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

Abstract

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 b-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 b-glucosidase from Caldocellum saccharolyticum, the a-glucosidase from brewers yeast, the b-mannosidase from snail, and the a-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 b-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 b-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 b-mannosidase. The a/b 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 a-glucosidase (IC 50 (5) 25 mm) and the a-mannosidase (K i (11) 0.60 mm). . The carboxymethyl group at C(2) does not appear to be important for the inhibitory activity, since debranched nagstatin analogues and related C(2)-unsubstituted glucose-and mannose-derived tetrahydroimidazopyridines are also potent inhibitors of b-glycosidases [5 ± 7]. These observations and the rationalisation of the inhibitory activity of these and analogous azoles ± their similarity with the putative reaction intermediate, and the cooperative interaction of the azole ring with the catalytic acid and nucleophile ± indicated a negligible role for the substituents at C(2) [8 ± 10]. Subsequently, however, it was shown that C(2)-substituents of tetrahydropyridoimidazoles (and corresponding substituents of related azoles and pyrroles) can strongly affect the inhibitory properties, either indirectly, by competing with the catalytic acid for H-bonding to the glycosidic heteroatom, and/or

Synthesis of N‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

“…Its inhibitory activity is essentially associated with the imidazole ring and not with the carboxymethyl substituent [2], although substituents on the imidazole ring may strongly affect the inhibition of b (and a-)-glycosidases [6 ± 8]. In the preceding paper [9], we described the influence of the hydrophobic character of C(2)-methyl ester and carboxylic acid substituents on the inhibition of b-glycosidases. Imidazole-2-propionates 10 ± 13 are stronger inhibitors of the b-glucosidase from Caldocellum saccharolyticum and of the b-mannosidase from snail than imidazole-2-acetates 6 ± 9, and these are stronger than imidazole-2-carboxylates 2 ± 5.…”

“…Hydrogenolysis of 28 yielded 98% of Tables 3 Table 4 in Exper. Part) were assigned by analogy to the gluco-and manno-analogues described in the preceding paper [9]. The formation of the methyl imidazole-2-acetates 20 and 21 is confirmed by the disappearance of the NH signal of 17,…”

“…The inhibition data of 14 and 15 for the hexosaminidases are summarized in Table 1 and compared to the inhibition by the parent acetamido-imidazole 16 and by nagstatin [2]. A comparison of the inhibition of the b-glucosidase and b-mannosidase by 14 and 15 to the inhibition by the glucose-and mannose-related analogues 6 ± 9 [9] is shown in Table 2.…”

“…± We planned to synthesize the gluco-analogue 15 of nagstatin (1) via the gluco-and manno-configured hydroxy-imidazoles 22 and 23. These imidazoles should be obtained by condensing the selectively protected thionolactams 17 [14] or 18 [15] with the b-amino ester 19 [9], followed by selective deprotection of the products. The resulting alcohols 22 and 23 should be transformed into 15 by a Mitsunobu substitution, similarly as described for the galacto-and talo-analogues in the synthesis of nagstatin [3] [4] (Scheme 1).…”

“…Condensation of the O-silylated thionolactam 17 2 ) with the b-amino ester 19 [9] followed by treatment of the crude with TsOH´H 2 O provided the gluco-and mannoconfigured imidazoles 20 and 21 (53%; 55 : 45), which were readily separated by chromatography to give 29% of 20 and 23% of 21. Standard desilylation [16] [17] of 20 and 21 led to the hydroxy-imidazoles 22 (93%) and 23 (93%).…”