1. Strategy for designing selective α-l-rhamnosidase inhibitors: Synthesis and biological evaluation of l-DMDP cyclic isothioureas.
- Author
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Miyawaki S, Hirokami Y, Kinami K, Hoshino M, Minehira D, Miyamoto D, Nash RJ, Fleet GW, Adachi I, Toyooka N, and Kato A
- Subjects
- Animals, Cyclization, Drug Design, Enzyme Inhibitors chemical synthesis, Glycoside Hydrolases metabolism, Humans, Penicillium enzymology, Pyrrolidines chemical synthesis, Thiourea chemical synthesis, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Glycoside Hydrolases antagonists & inhibitors, Pyrrolidines chemistry, Pyrrolidines pharmacology, Thiourea analogs & derivatives, Thiourea pharmacology
- Abstract
This study shows that the cyclization of l-DMDP thioureas to bicyclic l-DMDP isothioureas improved α-l-rhamnosidase 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 α-l-rhamnosidase; it also caused broad inhibition spectrum against β-glucosidase and β-galactosidase. In contrast, the corresponding N-benzyl-l-DMDP cyclic isothioureas display selective inhibition of α-l-rhamnosidase; 3',4'-dichlorobenzyl-l-DMDP cyclic isothiourea (3r) was found to display the most potent and selective inhibition of α-l-rhamnosidase, with IC
50 value of 0.22μM, about 46-fold better than the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ; IC50 =10μM) and occupied the active-site of this enzyme (Ki =0.11μM). Bicyclic isothioureas of ido-l-DMDP did not inhibit α-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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2017
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