Beta-aminoketones as prodrugs for selective irreversible inhibitors of type-1 methionine aminopeptidases.

We identified and characterized β-aminoketones as prodrugs for irreversible MetAP inhibitors that are selective for the MetAP-1 subtype. β-Aminoketones with certain structural features form α,β-unsaturated ketones under physiological conditions, which bind covalently and selectively to cysteines in the S1 pocket of MetAP-1. The binding mode was confirmed by X-ray crystallography and assays with the MetAPs from Escherichia coli, Staphylococcus aureus and both human isoforms.

Chemical, biochemical and microbiological properties of a brominated nitrovinylfuran with broad-spectrum antibacterial activity.

A di-bromo substituted nitrovinylfuran with reported broad-spectrum antibacterial activity was found to be a potent inhibitor of MurA, a key enzyme in peptidoglycan biosynthesis. Further characterization of the compound was carried out to assess its reactivity towards thiol nucleophiles, its stability and degradation under aqueous conditions, inhibitory potential at other enzymes, and antibacterial and cytotoxic activity. Our results indicate that the nitrovinylfuran derivative is reactive towards cysteine residues in proteins, as demonstrated by the irreversible inhibition of MurA and bacterial methionine aminopeptidase.