. The addition products obtained using the zinc derivative of ethyl 2-(bromomethyl)acrylate can be readily transformed into alpha-methylene-gamma-lactams using different cyclization procedures. The allylzinc reagent obtained from 3-bromo-1-acetoxy-1-propene directly affords protected 1,2-amino alcohols with a preference for the anti stereoisomer, regardless of the structure of the alpha-amidoalkylphenyl sulfone employed. This procedure can be extended to the use of zinc enolates obtained from alpha-bromo ketones and leads to the synthesis of N-protected beta-amino ketones.