New synthesis of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles, nanomolar inhibitors of glycogen phosphorylase

Abstract

triazoles are novel skeletons to inhibit glycogen phosphorylase in the nanomolar range.Best inhibitors of rabbit muscle R = 4-aminophenyl

C-Glycosyl 1,2,4-triazoles: Synthesis of the 3-β-d-glucopyranosyl-1,5-disubstituted and 5-β-d-glucopyranosyl-1,3-disubstituted variants

“…21 Scheme 1. Isomers of trisubstituted C-glycopyranosyl 1,2,4-triazoles (I-III) and retrosynthetic analysis of the target compounds II and III.…”

“…C-Glycosyl 1,2,4-triazoles are an even more uncommon type [15][16][17][18] and only in recent years has progress been made in this field with the syntheses of 3-glycopyranosyl-5-substituted-1,2,4-triazoles as glycogen phosphorylase inhibitors for potential antidiabetic use. [19][20][21][22][23][24] As a continuation of our efforts in the above syntheses, the preparation of trisubstituted Cglycopyranosyl 1,2,4-triazoles was envisaged to generate molecules for structure-activity relationships of glycogen phosphorylase inhibitors and also for other potential biological applications. From the three possible isomeric structures (Scheme 1) some examples of the 3-glycosyl-4,5-disubstituted-1,2,4-triazoles (I) were already described, 21 therefore, this work has focused on the 3-β-D-glucopyranosyl-1,5-disubstituted (II) and 5-β-D-glucopyranosyl-1,3-disubstituted (III) counterparts.…”

Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-d-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors

“…16 However, these ligands only demonstrated moderate potency at best, 2b and 3c the most potent with K i 's $ 30 mM. The 1,2,4-triazole moiety in the form of 3-(b-D-glucopyranosyl)-5-substituted-1,2,4-triazoles has very recently revealed some of the most potent inhibitors of the GP catalytic site, 13,14 with the 2-naphthyl derivative (1c in Fig. 1) the most potent.…”

“…13 The predicted target compounds of this study (5a,b) have been Fig. 4 The flipped 1,2,4-triazole binding conformation of tautomer t2 of 5a at GPb (dihedral angle u ¼ À176.7…”

“…In the flipped conformation, the 1,2,4-triazole NH is close to hydrogen bonding distance with the Glu88 carboxylate. The imidoyl chlorides 10a,b and prepared from N-benzyl-amides 9a,b as described earlier, 13 were reacted with tetrazole 6 without any purication to give the corresponding 4-benzyl-N-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-5-aryl-1,2,4-triazole-3-carboxamides 11a,b in moderate yields. In the case of the 1-naphthyl derivative 5c, the formation of 11c from 10c was unsuccessful, no transformation was detected and the desired compound has not been synthesized yet using any other synthetic methods.…”