Piperidine azasugars displaying competitive α-rhamnosidase inhibition and their kinetic mechanism

Azasugars derived from L-alanine and L-serine were screened for inhibitory activity against α-rhamnosidase. The enantiomers of 1,6-dideoxynojirimycin (ent-1,6-dDNJ) (1) and (2S,3R)-2-(hydroxymethyl)piperidin-3-ol (5) showed highly specific and potent inhibition against α-rhamnosidase with K i values of 4.2 and 16.6 μM, respectively. Structure of the best inhibitor features the same stereochemical configuration as L-rhamnose at C2, C3, and C4 centers. In kinetic studies, both compounds exhibited competitive inhibition behavior. Compound 1 manifested simple reversible slow-binding inhibition with the following kinetic parameters: k 3=1.17 nM−1 min−1, k 4 = 5.96 ×10−3 min−1, and K i app =5.1 mM.