ABSTRACT
The nitrone above is readily available via the intramolecular aza Diels-Alder reaction of an amino acid derived triene in acetic acid. Subsequent treatment of the nitrone in refluxing toluene with substituted actetylenes produced the pictured pyrrole. At lower temperatures a 2,3-dihydroisoxazole, which is the product of a 3+2 dipolar cycloaddition, is produced. Upon heating in refluxing toluene the 2,3-dihydroisoxazole is converted to the pyrrole.
Subject(s)
Alkaloids/chemistry , Azo Compounds/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Thiosemicarbazones/chemistry , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistryABSTRACT
MurF is a key enzyme in the biosynthesis of the bacterial cell wall in both gram-positive and gram-negative bacteria. This enzyme has not been extensively exploited as a drug target, possibly due to the difficulty in obtaining one of the substrates, UDP-MurNAc-L-Ala-gamma-D-Glu-meso-diaminopimelate, which is usually purified from bacteria. We have identified putative inhibitors of Escherichia coli MurF by a binding assay, thus bypassing the need for substrate. Inhibition of enzymatic activity was demonstrated in a high-performance liquid chromatography-based secondary assay with UDP-MurNAc-L-Ala-gamma-D-Glu-diaminopimelate substrate prepared in a novel way by using muropeptide ligase enzyme to add UDP-MurNAc to synthetic L-Ala-gamma-D-Glu-diaminopimelate; the substrate specificity of muropeptide ligase for peptides containing L-Lys in place of diaminopimelate was also investigated. Using the muropeptide ligase-generated MurF substrate, a thiazolylaminopyrimidine series of MurF enzyme inhibitors with 50% inhibitory concentration values as low as 2.5 microM was identified.
Subject(s)
Cell Wall/metabolism , Enzyme Inhibitors/isolation & purification , Escherichia coli/enzymology , Peptide Synthases/metabolism , Peptidoglycan/biosynthesis , Enzyme Inhibitors/pharmacology , Escherichia coli/chemistry , Peptide Synthases/antagonists & inhibitorsABSTRACT
[structure: see text] Intramolecular [4 + 2] cycloaddition using alpha,beta-unsaturated oximes was explored. The reactions proceeded under unusually facile conditions to furnish the nitrones. The latter were subsequently reacted with DMAD to afford [3 + 2] cycloaddition products.
