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

The gluco ‐configured C(2) ‐substituted tetrahydroimidazopyridines 8 – 14 were prepared and tested as inhibitors of the β ‐glucosidases from Caldocellum saccharolyticum and from sweet almonds, and of the α ‐glucosidase from brewer's yeast. All new imidazopyridines are nanomolar inhibitors of the β ‐glucosidases and micromolar inhibitors of the α ‐glucosidase. The 3‐phenylpropyl derivative 14 proved the strongest inhibitor of the Caldocellum β ‐glucosidase ( K i  = 0.9 n M ), only slightly weaker than the known 2‐phenylethyl analogue 7 , and the propyl derivative 13 is the strongest inhibitor of the sweet almond β ‐glucosidases ( K i  = 3.2 n M ), 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 gluco ‐analogues proved non‐competitive inhibitors of the Caldocellum β ‐glucosidase and mixed‐type or partial mixed‐type inhibitors of the sweet almond β ‐glucosidases.