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 have been prepared from the known 2,3‐unsubstituted imidazole 7 via the iodoimidazole 10 , and tested as inhibitors of β‐ and α‐glucosidases. Introduction of hydrophobic and flexible substituents, such as in 28 and 29 , led to a very strong inhibition of β‐glucosidases, with K_i values for 29 of 1.2 and 0.11 nM against β‐glucosidases from almonds and Caldocellum saccharolyticum, respectively. A slow onset of the inhibition was observed for the strongly inhibiting 16 , 28 – 31 , 37 , and 38 . While the introduction of a hydroxymethyl or a phenethyl substituent as in 17 and 30 led to stronger inhibition, the 1′‐hydroxyphenethyl derivatives 37 and 38 were weaker inhibitors than 16 and 29 . This result is interpreted in the light of a conformational change of the substrate on the way to the transition state. The substituent at C(2) has only a moderate influence on the selectivity of the inhibition of two β‐ and one α‐glucosidases, increasing it by a maximal factor of ca. 10 ( 16 ), or decreasing it by a maximal factor of ca. 15 ( 37 ).