Synthesis of C(2)‐Substituted manno‐Configured Tetrahydroimidazopyridines and Their Evaluation as Inhibitors of Snail β‐Mannosidase

It was shown that retaining β ‐glucosidases and galactosidases of families 1–3 feature a strong interaction between C(2)OH of the substrate and the catalytic nucleophile. An analogous interaction can hardly take place for retaining β ‐mannosidases. A structureactivity comparison between the inhibition of the β ‐glucosidase from Caldocellum saccharolyticum (family 1) and β ‐glucosidase from sweet almonds by the gluco ‐imidazoles 1 – 6 , and the inhibition of snail β ‐mannosidase by the corresponding manno ‐imidazoles 8 – 13 does not show any significant difference, suggesting that also the mechanisms of action of these glycosidases do not differ significantly. For this comparison, we synthesized and tested the manno ‐imidazoles 9 – 13, 28, 29, 32, 35, 40, 41, 43, 46, 47 , and 50 . Among these, the alkene 29 is the strongest known inhibitor of snail β ‐mannosidase ( K i =6 n M , non‐competitive); the aniline 35 is the strongest competitive inhibitor ( K i =8 n M ).