Monosaccharide as a Central Scaffold Toward the Construction of Salicylate-Based Bidentate PTP1B Inhibitors via Click Chemistry

Abstract

The discovery of carbohydrate-based bioactive compounds has recently received considerable interest in the drug development. This paper stresses on the application of 1-methoxy-O-glucoside as the central scaffold, whereas salicylic pharmacophores were introduced with diverse spatial orientations probing into the structural preference of an enzymatic target, i.e. protein tyrosine phosphatase 1B (PTP1B). By employing regioselective protection and deprotection strategy, 2,6-, 3,4-, 4,6-and 2,3-di-O-propynyl 1-methoxy-O-glucosides were previously synthesized and then coupled with azido salicylate via click chemistry in forming the desired bidentate salicylic glucosides with high yields. The inhibitory assay of the obtained triazolyl derivatives leads to the identification of the 2,3-disubstituted salicylic 1-methoxy-O-glucoside as the structurally privileged PTP1B inhibitor among this bidentate compound series with micromole-ranged IC 50 value and reasonable selectivity over other homologous PTPs tested. In addition, docking simulation was conducted to propose a plausible binding mode of this authorized inhibitor with PTP1B. This research might furnish new insight toward the construction of structurally different bioactive compounds based on the monosaccharide scaffold.

Deoxysugars as Antituberculars and Alpha-Mannosidase Inhibitors

“…A large number of modified sugars or glycomimetics have been found to act as glycosidase inhibitors, and many of these glycosidase inhibitors have been developed as drugs. Characteristic examples of modified sugar-based or glycomimetic drugs are the viral neuraminidase inhibitors zanamivir (Relenza) and oseltamivir (Tamiflu) for influenza A and B, miglustat (Zavesca) for the treatment of Gaucher disease, miglitol (Glyset) for the treatment of diabetes, and topiramate (Topamax) as an anticonvulsant drug (7)(8)(9). Another class of modified sugar, a series of 2,3-dideoxy hex-2-enopyranosid-4-uloses, was recently described by Saquib et al (10,11) as possessing very good antitubercular activity.…”