The uses of 1,2,4-oxadiazoles include those as agonists at muscarinic receptors, 5-hydroxytryptamine (5-HT) receptor antagonists, benzodiazepine receptor agonists, potent antagonists of the (serotonin) 5-HT1B/D receptors, muscarinic receptor ‘superagonists’, selective inhibitors of human neutrophil elastase, and as active and selective A2B adenosine receptor antagonists. Much interest stems from the use of the fully conjugated 1,2,4-oxadiazole as a hydrolysis resistant ester or amide bioisostere and peptidomimetic. Amongst the non- fully conjugated systems, the soluble guanylyl cyclase inhibitor ODQ is a potent and selective inhibitor of nitric oxide-sensitive guanylyl cyclase and (S)-quisqualic acid is a neuroexcitatory naturally occurring amino acid. Synthetic approaches to the fully conjugated system are dominated by the conversion of a carboxylic acid into an activated derivative, followed by O-acylation of an amidoxime fragment and ring closure. A second popular route is 1,3-dipolar cycloaddition of a nitrile oxide to a nitrile. The reaction of an amidoxime with a carbonyl or the 1,3-dipolar cycloaddition of a nitrile oxide to an imine, or of a nitrone to a nitrile, provides the major routes to the nonconjugated dihydro-1,2,4-oxadiazoles. The reactions of fully conjugated 1,2,4-oxadiazoles and their nonconjugated analogues are detailed together with an in-depth analysis of their structural, theoretical, and thermodynamic properties.
|Title of host publication
|Comprehensive Heterocyclic Chemistry III
|Alan R. Katritzky, Christopher A. Ramsden, Richard J.K. Taylor
|Number of pages
|Published - 1 Dec 2008