Triazoloquinazolines as a new class of potent α-glucosidase inhibitors
Currently, a wide range of oral antidiabetic drugs are being utilized due to the absence of effi-
cient and affordable interventions [7]. In most cases, the prescribed antidiabetic drugs are
responsible for various side effects such as liver problems, diarrhea, lactic acidosis, and high
rate of secondary failure.
α-Glucosidase is present in the brush border membrane of the intestine. It catalyzes the
hydrolysis of α-(1!4)-glycosidic linkage of sugar (disaccharides and starch), releasing free
monosaccharides (α-D-glucose) during the final step of carbohydrate digestion. Thus, α-glu-
cosidase inhibitors (AGIs) can suppress postprandial hyperglycemia and decrease carbohy-
drate digestion rate; therefore, reduce the glucose level in the blood stream [1,8–13].
α-Glucosidase inhibitors are a unique class of anti-diabetic drugs, described as an attractive
therapeutic target for type-II diabetes and may also be used for other diseases in which carbo-
hydrates or its biosynthesis are potential targets including cancer, hyperlipoproteinemia, HIV,
and obesity [14,15]. In contrast to other oral antidiabetic drugs, AGIs exert their effect locally
in the intestine, rather than modulating some biochemical processes in the body. Accordingly,
extensive research has been carried out, elucidating the possible role of AGIs in the treatment
of prediabetic conditions, such as impaired glucose tolerance IGT and impaired fasting glucose
IFG [16].
α-Glucosidase inhibitors (acarbose, miglitol, and voglibose) are characterized by similar
structure to that of the sugar moieties (disaccharides and oligosaccharides); thus, they bind to
α-glucosidase via the carbohydrate site [17–19]. During the last two decades, the AGIs have
been introduced as antidiabetic drugs and recommended as the first line therapy by the IDF
and American Association of Clinical Endocrinologists (AACE) [20]. These drugs are well tol-
erated; however, their localized gastrointestinal adverse effects such as diarrhea, bloating, and
flatulence restrict the long-term acquiescence for treatment [8,9].
Recently, nitrogen-containing heterocyclic compounds without glycosyl, such as triazole,
quinazoline, imidazole, thiazole, and pyrazole, have been documented as potent in vitro AGIs.
Moreover, some natural and synthesized flavonoids (such as luteolin, naringenin, anthocya-
nins, and baicalein), coumarin, chromones and their derivatives (Fig 1 d-f) have been targeted
as potent AGIs [8,9,21–26]. Triazole and quinazoline derivatives have gained considerable
attention owing to their important pharmacological activities (Fig 1). For instance, carbazole-
linked triazole compounds have shown potent α-glucosidase inhibition activity in relation to
that of the standard acarbose (Fig 1C) [22]. Furthermore, substituted quinazolines have been
reported to possess antihyperglycemic and α-glucosidase inhibition effects (Fig 1A and 1B). In
particular, the modified 4-Cl/Br-2-phenyl-quinazolines reversibly inhibited α-glucosidase
enzyme activity in a non-competitive manner (Fig 1B), resulting in excellent inhibitory activity
comparable to that of acarbose [24].
In our previous study, we have shown that benzoquinazoline derivatives have the potential
to act as a new class of AGIs. Their IC50 value was 69.20 1.76, 59.60 0.52, 49.40 0.50,
50.20 0.37, and 88.20 0.89 μM, whereas that of acarbose was 143.54 μM [8]. In addition,
our 2-phenoxy-pyridotriazolopyrimidine was found to possess potent α-glucosidase inhibiti-
ory (104.07 4.89 μM) in relation to acarbose (143.54 μM) (Fig 1G) [9]. Particularly, our study
suggested that different types of interactions between benzoquinazolines and α-glucosidase,
such as H-bonding, free binding energy, closest amino acids, and hydrophobic effects, are key
factors involved in increasing the inhibitory effects [8]. Further, structure–activity relationship
(SAR) study on benzoquinazolines suggested that the type of functional groups attached at
position 2 of benzoquinazoline was found to increase α-glucosidase inhibitory activity [8] and
that the activity largely depends on electron donating/withdrawing substituents (Fig 1H).
The undesired effects of available AGIs have encouraged researchers to discover safer and
new generation of α-glucosidase inhibitor agents. Therefore, it is necessary to clarify how the
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