J. Liu et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1715–1719
1717
they may cause side effects such as flatulence, abdominal cramps,
Table 1
2
1,22
In vitro a-glucosidase inhibitory activity of substituted phenylacetate derivatives
vomiting, diarrhea, serious hepatic injury, and acute hepatitis.
In recent years, much efforts have been devoted to develop effec-
tive non-sugar inhibitors of -glucosidase from natural sources
because of the high levels of natural abundance and biological
Entry
Compound
Inhibition ratioa (%)
IC50b
(lM)
a
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
15.32 ± 1.25
29.29 ± 1.64
18.42 ± 1.17
20.38 ± 1.48
NA
19.83 ± 2.05
20.76 ± 1.39
14.44 ± 1.18
65.27 ± 1.02
NA
34.05 ± 1.75
NA
28.66 ± 1.46
14.63 ± 0.93
NA
>200
185.26 ± 3.08
>200
2
3,24
efficacy.
182.68 ± 2.70
Schiff bases are attractive and versatile scaffolds with relevant
applications in several areas, including asymmetric catalysis,
chemosensors, photochemical switches, live cell imaging, or phar-
>200
190.17 ± 3.52
>200
2
5–29
macology.
Schiff bases have been reported as antiprotozoal
46.81 ± 1.17
activities, antibacterial activities, anti-HIV activities, anticonvul-
sant activities, antitumor activities, and anthelminthic activities,
1
1
1
0
1
2
137.45 ± 2.18
acetyl cholinesterase inhibitors,
ulate plants growth.
a
-glucosidase inhibitors and stim-
Another popular scaffold is tropic acid,
which is an important building block for biologically active tropane
3
0–32
13
14
15
186.50 ± 3.46
>200
3
3,34
alkaloids, such as anisodamine, anisodamine and scopolamine.
1
1
1
6
7
8
19.22 ± 1.55
NA
>200
They are typical acetylcholine M receptor antagonists, yet aniso-
damine appears to be less potent and less adverse reactions than
12.86 ± 1.72
13.68 ± 1.63
11.10 ± 1.82
15.85 ± 0.97
47.84 ± 1.96
27.28 ± 1.75
16.81 ± 2.16
14.09 ± 1.16
29.90 ± 1.59
52.52 ± 1.87
>200
>200
>200
>200
83.76 ± 2.07
>200
>200
>200
191.36 ± 4.03
109.15 ± 3.11
3
5
atropine. The ability to improve the microcirculation makes
anisodamine in the treatment of gastrointestinal smooth muscle
19
20
3
6
21
spasm, infective toxic shock and organophosphorus intoxication.
2
2
2
3
Also, anisodamine is applied in treatment of sudden deafness,
acute otitis media, anaphylactoid purpura, acute alcoholism, dia-
betes, myocardial infarction and bronchial asthma, etc. Recently,
24
25
25
26
2
2
6
7
a-substituted phenylacetic acid derivatives has been reported to
1-Deoxynojirimycin
the investigations of expressed antibacterial, bactericidal, insectici-
a
dal, antioxidant, anticancer, antidiabetic, anti-HIV virus, anti-
Percent inhibition at a concentration of 100
Inhibitor concentration (mean ± SD of three independent experiments) required
-glucosidase. NA = not active.
lM.
37
b
inflammatory and other biological activities. However, there is
no report about -substituted phenylacetic acid derivatives that
performing -glucosidase inhibitory activity. In addition, several
for 50% inactivation of
a
a
a
studies have already proved that rosmarinic acid derivatives pos-
better than those of 1-deoxynojirimycin (Table 1, entry 9 vs entry
27). However, while the R group in 9 changes from thiourea to
methoxy (10), it becomes no active to a-glucosidase (Table 1, entry
9 vs entry 10). These results indicate that the steric and electronic
properties of the substituted group in Schiff bases cause great
effect to their inhibition abilities. The similar results are obtained
3
sess a number of interesting biological activities, including antiox-
3
8
idant, anti-inflammatory, antiviral and antibacterial effects.
In this Letter, we have synthesized a series of Schiff bases of
arylacetates and the other -arylacetate derivatives from commer-
cial sources with simple methods. All of the -arylacetate deriva-
tives have been evaluated in in vitro -glucosidase inhibition
assay, hypoglycemic assay and antitumor assay. We found that
some compounds show strong inhibition against -glucosidase,
hypoglycemic activity, and even antitumor activity as well.
As described in Scheme 1, a series of -substituted arylacetate
derivatives have been synthesized followed by the literature
a-
a
a
a
between 11 and 12 (Table 1, entries 11 and 12). For the
a-hydrox-
ymethyl arylacetates (13–17), no significant inhibition against
a-
a
glucosidase is observed (Table 1, entries 13–17). After esterifica-
tion of compound 13 to 18, 19, 20 with different carboxylic acids,
the inhibition abilities against a-glucosidase become even worse
with low IC50 values and inhibition ratios (Table 1, entries 18–20
a
3
9–42
reported.
materials reacted with ethyl formate and sodium,
etate derivatives are obtained after acidified by hydrochloric acid.
With -formyl arylacetates in hand, the addition of methoxy
amine or thiosemicarbazide can provide the corresponding Schiff
bases, while the presence of sodium borohydride results in
hydroxymethyl arylacetates. The -hydroxymethyl arylacetates
With commercial arylacetates (1–5) as starting
vs entry 13). Compared with compound 16, there is no obvious
4
a-formyl arylac-
change on the inhibition ability with its ester form 21 bearing R
4
as 2-acetoxybenzoic group or 23 bearing R as benzoyl group
a
(Table 1, entries 21 and 23). However, compound 22 bearing with
4
R
as (E)-3-(3,4-dimethoxyphenyl)acryloyl group is a potent inhi-
-glucosidase with IC50 value of 83.76 M, that is bet-
a
-
bitor against
a
l
a
ter than 1-deoxynojirimycin (Table 1, entry 22 vs entry 27). Once
compound 17 forms the esters (24, 25 and 26), their inhibition
abilities become active although the inhibition ratios are not very
can be further transformed to the corresponding esterified esters
with carboxylic acids. Evidenced by full characterizations such as
IR, NMR, MS and elemental analysis, these
etate derivatives have been investigated by different biological
assays.
a
-substituted arylac-
high (Table 1, entries 24–26). Taken together, Schiff base of
stituted arylacetate 9 and ester form of -substituted arylacetate
22 have been found to be as potent inhibitors against -glucosi-
dase. Also, we found that the steric effect and electronic effect of
substituted groups in -substituted arylacetates could cause great
a-sub-
a
a
Using 1-deoxynojirimycin as a positive control, the
tuted arylacetates are examined by in vitro -glucosidase inhibi-
-substituted arylacetates and
-glucosidase are summarized in Table 1.
Compared to 1-deoxynojirimycin, -formyl arylacetate derivatives
1–5) do not show significant inhibition against -glucosidase
Table 1, entries 1–5). After the -formyl arylacetate derivatives
a-substi-
a
a
4
3
tion studies. The IC50 values of
their inhibition ratios of
a
effect to their inhibition abilities.
a
Kinetics of the representative a-glucosidase inhibitor was fur-
a
ther studied to determine the type of inhibition by theanalysis of
the Lineweave–Burk plots, as depicted in Figure 2. The value of
1/V increased with increasing concentrations of compound 9, but
the intercept on the x-axis remains constant, but with different
gradients. This result suggests a noncompetitive inhibition of com-
(
(
a
a
transformed to their corresponding Schiff bases, the inhibition
activity of compounds 6, 7 and 8 are comparable as their precur-
sors 1, 2 and 3 (Table 1, entries 6–8 vs 1–3). To our surprise, com-
pound 9. The K
inhibitor was expected to bind to a site other than the active site
of -glucosidase.
i
value for compound 9 was 65.36 lM. Hence, the
4
4
pound 9 shows strong inhibition against
a-glucosidase with IC50
value of 46.81 M and inhibition ratio of 65.27%, which are even
l
a
Liu, Jinbing
