Very Strong Inhibition of Glucosidases byC(2)-Substituted Tetrahydroimidazopyridines

Abstract

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 Ki 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).