Abstract:
Benzo[
b
]thiophene has been implicated as molecular framework in the drug discovery against broadspectrum of biological targets. In the antidiabetic drug regime, benzo[
b
]thiophene based SGLT2 andALR2 inhibitors have been recently developed but their potential towards α-amylase inhibitionremained unexplored to date. In this context, a series of novel small molecule benzo[
b
]thiophene-2- carboxylic acid derivatives
(3a-p)
was synthesized, characterized, and evaluated for antidiabeticactivity as α-amylase inhibitors. We found that, all benzo[
b
]thiophene derivatives exhibitedsignificant α-amylase inhibition with IC
value ranging from 5.37 ± 0.25 μM to 29.89 ± 0.68 μM. TheSAR studies showed benzo[
b
]thiophene carboxylate bearing bis(2-hydroxyethyl)amino group (
3b
)was most potent with IC
of 5.37 ± 0.25 μM compared to standard drug Acarbose (IC
= 6.40 ± 0.14μM). Further, the enzyme inhibition mechanism study regarded
3b
as competitive inhibitor of α-amylase with Ki value of 1.76 μM. A detailed
in silico
study was also performed in order to estimatebinding properties, drug likeness and predict toxicity profile of these agents. It was demonstratedthat novel small molecule benzo[
b
]thiophene derivative (
3b
) can effectively bind through H-bonding,hydrophobic and π-stacking interactions within α-amylase active site. Moreover, drug likeness andtoxicity prediction studies suggested compound
3b
as potential & safter α-amylase inhibitor. Overall,our present study disclosed a novel class of benzo[
b
]thiophene based α-amylase inhibitors andopened a template for further lead optimization and development.
