Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β‐ and α‐Glycosidases

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 HgCl2, 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 Ki 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⋅103 for 6; the manno-imidazoles are less selective. The methyl propionates proved the strongest inhibitors of the α-glucosidase (IC50 (5)=25 μM) and the α-mannosidase (Ki(11) =0.60 μM).