α-Glucosidase Inhibition, Antioxidant and Docking Studies of Hydroxycoumarins and their Mono and Bis O-alkylated/acetylated Analogs
Authors: Singh Parvesh , Ngcoya Nomandla , Mopuri Ramgopal , Kerru Nagaraju , Manhas Neha , Ebenezer Oluwakemi , Islam Md. Shahidul 
Published: March 2020

Background:

Diabetes Mellitus (DM) is a complex metabolic disease illustrated by
abnormally high levels of plasma glucose or hyperglycaemia. Accordingly, several α-glucosidase
inhibitors have been developed for the treatment of diabetes and other degenerative disorders.
While, a coumarin ring has the privilege to represent numerous natural and synthetic compounds
with a wide spectrum of biological activities e.g. anti-cancer, anti-HIV, anti-viral, anti-malarial,
anti-microbial, anti-convulsant, anti-hypertensive properties. Besides this, coumarins have also
shown potential to inhibit α-glucosidase leading to a generation of new promising antidiabetic
agents. However, the testing of O-substituted coumarins for α-glucosidase inhibition has evaded the
attention of medicinal chemists.

Methods:

For O-alkylation/acetylation reactions, the hydroxyl coumarins (A-B) initially activated by
K2CO3 in dry DMF were reacted with variedly substituted haloalkanes at room temperature under
nitrogen. The synthesized compounds were tested for their α-glucosidase (from Saccharomyces
cerevisiae) inhibitory activity and anti-oxidant activity using DPPH radical scavenging activity. In
silico docking simulations were conducted using CDocker module in DS (Accelrys) to explore the
binding modes of the representative compounds in the catalytic site of α-glucosidase.

Results:

All the coumarin analogues (A1, B1, A2-A10, B2-B8) including their precursors (A-B)
were evaluated for their in vitro α-glucosidase inhibition using acarbose as a standard inhibitor. All
the mono O-alkylated coumarins (except A1) showed significant (p <0.05) α-glucosidase inhibition
relative to the hydroxyl coumarin (A) with IC50 values ranging between 11.084±0.117 to 145.24±
29.22 µg/mL. Compound 7-(benzyloxy)-4, 5-dimethyl-2H-chromen-2-one (A9) bearing a benzyl
group (Ph-CH2-) at position 7 showed a remarkable (p <0.05) increase in the activity (IC50 =
11.084±0.117 µg/mL), almost four-fold more than acarbose (IC50 = 40.578±5.999 µg/mL). The
introduction of –NO2 group dramatically improved the anti-oxidant activity of coumarin, while the
O-alkylation/acetylation decreased the activity.

Conclusion:

The present study describes the synthesis of functionalized coumarins and their
evaluation for α-glucosidase inhibition and antioxidant activity under in vitro conditions. Based on
IC50 data, the mono O-alkylated coumarins were observed to be stronger inhibitors of α-glucosidase
with respect to their bis O-alkylated analogues. Coumarin (A9) bearing O-benzyloxy group
displayed the strongest α-glucosidase inhibition, even higher than the standard inhibitor acarbose.
The coumarin (A10) bearing –NO2 group showed the highest anti-oxidant activity amongst the
synthesized compounds, almost comparable to the ascorbic acid. Finally, in silico docking simulations
revealed the role of hydrogen bonding and hydrophobic forces in locking the compounds in
catalytic site of α-glucosidase.