Premium
Very Strong Inhibition of Glucosidases by C(2) ‐Substituted Tetrahydroimidazopyridines
Author(s) -
Panday Narendra,
Canac Yves,
Vasella Andrea
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(20000119)83:1<58::aid-hlca58>3.0.co;2-k
Subject(s) - chemistry , substituent , glucosidases , stereochemistry , imidazole , hydroxymethyl , selectivity , substrate (aquarium) , enzyme , biochemistry , catalysis , oceanography , geology
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 n M 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 ).