Bioorganic & Medicinal Chemistry Letters
Synthesis and biological evaluation of novel 1,2,4-triazine derivatives
bearing carbazole moiety as potent
a-glucosidase inhibitors
⇑
Guangcheng Wang , Jing Wang, Dianxiong He, Xin Li, Juan Li, Zhiyun Peng
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of 1,2,4-triazine derivatives bearing carbazole moiety 7a–7p were designed, synthesized, and
Received 1 January 2016
Revised 8 April 2016
Accepted 23 April 2016
Available online xxxx
evaluated for their
potent -glucosidase inhibitory activity, with IC50 values in the range of 4.27 0.07–47.75 0.25
compared to the standard drug acarbose. Among the series, compound 7k represented the most potent
-glucosidase inhibitory activity with IC50 values of 4.27 0.07 M. Kinetic analysis revealed that com-
pound 7k is a non-competitive inhibitor with a Ki of 4.43 M. Furthermore, the binding interactions of
compound 7k with -glucosidase was confirmed through molecular docking. This study showed these
1,2,4-triazine derivatives bearing carbazole moiety as a new class of -glucosidase inhibitors.
a
-glucosidase inhibitory activity. The majority of the screened compounds displayed
a
l
M as
a
l
l
Keywords:
1,2,4-Triazine
Carbazole
a
a
Ó 2016 Elsevier Ltd. All rights reserved.
a-Glucosidase inhibitor
Enzyme kinetic study
Molecular docking
Diabetes mellitus (DM) is a common group of chronic metabolic
diseases characterized by hyperglycemia, resulting from insuffi-
cient insulin secretion or inefficient utilization of insulin.1 The
chronic hyperglycemia of diabetes causes serious damage to many
of the body’s organs, especially the eyes, kidneys, nerves, heart, and
blood vessels.2,3 Therefore, control of postprandial blood glucose
level is critical for treatment of diabetes and for reducing chronic
vascular complications.4,5
with a wide range of biological activity including antimalarial,12
anticonvulsant,13 antifungal,14 antiinflammatory,15 anticancer,16
anti-HIV17 and neuroprotective18 properties. Besides this, triazi-
noindole is one of the triazine derivatives have been reported in
the literature to possess potent
a-glucosidase inhibitory
activities.19
On the other hand, carbazole and its derivatives are an impor-
tant type of nitrogen-containing aromatic heterocyclic compounds
possess a wide variety of biological activities including antimicro-
bial,20 anticancer,21 antifungal22 and antioxidant23 activities.
Furthermore, recent studies have shown that many natural and
synthetic molecules containing the carbazole moiety act as
a-Glucosidase is an enzyme of the intestinal brush border,
which catalyze the final step in the digestive process of carbohy-
drates to release absorbable monosaccharides resulting in
increased blood glucose levels.6 Thus, inhibition of
a-glucosidase
can significantly delay carbohydrate digestion and glucose absorp-
a
-glucosidase inhibitors.24–26
tion, resulting in reduced postprandial plasma glucose levels and
In our effort to identify novel
a-glucosidase inhibitors, we
suppression of postprandial hyperglycemia.7 Therefore,
a
-glucosi-
dase has been recognized as a therapeutic target for the treatment
type-2 diabetes mellitus.8
-Glucosidase inhibitors (acarbose,
miglitol, voglibose) have been widely used in clinic for treatment
of patients with type 2 diabetes.9,10 However, these classic
-glu-
designed and synthesized a new series of 1,2,4-triazine derivatives
bearing carbazole moiety. Herein, we report synthesis and charac-
terization of the novel compounds as well as their inhibitory activ-
a
ities on
A general synthesis of title compounds 7a–7p is exhibited in
Scheme 1. Compound was prepared by reaction between
a-glucosidase.
a
cosidase inhibitors cause various side effects including bloating,
2
flatulence, diarrhea, abdominal discomfort, and pain.11 Hence, the
2-(chloromethyl)oxirane and different substitute carbazoles 1 in
the presence of KOH as base. Treatment of different commercially
available aromatic aldehydes 3 with thiamine yielded compound
4.27 Oxidation of compound 4 with NH4NO3 and Cu(AcO)2ÁH2O in
80% acetic acid gave corresponding benzil 5,28 which condensation
with thiosemicarbazide in acetic acid at 120 °C for 3 h provided the
5,6-diaryl-1,2,4-triazine-3-thiol 6.29 Finally, compound 6 was con-
densed with intermediate 2 in ethanol at 80 °C for 4 h to result in
search of novel
a-glucosidase inhibitors with better activity and
fewer side effects is still in progress.
1,2,4-Triazine is a prominent structural core system found in
numerous natural and synthetic biologically active compounds
⇑
Corresponding author. Tel./fax: +86 743 8563911.
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.