ABSTRACT
This paper describes the discovery of alpha-trifluoroketoacetamides as potent antibacterial agents against Gram-positive organisms. The initial SAR indicates that the aryl ethyl side chain is essential in maintaining antibacterial activity. The SAR observations have been utilized to design a bioisostere for the alpha-trifluoroketoacetamide with good activity against Gram-positive organisms.
Subject(s)
Acetamides/pharmacology , Anti-Bacterial Agents/pharmacology , Fluoroacetates , Gram-Positive Bacteria/drug effects , Acetamides/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Gram-Negative Bacteria/drug effects , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Trifluoroacetic Acid/chemistryABSTRACT
Important resistance patterns in Gram-negative pathogens include active efflux of antibiotics out of the cell via a cellular pump and decreased membrane permeability. A 3-arylpiperidine derivative (1) has been identified by high-throughput assay as a potentiator with an IC(50) approximately 90 microM. This report details the evaluation of the tether length, aryl substitution and the importance of the fluorine on antibiotic accumulation. Evaluation of various tether lengths demonstrated that the two-carbon tethered analogues are optimal. Removal of the fluorine has a modest effect on antibiotic accumulation and the defluorinated analogue 17 is equally potent to the original lead 1.
Subject(s)
Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Gram-Negative Bacteria/drug effects , Piperidines/pharmacology , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Biological Transport, Active/physiology , Drug Resistance , Drug Synergism , Fluorine/chemistry , Gram-Negative Bacteria/pathogenicity , Inhibitory Concentration 50 , Microbial Sensitivity Tests/standards , Permeability , Piperidines/chemical synthesisABSTRACT
Peptidyl deformylase (PDF) is a metallo protease that catalyzes the removal of a formyl group from the N-termini of prokaryotic prepared polypeptides, an essential step in bacterial protein synthesis. Screening of our compound collection using Staphylococcus aureus PDF afforded a very potent inhibitor with an IC(50) in the low nanomolar range. Unfortunately, the compound that contains a hydroxamic acid did not exhibit antibacterial activity (MIC). In order to address the lack of activity in the MIC assay and to determine what portion of the molecule was responsible for binding to PDF, we prepared several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity to PDF. In addition, we identified an alternative class of PDF inhibitors, the N-hydroxy urea 18, which has both PDF and antibacterial activity.
Subject(s)
Amidohydrolases , Aminopeptidases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Hydroxamic Acids/pharmacology , Staphylococcus aureus/drug effects , Aminopeptidases/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Metalloendopeptidases/antagonists & inhibitors , Microbial Sensitivity Tests , Models, Molecular , Protein Conformation , Staphylococcus aureus/enzymology , Structure-Activity RelationshipABSTRACT
The structure of the title compound, C31H39NO7Si, was determined and found to be a fused tricyclic nitroso acetal. Remarkable features include a twist-boat conformation of the tetrahydro-1,2-oxazine ring and a highly pyramidalized N atom [Sigma (angles) = 310.6(6) degrees]. Three of the contiguous stereocenters in the nitroso acetal are of the same correct relative and absolute configuration as is found in (+)-crotanecine.