Amino(hydroxymethyl)cyclopentanetriols, an Emerging Class of Potent Glycosidase Inhibitors—Part I: Synthesis and Evaluation ofβ-D-Pyranoside Analogues in themanno, gluco, galacto, and GlcNAc Series

In order to rationalize the strong inhibition of α-D-mannosidases by mannostatin A (1), a series of 1-amino-5-hydroxymethyl-2,3,4-cyclopentanetriols 2 were prepared as analogues of this lead compound and of the natural glycopyranoside substrates. High inhibitory activities, with Ki values below 1 μM, were found in all stereochemical series studied (D-gluco, D-manno, D-galacto, and D-GlcNAc configuration). Based on the promising results for the parent compounds 2, the β-D-galacto-configured series was chosen for optimization by varying the substitution at the nitrogen atom of the amino group. Highly potent N-benzyl-substituted derivatives with Ki values down to 0.0007 μM were obtained such as the bromo compound 3.