A potent and selective inhibitor of platelet-activating factor acetylhydrolase 1B2 (PAFAH1B2) is described. The compound was derived by improvement of a modest affinity primary hit isolated from the screening of a bead-displayed peptoid–azapeptoid hybrid library tethered to an oxadiazolone ‘warhead’. The oxadiazolone moiety of the inhibitors was found to react covalently with the active site serine residue of PAFAH1B2. This screening strategy may be useful for the identification of many selective, covalent inhibitors of serine hydrolases. © 2016 Elsevier Ltd

Sarma B.K.

Liu X.

Kodadek T.

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Shiv Nadar University

Bioorganic and Medicinal Chemistry

Solid phase synthesis of 1,3,4-oxadiazin-5(6R)-one and 1,3,4-oxadiazol-2-one scaffolds from resin-bound acyl hydrazides is described. We demonstrate here that the reactions of resin-bound aryl or hetero-aromatic acyl hydrazides with 2-substituted-2-bromoacetic acids and 4-nitrophenyl chloroformate and subsequent treatment with DIEA lead to intramolecular cyclization reactions to produce six-membered 1,3,4-oxadiazin-5(6R)-ones and five-membered 1,3,4-oxadiazol-2-ones, respectively. We also show that acyl hydrazide-derived 1,3,4-oxadiazol-2-ones may be useful serine hydrolase inhibitors. This journal is © The Royal Society of Chemistry 2015.

Organic and Biomolecular Chemistry

Solid phase synthesis of 1,3,4-oxadiazin-5 (6R)-one and 1,3,4-oxadiazol-2-one scaffolds from acyl hydrazides

Nature Chemical Biology

Prolonged and tunable residence time using reversible covalent kinase inhibitors

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Expanding the Toolkit for the Serine Hydrolases

ACS Chemical Biology

Selective Inhibitor of Platelet-Activating Factor Acetylhydrolases 1b2 and 1b3 That Impairs Cancer Cell Survival

Current Opinion in Chemical Biology

Covalent protein modification: the current landscape of residue-specific electrophiles

Identification of selective covalent inhibitors of platelet activating factor acetylhydrolase 1B2 from the screening of an oxadiazolone-capped peptoid–azapeptoid hybrid library