Introduction: Feruloyl Sucrose Esters (FSEs) are a class of Phenylpropanoid
Sucrose Esters (PSEs) widely distributed in plants. They were investigated as potential selective
Alpha Glucosidase Inhibitors (AGIs) to eliminate the side effects associated with
the current commercial AGIs. The latter effectively lowers blood glucose levels in diabetic
patients but causes severe gastrointestinal side effects.
Methods: Systematic structure-activity relationship (SAR) studies using in silico, in vitro
and in vivo experiments were used to accomplish this aim. FSEs were evaluated for their
in vitro inhibition of starch and oligosaccharide digesting enzymes α-glucosidase and α-
amylase followed by in silico docking studies to identify the binding modes. A lead candidate,
FSE 12 was investigated in an STZ mouse model.
Results: All active FSEs showed desired higher % inhibition of α-glucosidase and desired
lower inhibition of α-amylase in comparison to AGI gold standard acarbose. This suggests
a greater selectivity of the FSEs towards α-glucosidase than α-amylase, which is
proposed to eliminate the gastrointestinal side effects. From the in vitro studies, the position
and number of the feruloyl substituents on the sucrose core, the aromatic ‘OH’ group,
and the diisopropylidene bridges were key determinants of the % inhibition of α-
glucosidase and α-amylase. In particular, the diisopropylidene bridges are critical for
achieving inhibition selectivity. Molecular docking studies of the FSEs corroborates the in
vitro results. The molecular docking studies further reveal that the presence of free aromatic
‘OH’ groups and the substitution at position 3 on the sucrose core are critical for the
inhibition of both the enzymes. From the in vitro and molecular docking studies, FSE 12
was selected as a lead candidate for validation in vivo. The oral co-administration of FSE
12 with starch abrogated the increase in post-prandial glucose and significantly reduced
blood glucose excursion in STZ-treated mice compared to control (starch only) mice.
Conclusion: Our studies reveal the potential of FSEs as selective AGIs for the treatment of
diabetes, with a hypothetical reduction of side effects associated with commercial AGIs.