ABSTRACT
A novel structural class of antibacterials, 2-(1H-indol-3-yl)quinolines, effective against methicillin-resistant Staphylococcus aureus (MRSA), was discovered from a combinatorial library. A structure-activity relationship (SAR) study was conducted to determine the pharmacophore and increase the potency of these compounds. Compounds were prepared that had minimum inhibitory concentrations (MICs) < 1.0 microg/mL against MRSA and retained activity against two strains of glycopeptide intermediate-resistant S. aureus (GISA).
Subject(s)
Anti-Bacterial Agents/pharmacology , Indoles/pharmacology , Methicillin Resistance , Quinolines/pharmacology , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemistry , Combinatorial Chemistry Techniques , Indoles/chemistry , Microbial Sensitivity Tests , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Ruthenium catalyzed ring opening cross-metathesis of resin-bound bicyclic alkenes with terminal aryl olefins was utilized for the construction of a combinatorial library containing highly functionalized cyclopentane derivatives. The technology described herein represents a convergent method for the diastereospecific synthesis of unique cyclopentane molecular scaffolds useful for exploratory medicinal chemistry.
Subject(s)
Cyclopentanes/chemical synthesis , Databases, Factual , Chemistry, Organic/methods , Cyclopentanes/chemistry , Indicators and Reagents , Mass Spectrometry , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Small molecule FKBP inhibitors were prepared with inhibitory activity ranging from micromolar to nanomolar. The design of these inhibitors derives from a structural analysis of the substrates for FKBP and cyclophilin. As a consequence of this analysis two key observations were made, namely: (1) amino ketone moieties are suitable as FKBP recognition elements at the P1-P1' site and (2) the P3'-P4' site will accept a trans-olefin as a suitable mimetic of a peptide moiety. The preparation of these non-peptide inhibitors is readily accomplished by a protocol which includes the synthesis of chiral propargylic amines and their subsequent conversion into vinyl zirconium reagents.
