The synthesis of 46 derivatives of (2R,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol is reported (Scheme 1 and Fig. 3), and their inhibitory activities toward a-mannosidases from jack bean (B) and almonds (A) are evaluated (Table ). The most-potent inhibitors are (2R,3R,4S)-2-{[([1,1'-biphenyl]-4-ylmethyl)amino]methyl}pyrrolidine-3,4-diol (3fs; IC 50 (B) 5 mm, 6, RH) and the three 2-(N-alkylamino)methyl derivatives 6fh, 6fs, and 6f are prepared (Scheme 2) and found to inhibit also a-mannosidases from jack bean and almonds (Table ). The best inhibitor of these series is (2S,3R,4S)-2-{[(2-thienylmethyl)amino]methyl}pyrrolidine-3,4-diol (6o; IC 50 (B) 105 mm, K i 40 mm). As expected (see Fig. 4), diamines 3 with the configuration of a-d-mannosides are better inhibitors of amannosidases than their stereoisomers 6 with the configuration of b-d-mannosides. The results show that an aromatic ring (benzyl, [1,1'-biphenyl]-4-yl, 2-thienyl) is essential for good inhibitory activity. If the C-chain that separates the aromatic system from the 2-(aminomethyl) substituent is longer than a methano group, the inhibitory activity decreases significantly (see Fig. 7). This study shows also that a-mannosidases from jack bean and from almonds do not recognize substrate mimics that are bulky around the O-glycosidic bond of the corresponding a-d-mannopyranosides. These observations should be very useful in the design of better amannosidase inhibitors.