Very strong inhibition of glucosidases by C(2)-substituted tetrahydroimidazopyridines

The C(2)-substituted imidazoles 11 15-17 19, 21, 23/24, 28-31 37 and 38 hav e been prepared from the known 2,3-unsubstituted imidazole 7 via the iodoim idazole 10, and tested as inhibitors beta- and alpha-glucosidases. Introduc tion of hydrophobic and flexible substituents, such as in 28 and 29, led to a very strong inhibition of beta-glucosidases, with K-i values for 29 of 1 .2 and 0.11 nM against beta-glucosidases from almonds and Caldocellum sacch arolyticum, respectively A slow onset of the inhibition was observed for th e strongly inhibiting 16, 28-31, 37 and 38. While the introduction of a hyd roxymethyl or a phenethyl substituent as in 17 and 30 led to stronger inhib ition, the 1'-hydroxyphenethyl derivatives 37 and 38 were weaker inhibitors than 16 and 29. This result is interpreted in the light of a conformationa l change of the substrate on the way to the transition state. The substitue nt at C(2) has only a moderate influence on the selectivity of the inhibiti on of two beta- and one a-glucosidases, increasing it by a maximal factor o f cn. 10 (16), or decreasing it by a maximal factor of cn. 15 (37).