Synthesis of New C(2)‐Substituted gluco‐Configured Tetrahydroimidazopyridines and Their Evaluation as Glucosidase Inhibitors

Abstract

Albert Eschenmoser zum 80. Geburtstag mit herzlichen Glückwünschen zugeeignet.The gluco-configured C(2)-substituted tetrahydroimidazopyridines 8 -14 were prepared and tested as inhibitors of the b-glucosidases from Caldocellum saccharolyticum and from sweet almonds, and of the a-glucosidase from brewer's yeast. All new imidazopyridines are nanomolar inhibitors of the b-glucosidases and micromolar inhibitors of the a-glucosidase. The 3-phenylpropyl derivative 14 proved the strongest inhibitor of the Caldocellum b-glucosidase (K i = 0.9 nM), only slightly weaker than the known 2-phenylethyl analogue 7, and the propyl derivative 13 is the strongest inhibitor of the sweet almond b-glucosidases (K i = 3.2 nM), again slightly weaker than 7. There is no strong dependence of the inhibition on the nature of the C(2)-substituent and no clear correlation between the inhibitory strength of the known manno-configured imidazopyridines 2 -6 and the gluco-analogues 8 -12. While most manno-imidazopyridines are competitive inhibitors, the glucoanalogues proved non-competitive inhibitors of the Caldocellum b-glucosidase and mixed-type or partial mixedtype inhibitors of the sweet almond b-glucosidases. We also found that the manno-configured inhibitors 2 -6 [17] for which there were no gluco-configured counterparts are particularly strong inhibitors of snail b-mannosidase, ca. 3 -5 times stronger than 1 (K i = 20 nM) [17], the manno-analogue of the glucoconfigured 2-phenylethyl imidazopyridine 7 that is so far the strongest known inhibitor of a retaining b-glucosidase (K i = 0.1 nM, C. saccharolyticum) [15]. The parallel effect of the C(2)-substituents on the strength of the inhibition suggested that the gluco-configured imidazopyridines 8 -12 corresponding to 2 -6 should be stronger inhibitors than 7. However, a comparison of the gluco-and manno-configured C(2)-substituted imidazopyridines shows that the analogous effect of the C(2)-substituent on the strength of the inhibition is not reflected by a similarity of the type of inhibition (mixed, competitive, or non-competitive), casting some doubt on the validity of the above extrapolation. In view of these considerations and of our interest in very strong glucosidase inhibitors, we decided to prepare the gluco-analogues 8 -12. Considering the strong inhibition by the

Glycosidase inhibition: assessing mimicry of the transition state

“…3 . These compounds have been synthesised to mimic different glycosides, 121-124 with a number of different functional groups attached to mimic the aglycon, 125-129 and in oligosaccharide forms. 117 It is interesting to note that if a triazole moiety is fused to the pseudo-glycoside ring ( i.e.…”

Mechanism, Structure, and Inhibition of O-GlcNAc Processing Enzymes

“…Following its discovery, nagstatin was synthesized [132] and the scaffold manipulated to make potent β-glucosidase inhibitors [133, 134]. These tetrahydroimidazopyridine compounds were substituted with a number of different functional groups in order to promote favourable interactions in the active site of enzymes of interest [135-138], and these have proven to be among the most potent β-glycosidase inhibitors studied [139]. The potency of the tetrahydroimidazopyridine compounds are attributed to the protonated nitrogen atom in the imidazole forming a strong hydrogen bond interaction with the general acid/base residue, and the pseudo-glycoside ring adopting a half chair/envelope conformation which mimics the proposed oxocarbenium transition state [140].…”

GlcNAcstatin: a Picomolar, Selective O-GlcNAcase Inhibitor That Modulates Intracellular O-GlcNAcylation Levels

“…Furthermore, critical evaluation of the nature of the C2 substituent showed that an aglyconmimicking group in this position results in stronger inhibition. 19,20 Combining the current body of knowledge on the glycoimidazoles together with the structural data of the bOGA-PUGNAc complex, we designed a series of GlcNAc-configured nagstatin derivatives (GlcNAcstatins) that address specificity toward the OGA enzymes through elaborated N8 (tetrahydroimidazopyridine numbering) acyl derivatives while providing a source of increased affinity through the incorporation of suitable C2 substituents. Here we report the synthesis of GlcNAcstatin (1, Figure 1), a glucoimidazole with molecular architecture noticeably similar to that of PUGNAc, but bearing a larger isobutanamido group on N8 and a phenethyl group on C2.…”

“…In 1995 Tatsuta reported the total synthesis of this compound and a series of related glycoimidazole derivatives with variable configuration of the sugar ring, showing up to nanomolar inhibition against a panel of glycosidases. , Subsequent work by the Vasella group defined the structure−activity relationships of nagstatin analogues (tetrahydroimidazo[1,2- a ]pyridines) as glycosidase inhibitors, making use of an original synthetic approach to the bicyclic core structure, showing that the molecular architecture of these compounds in the ground state accurately mimics the assumed flattened half-chair/envelope conformation of the sugar ring in the transition state, while protonation of the imidazole ring effectively emulates the charge distribution in the oxocarbenium ion. Furthermore, critical evaluation of the nature of the C2 substituent showed that an aglycon-mimicking group in this position results in stronger inhibition. , Combining the current body of knowledge on the glycoimidazoles together with the structural data of the bOGA−PUGNAc complex, we designed a series of GlcNAc-configured nagstatin derivatives (GlcNAcstatins) that address specificity toward the OGA enzymes through elaborated N8 (tetrahydroimidazopyridine numbering) acyl derivatives while providing a source of increased affinity through the incorporation of suitable C2 substituents. Here we report the synthesis of GlcNAcstatin ( 1 , Figure ), a glucoimidazole with molecular architecture noticeably similar to that of PUGNAc, but bearing a larger isobutanamido group on N8 and a phenethyl group on C2.…”