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Strategy for designing selective α-l-rhamnosidase inhibitors: Synthesis and biological evaluation of l-DMDP cyclic isothioureas.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 Jan 01; Vol. 25 (1), pp. 107-115. Date of Electronic Publication: 2016 Oct 15. - Publication Year :
- 2017
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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 <subscript>50</subscript> value of 0.22μM, about 46-fold better than the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ; IC <subscript>50</subscript> =10μM) and occupied the active-site of this enzyme (K <subscript>i</subscript> =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.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 25
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27789075
- Full Text :
- https://doi.org/10.1016/j.bmc.2016.10.015