This study shows that the cyclization of L-DMDP thioureas to bicyclic L-DMDP isothioureas improved a-Lrhamnosidase inhibition which was further enhanced by increasing the length of the alkyl chain. The addition of a long alkyl chain, such as decyl or dodecyl, to the nitrogen led to the production of highly potent inhibitors of a-L-rhamnosidase; it also caused broad inhibition spectrum against b-glucosidase and b-galactosidase. In contrast, the corresponding N-benzyl-L-DMDP cyclic isothioureas display selective inhibition of a-L-rhamnosidase; 30,40-dichlorobenzyl-L-DMDP cyclic isothiourea (3r) was found to display the most potent and selective inhibition of a-L-rhamnosidase, with IC50 value of 0.22 lM, about 46-fold better than the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ; IC50 = 10 lM) and occupied the active-site of this enzyme (Ki = 0.11 lM). Bicyclic isothioureas of ido-L-DMDP did not inhibit a-L-rhamnosidase. These new mimics of L-rhamnose may affect other enzymes associated with the biochemistry of rhamnose including enzymes involved in progression of tuberculosis.
