Journal of Chemistry

Volume 2014 (2014), Article ID 590129, 6 pages

http://dx.doi.org/10.1155/2014/590129

Research Article

Synthesis and Biological Evaluation of New Substituted 3-[4-(Phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one Derivatives as α-Glucosidase Inhibitors

Yu-ling Wang,¹ Ting-jian Zhang,¹ Jing-wei Liang,¹ Fan-hao Meng,¹ and Shao-jie Wang²

¹School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China

²Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China

Received 17 January 2014; Accepted 10 March 2014; Published 6 April 2014

Academic Editor: Gabriel Navarrete-Vazquez

Copyright © 2014 Yu-ling Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

A series of new substituted 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives bearing groups methoxy, tert-butyl, and atoms of halogens at the para-position of the A-ring were synthesized and in vitro biological activities were evaluated as nonsugar α-glucosidase inhibitors. Most of the test compounds demonstrated significant α-glucosidase inhibitory activity relative to that of Acarbose (IC₅₀ = 29.26 μM). The para-substitution with a methoxy group or halogens could notably increase the potency. Compounds 17, 18, and 23, with IC₅₀ values of 0.025 μM, 0.014 μM, and 0.018 μM, respectively, may be of significance for the further development of new nonsugar α-glucosidase inhibitors.

1. Introduction

α-Glucosidase (EC 3.2.1.20), located in the brush-border surface membrane of intestinal cells, is a key enzyme catalyzing the final step in the digestive process of carbohydrates into glucose [1]. This enzyme has drawn a special interest in the pharmaceutical research community because the inhibition of its catalytic activity can retard the liberation of glucose from dietary complex carbohydrates and delay glucose absorption, resulting in reduced postprandial plasma blood glucose level and suppression of postprandial hyperglycemia [2]. Thus, α-glucosidase inhibitors exhibit high promise as therapeutic agents for the treatment of metabolic disorders, such as type II non-insulin-dependent diabetes mellitus, obesity, and hyperglycemia [3]. α-Glucosidase inhibitors are also known to be promising as antiviral and antitumor agents that interfere with the biosynthesis of N-linked oligosaccharide chains [4].

Classically, efforts for the development of a new set of α-glucosidase inhibitors have focused mainly on sugar mimics, such as disaccharides, iminosugars, carbasugars, and thiosugars. However, numerous disadvantages exist for this strategy, including poor activity, low natural abundance, or complicated stereochemistry, which makes them difficult to approach synthetically. A more modern approach is to investigate nonsugar α-glucosidase inhibitors [5–9].

We had previously reported that 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives [10], designed by incorporating the phenylsulfonamide chalcone substructure into the benzopyran backbone shown in Figure 1 [11], have the potential to act as a new class of nonsugar α-glucosidase inhibitors. The preliminary study on the structure-activity relationship had focused on the C-ring, which showed that the modification of this substructure with halogen or bulky groups can reduce the inhibitory activity, whereas introducing diethylamino group at C7 and methoxy and hydroxy groups at C6 and C7, respectively, can increase the potency significantly. In addition, we found that compounds bearing the methyl group displayed higher activities than those bearing a hydrogen atom, such as compounds 7u and 7j (Figure 1). This observation encouraged us to further investigate the influence of A-ring substituents on the α-glucosidase inhibitory activity of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives.

Figure 1: Chemical structures of compounds 7a, 7h, 7i, 7j, and 7u.

In the present study, a series of new substituted 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives (Scheme 1), bearing halogen atoms, methoxy, or tert-butyl groups at the para-position of the A-ring while keeping the favorable substituents on the C-ring unchanged, were synthesized and assayed on yeast α-glucosidase to explore the effect of these substituents on the α-glucosidase inhibitory activity and obtain a comprehensive understanding of the structure-activity relationships of this class of compounds.

Scheme 1: Synthesis of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives 10 –26. Reagents and conditions: (a) SOCl₂, 1,2,3-benzotriazole, and reflux; (b) ethyl acetoacetate, NaH, THF, and rt; (c) SnCl₂, ethyl acetate, and reflux; (d) substituted benzenesulfonyl chloride, pyridine, CH₂Cl₂, −10°C, and then rt; (e) substituted salicylaldehyde, piperidine, acetic acid, EtOH, and reflux.

2. Results

The compounds 2 –9 were synthesized according to the literature [12]. 4-Nitrobenzoic acid with thionyl chloride and 1,2,3-benzotriazole was refluxed to get 4-nitrobenzoyl-1,2,3-benzotriazole (2) as shown in Scheme 1 [12]. The resulting compound reacted with ethyl acetoacetate in the presence of sodium hydride, followed by hydrolysis to form ethyl 3-(4-nitrophenyl)-3-oxopropanoate (3) [13], which was subsequently reduced with stannous chloride in ethyl acetate to provide the key intermediate ethyl 3-(4-aminophenyl)-3-oxopropanoate (4) as shown in Scheme 1 [14]. Afterward, compound 4 was acylated with a series of para-substituted phenylsulfonyl chlorides to obtain ethyl 3-[4-(phenylsulfonamido)phenyl]-3-oxopropanoates (5 –9). Lastly, compounds 5 –9 were reacted separately with substituted salicylaldehydes via Knoevenagel condensation. The target compounds 10 –26 were prepared as shown in Scheme 1 and seventeen target compounds were obtained in modest yields.

All target compounds were evaluated spectrophotometrically at 490 nm on yeast α-glucosidase to evaluate their potential as α-glucosidase inhibitors. Acarbose was included as a reference compound. The in vitro α-glucosidase inhibitory activity of the test compounds was assayed as described previously [10]. The test compounds were initially assayed for their ability to inhibit α-glucosidase at a concentration of 1 μg·mL⁻¹. Compounds that displayed more than 50% inhibition were selected for concentration dependent activity evaluation and calculation of IC₅₀ values, as shown in Table 1.

Table 1: The α-glucosidase inhibitory activity of new substituted 3-4-(phenylsulfonamido)benzoyl-2H-1-benzopyran-2-one derivatives.

Number

IC₅₀ (M)a

10
H
H
F
7.568 ± 0.575

11
H
OH
F
0.282 ± 0.038

12
H
N(C₂H₅)₂
F
0.085 ± 0.014

13
OCH₃
OH
F
0.075 ± 0.012

14
H
H
Cl
1.088 ± 0.232

15
H
OH
Cl
0.171 ± 0.034

16
H
N(C₂H₅)₂
Cl
0.108 ± 0.019

17
OCH₃
OH
Cl
0.025 ± 0.005

18
H
H
Br
0.014 ± 0.003

19
H
OH
Br
0.199 ± 0.016

20
H
N(C₂H₅)₂
Br
0.125 ± 0.035

21
OCH₃
OH
Br
0.036 ± 0.008

22
H
H
OCH₃
0.073 ± 0.012

23
H
OH
OCH₃
0.018 ± 0.003

24
H
N(C₂H₅)₂
OCH₃
0.037 ± 0.006

25
OCH₃
OH
OCH₃
0.069 ± 0.011

26
H
N(C₂H₅)₂
C(CH₃)₃
—b

Acarbose

29.26 ± 3.23

IC₅₀ values are represented as means ± SD ( = 2-3). bLess than 50% inhibition at 10 g/mL.

3. Discussion

Except for compound 10 (IC₅₀ = 7.568 μM) in the halogen substituted series, most of the tested compounds showed stronger inhibitory activity than that of compound 7a, previously studied in [10] (IC₅₀ = 3.283 μM). Compound 18 (IC₅₀ = 0.014 μM) presented as the strongest inhibitor which was nearly 235 times higher than compound 7a. The activities of compounds 13 (IC₅₀ = 0.075 μM), 17 (IC₅₀ = 0.025 μM), and 21 (IC₅₀ = 0.036 μM) were increased about 3, 8, and 6 times, respectively, compared with the activity of compound 7j, previously described in [10] (IC₅₀ = 0.199 μM). This observation suggested that the halogen atoms at the para-position of the A-ring could greatly enhance the activity. However, this fact was contrary to the disadvantageous effect observed for the halogen groups presented on the C-ring [10].

The activity of compound 22 (IC₅₀ = 0.073 μM) in the methoxy substituted series (R₃ = OCH₃) was 45-fold higher than that of compound 7a. Compound 23 displayed an IC₅₀ value of 0.018 μM, which was 320-fold more potent than compound 7 h and was ranked as the strongest inhibitor in this series.Compounds 24 (IC₅₀ = 0.037 μM) and 25 (IC₅₀ = 0.069 μM) also exhibited a much better inhibitory activity compared with compounds 7i and 7j. Interestingly, most compounds in this series showed higher activities than those in the methyl substituted series. The activities of compounds 22, 23, and 24 were higher than those of compounds 7l (IC₅₀ = 3.577 μM), 7s (IC₅₀ = 1.125 μM), and 7t (IC₅₀ = 0.347 μM), respectively. All these observations indicated that the methoxy group substituted at the para-position of the A-ring was favorable for increasing the α-glucosidase inhibitory activity of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives.

The activity of compound 26 with tert-butyl group at the para-position of the A-ring disappeared, suggesting that this bulky group is unfavorable for binding with α-glucosidase, which is in agreement with what we had found on the C-ring [10].

4. Experimental

4.1. Chemistry

Melting points were recorded using YRT-3 melting point apparatus. The ¹H-NMR spectra were recorded in DMSO- on a Bruker ARX-300 spectrometer, and chemical shifts (δ) were expressed in ppm downfield from the TMS and were used as the internal standard. Coupling constant (J) values were in Hz. The IR spectra were determined as KBr pellets on the Bruker IFS-55 spectrometer and were expressed in cm⁻¹. The progress of the reactions was monitored by TLC using several solvent systems with different polarities. The TOF-HRMS spectra were recorded on a Bruker Micro-TOFQ. All solvents and reagents were of analytical grade.

General Procedure for the Synthesis of Compounds 10 – 26 . Compounds 5 –9 (1.4 mmol) reacted with substituted salicylaldehyde (1.6 mmol) separately; five drops of piperidine, one drop of glacial acetic acid, and ethanol (10 mL) were added and stirred under reflux in an argon atmosphere for 0.5 h. The mixture was cooled to room temperature, filtered to collect the solid (if there was no precipitate, 25 mL water was added), and then washed with a small amount of ethanol. In most cases, the products were sufficiently pure. Products with impurities were purified via column chromatography, petroleum ether, and ethyl acetate systems with different polarities as eluent.

4.1.1. [4-(4-Fluorophenylsulfonamido])benzoyl]-2H-1-benzopyran-2-one (10)

White solid, 49% yield. M.p.: 204.5-205.5°C; ¹H-NMR (DMSO-, ppm): δ 7.22 (d, 2H, J = 8.7 Hz, H-3′, 5′), 7.44 (m, 4H, H-6, 8, 3′′, 5′′), 7.73 (m, 1H, H-7), 7.83 (m, 3H, H-5, 2′, 6′), 7.90 (m, 2H, H-2′′, 6′′), 8.34 (s, 1H, H-4), 11.03 (s, 1H, NH); IR (KBr, cm⁻¹): 3432, 3240, 1732, 1652, 1601, 1567, 1510, 1240, 1169, 838, 800; TOF-HRMS: m/z 424.0649 [M+H]⁺ (C₂₂H₁₅FNO₅S requires 424.0656).

4.1.2. 3-[4-(4-Fluorophenylsulfonamido)benzoyl]-7-hydroxy-2H-1-benzopyran-2-one (11)

Brown solid, 54% yield. M.p.: 159-160°C; ¹H-NMR (DMSO-, ppm): δ 6.76 (s, 1H, H-8), 6.82 (d, 1H, J = 8.6 Hz, H-6), 7.12 (d, 2H, J = 8.6 Hz, H-3′, 5′), 7.39 (t, 2H, J = 8.8 Hz, H-3′′, 5′′), 7.64 (d, 1H, J = 8.6 Hz, H-5), 7.70 (d, 2H, J = 8.6 Hz, H-2′′, 6′′), 7.88 (dd, 2H, J = 8.8 Hz and 5.2 Hz, H-2′, 6′), 8.22 (s, 1H, H-4); IR (KBr, cm⁻¹): 3474, 2924, 1730, 1601, 1228, 1166, 839, 816; TOF-HRMS: m/z 440.0599 [M+H]⁺ (C₂₂H₁₅FNO₆S requires 440.0605).

4.1.3. 3-[4-(4-Fluorophenylsulfonamido)benzoyl]-7-(N,N-diethylamino)-2H-1-benzopyran-2-one (12)

Yellow solid, 51% yield. M.p.: 207-208°C; ¹H-NMR (DMSO-, ppm): δ 1.13 (t, 6H, J = 6.9 Hz, 2CH₂CH₃), 3.48 (q, 4H, J = 6.9 Hz, 2CH₂CH₃), 6.57 (s, 1H, H-8), 6.75 (d, 1H, J = 9.0 Hz, H-6), 7.18 (d, 2H, J = 8.6 Hz, H-3′, 5′), 7.43 (t, 2H, J = 8.7 Hz, H-3′′, 5′′), 7.56 (d, 1H, J = 9.0 Hz, H-5), 7.68 (d, 2H, J = 8.6 Hz, H-2′, 6′), 7.92 (dd, 2H, J = 8.7 Hz and 5.3 Hz, H-2′′, 6′′), 8.17 (s, 1H, H-4), 10.90 (s, 1H, NH); IR (KBr, cm⁻¹): 3441, 3164, 2973, 1690, 1617, 1599, 1580, 1508, 1234, 1166, 827, 812; TOF-HRMS: m/z 495.1384[M+H]⁺ (C₂₆H₂₄FN₂O₅S requires 495.1391).

4.1.4. 3-[4-(4-Fluorophenylsulfonamido)benzoyl]-7-hydroxy-6-methoxy-2H-1-benzopyran-2-one (13)

Yellow solid, 39% yield. M.p.: 226-227°C; ¹H-NMR (DMSO-, ppm): δ 3.81 (s, 3H, OCH₃), 6.84 (s, 1H, H-8), 7.22 (d, 2H, J = 8.5 Hz, H-3′, 5′), 7.35 (s, 1H, H-5), 7.44 (m, 2H, H-3′′, 5′′), 7.77 (d, 2H, J = 8.6 Hz, H-2′, 6′), 7.91 (m, 2H, H-2′′, 6′′), 8.22 (s, 1H, H-4), 10.89 (s, 1H, NH); IR (KBr, cm⁻¹): 3429, 3206, 2922, 1680, 1658, 1602, 1569, 1509, 1261, 1156, 840, 790; TOF-HRMS: m/z 470.0704 [M+H]⁺ (C₂₃H₁₇FNO₇S requires 470.0711).

4.1.5. 3-[4-(4-Chlorophenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one (14)

White solid, 87% yield. M.p.: 208-209°C; ¹H-NMR (DMSO-, ppm): δ 7.21 (d, 2H, J = 8.7 Hz, H-3′, 5′), 7.42 (m, 2H, H-6, 8), 7.66 (d, 2H, J = 8.7 Hz, H-3′′, 5′′), 7.73 (m, 1H, H-7), 7.84 (m, 5H, H-5, 2′, 6′, 2′′, 6′′), 8.34 (s, 1H, H-4), 11.08 (s, 1H, NH); IR (KBr, cm⁻¹): 3441, 3243, 1736, 1653, 1603, 1510, 1240, 1164, 828, 801; TOF-HRMS: m/z 440.0354 [M+H]⁺ (C₂₂H₁₅ClNO₅S requires 440.0360).

4.1.6. 3-[4-(4-Chlorophenylsulfonamido)benzoyl]-7-hydroxy-2H-1-benzopyran-2-one (15)

Brown solid, 24% yield. M.p.: 186-187°C; ¹H-NMR (DMSO-, ppm): δ 6.75 (s, 1H, H-8), 6.81 (d, 1H, J = 8.6 Hz, H-6), 7.01 (d, 2H, J = 8.6 Hz, H-3′, 5′), 7.55 (d, 2H, J = 8.5 Hz, H-3′′, 5′′), 7.62 (d, 3H, J = 8.5 Hz, H-5, 2′, 6′), 7.77 (d, 2H, J = 8.5 Hz, H-2′′, 6′′), 8.16 (s, 1H, H-4); IR (KBr, cm⁻¹): 3445, 1716, 1601, 1506, 1225, 1162, 850, 790; TOF-HRMS: m/z 456.0303 [M+H]⁺ (C₂₂H₁₅ClNO₆S requires 456.0309).

4.1.7. 3-(4-Chlorophenylsulfonamidobenzoyl)-7-(N,N-diethylamino)-2H-1-benzopyran-2-one (16)

Brown solid, 31% yield. M.p.: >250°C; ¹H-NMR (DMSO-, ppm): δ 1.13 (t, 6H, J = 7.0 Hz, 2CH₃), 3.47 (q, 4H, J = 7.0 Hz, 2CH₂), 6.56 (s, 1H, H-8), 6.76 (d, 1H, J = 8.6 Hz, H-6), 7.09 (d, 2H, J = 8.2 Hz, H-3′, 5′), 7.61 (m, 5H, H-5, 2′, 6′, 3′′, 5′′), 7.82 (d, 2H, J = 8.1 Hz, H-2′′, 6′′), 8.11 (s, 1H, H-4); IR (KBr, cm⁻¹): 3433, 3173, 2973, 1718, 1689, 1617, 1581, 1508, 1233, 1163, 825, 789; TOF-HRMS: m/z 511.1089 [M+H]⁺ (C₂₆H₂₄ClN₂O₅S requires 511.1095).

4.1.8. 3-[4-(4-Chlorophenylsulfonamido)benzoyl]-7-hydroxy-6-methoxy-2H-1-benzopyran-2-one (17)

Yellow solid, 37% yield. M.p.: >250°C; ¹H-NMR (DMSO-, ppm): δ 3.81 (s, 3H, OCH₃), 6.84 (s, 1H, H-5), 7.22 (d, 2H, J = 8.4 Hz, H-3′, 5′), 7.35 (s, 1H, H-8), 7.66 (d, 2H, J = 8.4 Hz, H-3′′, 5′′), 7.77 (d, 2H, J = 8.5 Hz, H-2′, 6′), 7.84 (d, 2H, J = 8.5 Hz, H-2′′, 6′′), 8.22 (s, 1H, H-4), 10.91 (s, 1H, NH); IR (KBr, cm⁻¹): 3433, 3310, 1681, 1601, 1569, 1509, 1258, 1160, 847, 827; TOF-HRMS: m/z 508.0228 [M+Na]⁺ (C₂₃H₁₆ClNNaO₇S requires 508.0234).

4.1.9. 3-[4-(4-Bromophenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one (18)

Yellow solid, 27% yield. M.p.: 205–207°C; ¹H-NMR (DMSO-, ppm): δ 7.20 (d, 2H, J = 8.7 Hz, H-3′, 5′), 7.42 (m, 3H, H-6, 7, 8), 7.73 (d, 1H, J = 8.6 Hz, H-5), 7.78 (m, 6H, H-2′, 6′, 2′′, 3′′, 5′′, 6′′), 8.34 (s, 1H, H-4); IR (KBr, cm⁻¹): 3433, 3245, 1721, 1604, 1571, 1510, 1240, 1163, 823, 758; TOF-HRMS: m/z 483.9849 [M+H]⁺ (C₂₂H₁₅BrNO₅S requires 483.9855).

4.1.10. 3-[4-(4-Bromophenylsulfonamido)benzoyl]-7-hydroxy-2H-1-benzopyran-2-one (19)

Yellow solid, 43% yield. M.p.: 203.5-204.5°C; ¹H-NMR (DMSO-, ppm): δ 6.77 (s, 1H, H-8), 6.83 (d, 1H, J = 8.6 Hz, H-6), 7.22 (d, 2H, J = 8.7 Hz, H-3′, 5′), 7.66 (d, 1H, J = 8.6 Hz, H-5), 7.76 (m, 6H, H-2′, 6′, 2′′, 3′′, 5′′, 6′′), 8.26 (s, 1H, H-4), 10.94 (s, 1H, OH), 11.03 (s, 1H, NH); IR (KBr, cm⁻¹): 3205, 1715, 1601, 1573, 1508, 1226, 1161, 852, 805; TOF-HRMS: m/z 499.9798 [M+H]⁺ (C₂₂H₁₅BrNO₆S requires 499.9804).

4.1.11. 3-[4-(4-Bromophenylsulfonamido)benzoyl]-7-(N,N-diethylamino)-2H-1-benzopyran-2-one (20)

Yellow solid, 50% yield. M.p.: 215-216°C; ¹H-NMR (DMSO-, ppm): δ 1.14 (t, 6H, J = 6.9 Hz, 2CH₂CH₃), 3.47 (q, 4H, J = 6.9 Hz, 2CH₂CH₃), 6.58 (s, 1H, H-8), 6.76 (d, 1H, J = 8.9 Hz, H-6), 7.20 (d, 2H, J = 8.7 Hz, H-3′, 5′), 7.59 (d, 1H, J = 9.0 Hz, H-5), 7.69 (d, 2H, J = 8.7 Hz, H-3′′, 5′′), 7.77 (q, 4H, H-2′, 6′, 2′′, 6′′), 8.17 (s, 1H, H-4), 10.95 (s, 1H, NH); IR (KBr, cm⁻¹): 3438, 3180, 2974, 1715, 1688, 1617, 1600, 1579, 1508, 1233, 1162, 823, 740; TOF-HRMS: m/z 555.0584 [M+H]⁺ (C₂₆H₂₄BrN₂O₅S requires 555.0590).

4.1.12. 3-[4-(4-Bromophenylsulfonamido)benzoyl]-7-hydroxy-6-methoxy-2H-1-benzopyran-2-one (21)

Yellow solid, 33% yield. M.p.: >250°C; ¹H-NMR (DMSO-, ppm): δ 3.81 (s, 3H, OCH₃), 6.84 (s, 1H, H-5), 7.21 (d, 2H, J = 8.6 Hz, H-3′, 5′), 7.36 (s, 1H, H-8), 7.77 (m, 6H, H-2′, 6′, 2′′, 3′′, 5′′, 6′′), 8.22 (s, 1H, H-4), 10.93 (s, 1H, NH); IR (KBr, cm⁻¹): 3426, 3304, 2924, 1682, 1602, 1569, 1510, 1257, 1157, 823, 787; TOF-HRMS: m/z 529.9904 [M+H]⁺ (C₂₃H₁₇BrNO₇S requires 529.9910).

4.1.13. 3-[4-(4-Methoxyphenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one (22)

White solid, 58% yield. M.p.: 175.5-176.5°C; ¹H-NMR (DMSO-, ppm): δ 3.81 (s, 3H, OCH₃), 7.11 (d, 2H, J = 8.9 Hz, H-3′′, 5′′), 7.20 (d, 2H, J = 8.7 Hz, H-3′, 5′), 7.44 (m, 2H, H-6, 8), 7.70 (d, 1H, J = 8.5 Hz, H-7), 7.78 (m, 5H, H-5, 2′, 6′, 2′′, 6′′), 8.33 (s, 1H, H-4), 10.88 (s, 1H, NH); IR (KBr, cm⁻¹): 3444, 3249, 1741, 1653, 1598, 1498, 1241, 1156, 836, 801; TOF-HRMS: m/z 436.0849 [M+H]⁺ (C₂₃H₁₈NO₆S requires 436.0856).

4.1.14. 3-[4-(4-Methoxyphenylsulfonamido)benzoyl]-7-hydroxy-2H-1-benzopyran-2-one (23)

Orange solid, 59% yield. M.p.: 135–145°C; ¹H-NMR (DMSO-, ppm): δ 3.80 (s, 3H, OCH₃), 6.76 (s, 1H, H-8), 6.83 (d, 1H, J = 8.6 Hz, H-6), 7.10 (d, 2H, J = 8.9 Hz, H-3′′, 5′′), 7.17 (d, 2H, J = 8.7 Hz, H-3′, 5′), 7.64 (d, 1H, J = 8.6 Hz, H-5), 7.73 (m, 4H, H-2′, 6′, 2′′, 6′′), 8.23 (s, 1H, H-4); IR (KBr, cm⁻¹): 3317, 3227, 1732, 1646, 1600, 1497, 1228, 1146, 850, 829; TOF-HRMS: m/z 452.0798 [M+H]⁺ (C₂₃H₁₈NO₇S requires 452.0805).

4.1.15. 3-[4-(4-Methoxyphenylsulfonamido)benzoyl]-7-(N,N-diethylamino)-2H-1-benzopyran-2-one (24)

Yellow solid, 37% yield. M.p.: 161-162°C; ¹H-NMR (DMSO-, ppm): δ 1.13 (s, 6H, J = 6.9 Hz, 2CH₃), 3.47 (s, 4H, J = 6.9 Hz, 2CH₂), 3.80 (s, 3H, OCH₃), 6.57 (s, 1H, H-8), 6.76 (s, 1H, H-6), 7.08 (d, 2H, J = 7.6 Hz, H-3′′, 5′′), 7.20 (d, 2H, J = 8.4 Hz, H-3′, 5′), 7.58 (d, 1H, J = 8.7 Hz, H-5), 7.70 (d, 2H, J = 8.1 Hz, H-2′, 6′), 7.78 (d, 2H, J = 8.4 Hz, H-2′′, 6′′), 8.16 (s, 1H, H-4), 10.76 (s, 1H, NH); IR (KBr, cm⁻¹): 3438, 3232, 2973, 1696, 1618, 1598, 1581, 1510, 1233, 1158, 832, 803; TOF-HRMS: m/z 507.1584 [M+H]⁺ (C₂₇H₂₇N₂O₆S requires 507.1591).

4.1.16. 3-[4-(4-Methoxylphenylsulfonamido)benzoyl]-7-hydroxy-6-methoxy-2H-1-benzopyran-2-one (25)

Yellow solid, 36% yield. M.p.: 167-168°C; ¹H-NMR (DMSO-, ppm): δ 3.80 (s, 6H, 2OCH₃), 6.84 (s, 1H, H-5), 7.11 (d, 2H, J = 8.9 Hz, H-3′′, 5′′), 7.21 (d, 2H, J = 8.5 Hz, H-3′, 5′), 7.35 (s, 1H, H-8), 7.75 (m, 4H, H-2′, 6′, 2′′, 6′′), 8.20 (s, 1H, H-4), 10.81 (s, 1H, NH); IR (KBr, cm⁻¹): 3430, 1715, 1598, 1567, 1508, 1263, 1156, 836, 789; TOF-HRMS: m/z 482.0904 [M+H]⁺ (C₂₄H₂₀NO₈S requires 482.0910).

4.1.17. 3-[4-(4-tert-Butylphenylsulfonamido)benzoyl]-7-(N,N-diethylamino)-2H-1-benzopyran-2-one (26)

Orange solid, 33% yield. M.p.: 118–120°C; ¹H-NMR (DMSO-, ppm): δ 1.14 (t, 6H, J = 7.0 Hz, 2CH₃), 1.16 (s, 9H, –C (CH₃)₃), 3.46 (q, 4H, J = 7.0 Hz, 2CH₂), 6.57 (s, 1H, H-8), 6.75 (d, 1H, J = 9.0 Hz, H-6), 7.18 (d, 2H, J = 8.7 Hz, H-3′, 5′), 7.58 (m, 3H, H-5, 2′, 6′), 7.68 (d, 2H, J = 8.7 Hz, H-3′′, 5′′), 7.78 (d, 2H, J = 8.6 Hz, H-2′′, 6′′), 8.16 (s, 1H, H-4), 10.88 (s, 1H, NH); IR (KBr, cm⁻¹): 3436, 2967, 1721, 1618, 1600, 1510, 1234, 1162, 828, 788; TOF-HRMS: m/z 533.2105 [M+H]⁺ (C₃₀H₃₃N₂O₅S requires 533.2111).

4.2. Assay of the In Vitro   α-Glucosidase Inhibitory Activity

A 100 μL reaction system containing 0.02 U of α-glucosidase, 67 nM sodium phosphate buffer (pH 6.8), and a test compound were preincubated at 37°C for 10 min. A negative control in the absence of a test compound and a blank control in the absence of either an enzyme or the test compound were run simultaneously. The reaction was initiated by the addition of 0.1 M maltose, and the reaction mixture was incubated at room temperature for 10 min. Then, the 200 μL glucose-detecting agent was added, and the absorbance (A) at 490 nm was recorded on a SPECTRAmax Plus 384 reader (MD, USA). The test compounds were initially assayed for their inhibition of α-glucosidase at a concentration of 10 μg/mL. Calculate inhibition ratio according to OD value; inhibition ratio = . Each monoconcentration had two replicates when preliminary screened. If an inhibition ratio of more than 70% was observed, diluted 10 times and re-screened. If an inhibition ratio of re-screening was more than 70%, measured IC₅₀ value. The active compounds were consequently tested at six gradient dilute concentrations, with each concentration having two replicates. On the basis of inhibition ratio, the IC₅₀ values were calculated using 4-Parameter Logistic Model of Xlfit software.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

This work was financially supported by Key Project for Drug Innovation of the Ministry of Science and Technology of China (2009ZX09301-012).

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