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Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β ‐ and α ‐Glycosidases
Author(s) -
Terinek Miroslav,
Vasella Andrea
Publication year - 2004
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/hlca.200490273
Subject(s) - chemistry , substituent , imidazole , acetic acid , hydrolysis , stereochemistry , aldehyde , medicinal chemistry , organic chemistry , catalysis
The gluco ‐ and manno ‐tetrahydropyridoimidazole‐2‐acetates and ‐acetic acids 16 and 17 , and 20 and 21 , respectively, were synthesized by condensation, in the presence of HgCl 2 , of the known thionolactam 26 with the β ‐amino ester 25 that was obtained by addition of AcOMe to the imine 22 , followed by debenzylation. The resulting methyl esters 16 and 20 were hydrolyzed to the acetic acids 17 and 21 . The (methoxycarbonyl)‐imidazole 14 and the acid 15 were obtained via the known aldehyde 29 . The imidazoles 14 – 17, 20 , and 21 were tested as inhibitors of the β ‐glucosidase from Caldocellum saccharolyticum , the α ‐glucosidase from brewer's yeast, the β ‐mannosidase from snail, and the α ‐mannosidase from Jack beans ( Tables 1–3 ). There is a similar dependence of the K i values on the nature of the C(2)‐ substituent in the gluco ‐ and manno ‐series. With the exception of 19 , manno ‐imidazoles are weaker inhibitors than the gluco ‐analogues. The methyl acetates 16 and 20 are 3–4 times weaker than the methyl propionates 5 and 11 , in agreement with the hydrophobic effect. The gluco‐ configured (methoxycarbonyl)‐imidazole 14 is 20 times weaker than the methyl acetate 16 , reflecting the reduced basicity of 14 , while the manno ‐configured (methoxycarbonyl)‐imidazole 18 is only 1.2 times weaker than the methyl acetate 20 , suggesting a binding interaction of the MeOCO group and the β ‐mannosidase. The carboxylic acids 6, 12, 15, 17, 19 , and 21 are weaker inhibitors than the esters, with the propionic acids 6 and 12 being the strongest and the carboxy‐imidazoles 15 and 19 the weakest inhibitors. The manno ‐acetate 21 inhibits the β ‐mannosidase ca. 8 times less strongly than the propionate 12 , but only 1.5 times more strongly than the carboxylate 19 , suggesting a compensating binding interaction also of the COOH group and the β ‐mannosidase. The α / β selectivity for the gluco ‐imidazoles ranges between 110 for 15 and 13.4⋅10 3 for 6 ; the manno ‐imidazoles are less selective. The methyl propionates proved the strongest inhibitors of the α ‐glucosidase ( IC 50 ( 5 )=25 μ M ) and the α ‐mannosidase ( K i ( 11 ) =0.60 μ M ).