Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles as peptidomimetic building blocks

The design and synthesis of Ala-Glu/iGln mimetics: heterocyclic building blocks for pseudopeptides

“…13 Subsequent dehydration of the amide, employing cyanuric acid/ DMF, 19 afforded the corresponding nitrile 2 20 in high yield. Further, treatment of nitrile 2 with hydroxylamine hydrochloride in refluxing ethanol, 6 in the presence of triethylamine, yielded amidoxime 3. Subsequently, the amidoxime 3 was acetylated and the O-acetyl intermediate subjected to a fluoride-catalyzed cyclodehydration, 21 affording the 1,2,4-oxadiazole-containing L-Ala-D-Glu/D-iGln building block, compound 4.…”

“…2 In the context of bioisosterism, it has long been known that the 1,2,4-oxadiazole moiety can be used as a non-classical bioisostere of the ester/amide moiety, and its use as a peptide bond replacement in the construction of peptide mimics has been widely reported. [3][4][5][6] While peptides in general are susceptible to metabolic degradation, 1,2,4-oxadiazole-containing surrogates are, in many cases, as active as the parent peptide but exhibit greater metabolic stability than their ester/amide counterparts. [3][4][5] Further, several amino acid derived 1,2,4-oxadiazole compounds have been described.…”

“…[3][4][5] Further, several amino acid derived 1,2,4-oxadiazole compounds have been described. [6][7][8][9][10][11] The L-Ala-D-iGln/D-Glu dipeptide motif is present in several bioactive compounds, in particular in agonists of intracellular pattern recognition receptors, nucleotide-binding oligomerization domains (NOD1 and NOD2), as well as in Mur ligase inhibitors. 12-16 L-Ala-D-Glu-containing NOD2 agonistic compounds have been shown to be superior to their L-Ala-D-iGln counterparts.…”

Synthesis of 1,2,4-oxadiazole-linked orthogonally urethane-protected dipeptide mimetics

“…13 In peptide chemistry, this group has been studied mainly as an efficient amide and ester bond bioisoester. 14,15 The development of a reliable method for the insertion of 1,2,4-oxadiazole into peptides finds utility in the synthesis of large libraries of small peptide segments for their biological and therapeutical scrutiny. The general synthesis of 1,2,4-oxadiazoles involves coupling of an amidoxime with an activated carboxyl group, yielding an O-acyl amidoxime followed by its dehydrative cyclization.…”

“…18 1,2,4-Oxadiazoles have been incorporated in the synthesis of a Phe-Gly segment mimetic in the biologically active peptides such as dermorphin, and in substance P. 19 A new variety of 1,2,4-oxadiazole-linked peptidomimetics have been reported via reaction of Boc-amino acid-derived amidoximes with succinic/glutaric acid anhydrides in DMF at reflux. 15 Similar chemistry was explored also for the synthesis of 1,2,4-oxadiazole-containing b…”