10 research outputs found
Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors
Interest in drugs that covalently
modify their target is driven
by the desire for enhanced efficacy that can result from the silencing
of enzymatic activity until protein resynthesis can occur, along with
the potential for increased selectivity by targeting uniquely positioned
nucleophilic residues in the protein. However, covalent approaches
carry additional risk for toxicities or hypersensitivity reactions
that can result from covalent modification of unintended targets.
Here we describe methods for measuring the reactivity of covalent
reactive groups (CRGs) with a biologically relevant nucleophile, glutathione
(GSH), along with kinetic data for a broad array of electrophiles.
We also describe a computational method for predicting electrophilic
reactivity, which taken together can be applied to the prospective
design of thiol-reactive covalent inhibitors
Potent Inhibitors of LpxC for the Treatment of Gram-Negative Infections
In this paper, we present the synthesis and SAR as well
as selectivity, pharmacokinetic, and infection model data for representative
analogues of a novel series of potent antibacterial LpxC inhibitors
represented by hydroxamic acid <b>1a</b>
Pyridone Methylsulfone Hydroxamate LpxC Inhibitors for the Treatment of Serious Gram-Negative Infections
The synthesis and biological activity of a new series
of LpxC inhibitors represented by pyridone methylsulfone hydroxamate <b>2a</b> is presented. Members of this series have improved solubility
and free fraction when compared to compounds in the previously described
biphenyl methylsulfone hydroxamate series, and they maintain superior
Gram-negative antibacterial activity to comparator agents