LpXC inhibitor

Keywords Antibacterials LpxC inhibitors Oxazolidinones PDF inhibitors ... 

Oxazoline Hydroxamates as Potential LpxC Inhibitors and Antibacterial Agents... 

An open transition state has also been evoked for nitronate addition to sulfinamide 253. The reaction was used as part of a sequence to synthesise an LpxC inhibitor 255 for the treatment of bacterial infections (Scheme 14.83). ° Compound 254 was obtained in 96% de. 

An alternative procedure for the synthesis of aliphatic 2-substituted oxazoline hydroxamates was described by Pirrung and colleagues in the context of preparing inhibitors of E. coli LpxC zinc amidase [378], As shown in Scheme 6.210 a, the protocol involved the cyclization of suitable amides, formed in situ by acylation of a serine-derived 0-2,4-dimethoxybenzyl (DMB)-protected hydroxamate. The cyclization... 

Synthesis of a Carbohydrate-Derived Hydroxamic Acid Inhibitor of LpxC. 200... 

The discovery of oxazoline hydroxamates as potential inhibitors of LpxC was the result of high-throughput screening of large libraries of compounds at the Merck Research Laboratories in collaboration with the Department of Biochemistry, Duke University Medical Center [95]. The lead compound, L-573,655, was a racemic mixture of 4-carbohydroxamido-2-phenyl-2-oxazoline, which had been previously made by Stammer et al. [96] as a precursor in the chemical synthesis of cyclosporine. Namely, (R,S)-serine methyl ester hydrochloride (149) is converted into (R,S)-4-carbomethoxy-2-phenyl-2-oxazoline (150) via treatment with ethyl benzimidate using the Elliot procedure [97]. Treatment of this ester with one equivalent each of hydroxylamine and sodium methoxide in methanol at room temperature affords the desired (R,S)-4-carbohydroxamido-2-phenyl-2-oxazoline (151), as depicted in Scheme 30. 

Coggins, B.E., Li, X., McClerren, A.L., Hindsgaul, O., Raetz, C.R.H., Zhou, P. Structure of the LpxC deacetylase with abound substrate-analog inhibitor. Nat Struct Biol 10 (2003) 645-651. 

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