Strategy for designing selective α-l-rhamnosidase inhibitors: Synthesis and biological evaluation of l-DMDP cyclic isothioureas. Issue 1 (1st January 2017)

• Record Type: Journal Article
• Authors: Miyawaki, Shota; Hirokami, Yuki; Kinami, Kyoko; Hoshino, Masako; Minehira, Daisuke; Miyamoto, Daiki; Nash, Robert J.; Fleet, George W.J.; Adachi, Isao; Toyooka, Naoki; Kato, Atsushi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 1(2017)
• Page Start: 107
• Page End: 115
• Publication Date: 2017-01-01
• Subjects: α-l-Rhamnosidase -- l-DMDP cyclic isothiourea -- Iminosugars -- Structure–activity relationships -- Glycosidase inhibitor -- Mycobacterium tuberculosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.10.015
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: This study shows that the cyclization ofl -DMDP thioureas to bicyclicl -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 IC50 value of 0.22 μM, about 46-fold better than the positive control 5- epi -deoxyrhamnojirimycin (5- epi -DRJ; IC50 = 10 μM) and occupied the active-site of this enzyme ( K i = 0.11 μM). Bicyclic isothioureas of ido -l -DMDP did not inhibit α-l -rhamnosidase. These new mimics ofl -rhamnose may affect other enzymes associated with the biochemistry of rhamnose including enzymes involved in progression of tuberculosis.