Aspects of extraction and biological evaluation of naturally occurring sugar-mimicking sulfonium-ion and their synthetic analogues as potent α-glucosidase inhibitors from Salacia: a review

Abstract

Human maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) are membrane bound small intestinal α-glucosidase enzymes which are responsible for the hydrolysis of terminal starch products and sugars into glucose. Each enzyme contains a catalytic N- and C-terminal subunit, ntMGAM, ctMGAM, ntSI, and ctSI, respectively. Inhibition of MGAM and SI is an important strategy for treatment of type-2 diabetes. In drug discovery, several plants from the Salacia species have been used for many years to treat diabetic conditions. Attempt to identify the source of the antidiabetic phytoconstituents in water-soluble fraction of this plant extract stimulated interest in its phytochemistry. This led to the identification of several novel class of sulfonium-ion. So far, eight sulfonium-ion glucosidase inhibitors have been isolated i.e. salacinol, kotalanol, ponkoranol, salaprinol and four of their corresponding de-O-sulfonated compounds. Due to both the intriguing structure and strong α-glucosidase inhibitory activity, much attention has been focused on salacinol and related compounds. Structural modification of sulfonium-ion represents a promising approach in the search for novel antidiabetic drugs. Several papers have described the synthetic route of sulfonium ion-based inhibitors. In this context, this review covers up to date information on sulfonium-ion from 1997 to till date and discusses the role of Salacia as antidiabetic drug as well as the extraction, isolation, structural elucidation, biological evaluation and structure–activity relationship studies of sulfonium-ion as potent α-glucosidase inhibitors coupled with crystallographic analysis and docking studies. We highlighted all the selective inhibitory activities of compounds against the intestinal glucosidases and also summarise the structural features which are important for its effective inhibition. The structural refinement of the sulfonium-ion generates inhibitors that selectively inhibit the activity of mucosal α-glucosidases. Further, the approach of toggling has been reviewed in aspects for controlling starch digestion and glucose release to the body and thus provides insight for designing most potent inhibitors for each subunit with low nanomolar inhibitory activities. This strategy will give a lead from the perspective of management of diabetes and associated metabolic disorders. The knowledge gained from this article will be helpful to a search for new potent inhibitors of human MGAM and SI. A summary of the inhibition data of all the compounds covered in this review have also been incorporated in tabular form as an Appendix.