ABSTRACT
3-Methoxybenzamide (1) is a weak inhibitor of the essential bacterial cell division protein FtsZ. Alkyl derivatives of 1 are potent antistaphylococcal compounds with suboptimal drug-like properties. Exploration of the structure-activity relationships of analogues of these inhibitors led to the identification of potent antistaphylococcal compounds with improved pharmaceutical properties.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Cytoskeletal Proteins/antagonists & inhibitors , Pyridines/chemical synthesis , Staphylococcus aureus/drug effects , Thiazoles/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biological Availability , Blood Proteins/metabolism , Caco-2 Cells , Cell Division/drug effects , Cell Membrane Permeability , Hepatocytes/metabolism , Humans , Mice , Microbial Sensitivity Tests , Models, Molecular , Protein Binding , Pyridines/chemistry , Pyridines/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/cytology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
3-Methoxybenzamide is a weak inhibitor of the essential bacterial cell division protein FtsZ. Exploration of the structure-activity relationships of 3-methoxybenzamide analogues led to the identification of potent anti-staphylococcal compounds.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzamides/pharmacology , Cytoskeletal Proteins/antagonists & inhibitors , Staphylococcus/drug effects , Anti-Bacterial Agents/chemistry , Benzamides/chemistry , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
The synthesis of enantiopure gamma-substituted gamma-amino acids with proteinogenic side chains, starting from the corresponding natural alpha-amino acids, was studied. N-Protected amino aldehydes containing various protective groups were prepared from the corresponding amino alcohols by oxidation with NaOCl in the presence of AcNH-TEMPO and directly reacted with methyl, benzyl and tert-butyl phosphoranylidene acetate to produce alpha,beta-unsaturated gamma-amino esters. Simultaneous hydrogenation of the double bond and removal of either the benzyl or benzyloxycarbonyl group led to N- or C-protected gamma-amino acids in high yield. The enantiomeric purity was studied by 1H NMR analysis of Mosher amides and chiral HPLC analysis.
Subject(s)
Amino Acids/chemical synthesis , Aldehydes/chemistry , Amino Acids/chemistry , Amino Alcohols/chemistry , Chromatography, High Pressure Liquid/methods , Hydrogenation , Magnetic Resonance Spectroscopy , Oxidation-Reduction , StereoisomerismABSTRACT
Carboxylic acids are converted into alcohols by chemoselective reduction of their corresponding fluorides with sodium borohydride and dropwise addition of methanol. The method is general and mild and displays a high level of functional group compatibility. N-Protected amino and peptide alcohols, bearing varieties of protecting groups, are prepared in the same way from their corresponding amino acids and peptides without racemization.
