Synthesis of new coumarin compounds and its hypoglycemic activity and structure-activity relationship

Article abstract of DOI:10.14233/ajchem.2013.15453

Novel coumarin compounds were designed and synthesized by combining the active moieties of hypoglycemic drugs. The coumarin compounds were made by sulfanilamide with isocynate, the intermediate sulfanilamide was formed from coumarin by chlorosulfonated and aminated. These targeted compounds were characterized by FT-IR, ¹H NMR and MS spectra and their hypoglycemic activities were evaluated in mice. The preliminary results showed that some compounds exhibited evident hypoglycemic effect (P > 0.01, CMC-Na as negative control). The relationship between these compounds structure with their hypoglycemic activities were studied in order to design new antidiabetic agents.

Full text of DOI:10.14233/ajchem.2013.15453

Asian Journal of Chemistry; Vol. 25, No. 17 (2013), 9835-9839
http://dx.doi.org/10.14233/ajchem.2013.15453
Synthesis of New Coumarin Compounds and Its Hypoglycemic
Activity and Structure-Activity Relationship
*
GANG QI and WENGUO ZHANG
Department of Chemistry and Biology,Yancheng Institute of Technology,Yancheng 224051, P.R. China
*Corresponding author: E-mail: qigang@ycit.cn
(
Received: 7 March 2013;
Accepted: 25 October 2013)
AJC-14285
Novel coumarin compounds were designed and synthesized by combining the active moieties of hypoglycemic drugs. The coumarin
compounds were made by sulfanilamide with isocynate, the intermediate sulfanilamide was formed from coumarin by chlorosulfonated and
1
aminated. These targeted compounds were characterized by FT-IR, H NMR and MS spectra and their hypoglycemic activities were evaluated
in mice. The preliminary results showed that some compounds exhibited evident hypoglycemic effect (P < 0.01, CMC-Na as negative
control). The relationship between these compounds structure with their hypoglycemic activities were studied in order to design new
antidiabetic agents.
Key Words: Coumarin, Synthesis, Hypoglycemic activity, Structure-activity relationship.
6
-position, in order to investigate the impact of the substi-
INTRODUCTION
tuted position of sulfonylurea group on the hypoglycemic
activity and thereby 6-methylcoumarin sulfonylurea series of
compounds (II) were synthesized.
Non-insulin-dependent diabetes is quite common in the
middle-aged people and as the cause is different, a single
hypoglycemic agent gets poor efficacy and long-term medi-
cation secondary shows high efficiency. Therefore, the combi-
nation can control the disease effectively and achieve better
O
O
R
2
O
O
SO
CH
2
NHCONHR
1
2
efficacy . As reported in the literature that the coumarin got
hypoglycemic activity evidently and sulfonylurea compounds
were also commonly used as hypoglycemic agents. Sulfony-
lurea hypoglycemic drugs could act on pancreatic cells selec-
tively, promoting the secretion of insulin and then got hypo-
glycemic effect on normal subjects and diabetes. But the vivo
pancreatic cells secreting insulin must be present in vivo, so
such drug could not have hypoglycemic effect on the class of
type1 diabetes or alloxan hyperglycemia rat animal model.
2 3
SO NHCONHR
Br
R
1
R
,R
: H or CH
2 3
3
1
R3: aryl or alkyl
I
II
Preparation of 3-bromocoumarin sulfonylurea comp-
ounds (I): There are two routes to prepare the 3-bromocoumarin
sulfonylurea compounds. Route 1 is shown in Fig. 1. The
coumarin after addition of bromine were taken hydrogen
bromide out and then obtained 3-bromocoumarin sulfona-
mides by chlorosulfonation and ammonification. Finally, the
resultant was reacted with isocyanate to obtain the target comp-
ounds. In route 2 the resultant 3-bromocoumarin sulfonamides
was reacted with ethyl chloroformate to obtain 3-bromocoumarin
sulfamido ethyl ester and the synthetic object was then reacted
with the corresponding primary amine, but failed.
3
However, experiments show coumarin could have hypogly-
cemic effect on the normal murine animal model and alloxan
hyperglycemia mice animal models, which indicates its
mechanism of action is different with the sulfonylurea hypo-
glycemic drugs. In addition, coumarin also has antibacterial,
anti-coagulation action and plays a remedial role on diabetic
4
complication . So our group put sulfonylurea and coumarin
together and then introduced an electron-withdrawing group
in order to obtain high activity, synthesized the 3-bromo-
coumarin sulfonylurea compounds (I). Further, the changing
substituted position of sulfonylurea on the parent ring of
coumarin made it substitute in the 7-position in place of the
The coumarin and substitutive coumarin can be obtained
by Pechmann condensation reaction. 7-Methylcoumarin and
4,7-dimethylcoumarin were synthesized according to the lite-
5
rature . 3-Bromocoumarin and 3-bromo-substituted coumarin
6
were synthesized by synthetic route (Fig. 1). In Fig. 1 the

9
836 Qi et al.
Asian J. Chem.
Route1
O
O
R2
O
O
R2
Pyridine
R2
O
O
Br2
CH3COOHBr
Br
Br
R1
R1
R1
O
R2
O
O
O
R2
HOSO Cl
2
NH H O
3 2
O
O
R2
RNCO
K CO
2
SO NH
2 2
3
Br
SO Cl
2
Br
Br
SO NHCONHR
2
R1
R1
R1
Route2
O
O
R2
RNH2
O
O
R2
O
O
R2
RNCO
K CO
2
2
3
Br
SO NH
2
Br
SO NHCOOC H
2 5
SO NHCONHR
2
Br
2
R1
R1
R1
Fig.1. Synthesis route of 3-bromine-6-sulfonylurea-coumarin compounds
temperature had a great influence on the addition reaction of
bromine in the first step reaction, the optimum temperature at
around 20 °C. The high temperature could cause bromine to
escape easily and then got the low yield. The low temperature
could cause the reaction slowly. In the second step the sulfonyl
chloride of coumarin was easy to hydrolyze by changing
ambient conditions to heat under reflux and causing the
reaction time reduce from 10 h to 3 h in the pyridine catalytic
reaction of hydrogen bromide. Meanwhile, the introduction
of electron-withdrawing caused the reaction hydrolyze more
easily. Experiments found that the introduction of a bromine
atom in the nucleus caused the production rate decrease and
the introduction of a nitro group or an acetyl group can not
obtain the sulfonyl chloride, which were hydrolyzed to
generate a sulfonic acid. Further, the sulfonamides were also
easy to hydrolyze as heated in the acidic condition, which
was required to be neutral in the post processing; otherwise
the yield would be decreased. Moreover, the product would
be much better by using water replace ethanol in the process
of recrystallization. The reaction conditions were subject to
change due to the change of property caused by the introduction
of the methyl. In the sulfochlorination reaction of methyl-
substituted coumarin, the molar ratio of the reactant was
changed; and the amount of chlorosulfonic acid was changed
from 2.5 times to 4 times the amount of the raw material.
There are several methods to synthesize the isocyanate, in the
experiment the solid triphosgene was reacted with amine. That
is because triphosgene is a white solid, easy to weigh and
with low price.
adding organic solvent did not improve the yield of the reaction
and increasing the temperature could make the yield increase,
but the yield was still low.
O
O
O
O
SO
2
Cl
O
O
HOSO
CH
2
Cl
2 2
SO NH
NH
3 2
H O
3
CH3
CH3
K2CO3
RNH
2
RNCO
O
O
2
SO NHCONHR
CH
3
Fig. 2. Synthesis route of 7-sulfonylurea-coumarin compounds
EXPERIMENTAL
The melting point was determine by XT-4 binocular
microscope and the thermometer was not corrected; Infrared
spectrometer (Nicolet Impact 410); Nuclear magnetic reso-
nance (Bruker ACF-300, TMS used as the internal standard);
Mass spectrometer (HP1100LC/MSD). The reagents was
analytically pure.
General method for synthesis of isocyanate: The solid
triphosgene (0.40 mo1) was dissolved in 50 mL chloroform;
after stirring dissolved the 10 mL chloroform solution of corres-
ponding amine (0.20 mo1) was dripped with ice bath cooling.
The reaction was occurred within 1 h at room temperature and
heated with reflux for 6 h, then obtained corresponding products
by distillation.
General method for synthesis of the target compound:
The sulfonamide (1g, 3.01 mmo1) was mixed with 20 mL
acetone, adding potassium carbonate (1g, 7.2 mmo1) and then
the reaction mixture was heated with reflux for 1 h. The solution
was dripped into the acetone solution of isocyanate (3.14
mmo1) with backflow for 6 h. Cooling and filtering the
product, then the filter cake was dissolved with 20 mL water.
The solid was obtained by adjusting pH = 1 with 20 mL concen-
trated hydrochloric acid and then the solution was neutral by
filtering and washing with water. The products were dried.
The data of the yield, melting point, infrared spectroscopy,
nuclear magnetic resonance spectroscopy, high resolution
mass spectrometry of the partial target compounds BSU-1-
BSU-14 were shown in Table-1.
Preparation of 6-methylcoumarin sulfonylurea comp-
ounds (II): In the post treatment process of the synthesis of
7
6
-methylcoumarin , using steam distillation to replace solvent
extraction or vacuum distillation not only could improve the
yield, but also made the operation simple. The reaction yield
of 6-methylcoumarin chlorosulfonation is very low, trying to
change the different reaction conditions to improve the yield
8
(
Fig. 2). The literature reported in the reaction of chloro-
sulfonation process, the reaction system was viscous and could
join inert organic solvent. The liquidity of solution was
enhanced due to the dispersion of the solvent and then the
yield of the reaction was improved. But in the experiment

Vol. 25, No. 17 (2013)
Synthesis of New Coumarin Compounds and Its Hypoglycemic Activity 9837
TABLE-1
PHYSICAL CONSTANTS, YIELDS AND SPECTRA DATA OF THE COMPOUNDS
O
O
R2
Br
SO2NHCONHR
R1
-
1
1
Compd.
BMSU-1 -CH CH CH
3
R
R1
H
R2
H
Formula Yield
%)
m.p.
(°C)
IR (cm )
H NMR(DMSO-d )δ
6
(
386.9645
80
138-140 3371, 3072, 1752, 0.74-0.78 (3H, t), 1.24-1.39 (2H, m), 2.60-2.91
2
2
1
1
688, 1605, 1537, (2H, t), 6.44 (1H, br), 7.59-7.62 (1H, d),
340, 1159 8.06-8.09 (1H, dd), 8.28 (1H, s), 8.79 (1H, s),
0.70 (1H, br)
3370, 3072, 1757, 0.79-0.83 (3H, t), 1.14-1.34 (4H, m), 2.85-2.91
1
BMSU-2 -CH (CH ) CH
3
H
H
H
H
400.9777
400.9820
77
65
94-95
2
2
2
1
683, 1605, 1538, (2H, t), 6.24 (1H, br), 7.53-7.56 (1H, d),
1338, 1157 8.03-8.07 (1H, dd), 8.22 (1H, s), 8.76(1H, s)
BMSU-3 -CH CH(CH )
3 2
104-107 3382, 3073, 1756, 0.74-0.76 (6H, d), 1.56-1.62 (1H, m), 2.65-2.77
2
1
688, 1606, 1547, (2H, m), 6.39 (1H, br), 7.57-7.60 (1H, d), 8.06-
340, 1158 8.09 (1H, d), 8.26 (1H, s), 8.78 (1H, s), 10.67
1H, br)
122-125 3369, 3069, 1753, 0.78-0.83 (3H, t), 1.12-1.33 (6H, m), 2.87-2.93
1
(
BMSU-4 -CH (CH )CH
H
H
414.9949
71
2
2
3
1
6189,
1605, (2H, t), 6.38 (1H, br), 7.58-7.61 (1H,d), 8.05-
8.09 (1H,dd), 8.26 (1H,s), 8.78(1H,s),
0.69(1H,br)
236-238 3335, 3052, 1717, 2.12 (3H, s), 2.68 (3H, s), 6.85-6.89 (1H, d),
1536, 1342, 1160
1
BMSU-5
BMSU-6
BMSU-7
BSU-8
CH3
H
H
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
448.9801
434.9645
462.9958
414.9958
414.9958
429.0114
471.0580
448.9801
429.0125
443.0270
64
72
69
80
81
65
78
57
42
59
1
1
609, 1553, 1330, 6.99-7.10 (2H, m), 7.45 (1H, br), 7.59 (1H, d),
3159 7.77 (1H, br), 8.30 (1H, s), 8.75 (1H, s)
156-157 3335, 3055, 1727, 2.66 (3H, s), 6.69-6.74 (1H, t), 7.03-7.08 (2H,
614, 1547, 1338, t), 7.26 (1H, s), 7.37-7.40 (2H, d), 8.21 (1H, s),
146 8.40 (1H, br), 8.75 (1H, s)
148-149 3370, 3070, 1730, 2.01 (3H, s), 2.09 (3H, s), 2.67 (3H, s), 6.67-
613, 1547, 1344, 6.70 (1H, d), 6.81-6.86 (1H, t), 7.25 (1H, s),
154 7.39-7.41 (1H, d), 8.16 (1H, s), 8.75 (1H, s)
3363, 3073, 1750, 0.78-0.88 (3H, m), 1.16-1.29 (4H, m), 2.63
1
1
H C
3
CH3
H
1
1
-CH (CH ) CH
3
H
82-85
2
2
2
1
722, 1635, 1559, (3H, s), 2.90-2.97 (2H, m), 5.69 (H, br), 6.30
1341, 1156 (1H, br), 7.46 (1H, s), 8.31 (1H, s), 8.75 (1H, s)
BSU-9
-CH CH(CH )
3 2
H
109-110 3370, 3067, 1752, 0.74-0.83 (6H, m), 1.53-1.62 (1H, m), 2.64
2
1
1
681, 1620, 1548, (3H, s), 2.73-2.82 (2H, m), 7.68 (1H, s), 8.30
342, 1152 (1H, s), 8.75 (1H, s)
BSU-10
BSU-11
BSU-12
BSU-13
BSU-14
-CH (CH ) CH
3
H
117-119 3371, 3068, 1750, 0.78-0.86 (3H, m), 1.12-1.32 (6H, m), 2.63
2
2
3
1
682, 1617, 1545, (3H, s), 2.84-2.88 (2H, t), 6.13 (1H, br), 7.40
1343, 1152 (1H, s), 8.26 (1H, s), 8.73 (1H, s)
-CH (CH ) CH
3
H
121-124 3380, 3072, 1720, 0.81-0.86 (3H, t), 1.08-1.36 (12H, m,), 2.62
2
2
6
1
1
683, 1619, 1549, (3H, s), 2.91-2.93 (2H, m), 5.32 (1H, br), 7.38
343, 1154 (1H, s), 8.23 (1H, s), 8.74 (1H, s)
-CH3
-CH3
-CH3
198-200 3334, 1716, 1613, 2.61 (3H, s), 2.69 (3H, s),6.81-6.86 (1H, t),
601, 1544, 1334, 7.11-7.16 (2H, t), 7.34-7.58 (3H, m), 8.30 (1H,
150 s), 8.55 (1H, br)
220-221 3369, 3078, 1741, 0.76-0.85 (3H, t), 1.11-1.26 (4H, m), 2.60 (3H,
1
1
-CH (CH ) CH
3
2
2
2
1
1
675, 1642, 1548, s), 2.63 (3H, s), 2.86-2.88 (2H, m), 6.22 (1H,
330, 1154 br), 7.42 (1H, s), 8.25 (1H, s)
-CH (CH ) CH
3
168-169 3355, 1741, 1676, 0.76-0.81(3H ,t), 1.09-1.30 (6H, m), 2.60 (3H,
604, 1548, 1332, s), 2.64 (3H, s), 2.85-2.88 (2H, m), 7.44 (1H,
155 s), 8.26 (1H, s)
2
2
3
1
1
Study on pharmacodynamics: Fourteen compounds
selected from the initial screening out of the active compounds
with hypoglycemic effect were continued to carry out pharma-
codynamic studies. The methods were as follows: 60 mice
were divided into 6 groups randomly by the weight each time
and intragastric administration of different doses of the drug,
depressed percentage of the concentration of blood glucose
before and after drug administration and dosage by Scott
method (Table-2).
Analysis of structure-activity relationship: The energy
optimization of molecular structure, the calculation of structure
parameter and the analysis of structure-activity relationship
were all carried out on the SGI-4D computer. The molecular
structure of compound was optimized and the structure
parameters were calculated by using the POLYGEN software
package, which used QUANTA (90.0919 Edition) as the main
procedures. In this paper the study on structure-activity rela-
tionship was stepwise multiple linear regression analysis by
using SAS (Statistical Analysis System) program. The low
active contribution parameters were deleted automatically
through the two critical values (F1 and F2) of the control
program in the calculation process. After inputting molecular
2
00, 130, 80, 50, and 30 mg/kg, respectively; another group
was given 0.5 % CMC-Na; giving a total of 14 times. The
concentrations of blood glucose were determined before and
after administration of two different rats, respectively. The
method was as follows:After blooding from the venous plexus
of the eye socket of the mouse with the capillary tube and
centrifuging (3000 rpm, 10 min), 10 µL serum was taken to
determine the concentration of the glucose by glucose kit
(
GOD-PAP). The Emax, K, D50 and avidity index PD
2
of each
drug were calculated based on the relationship between the

9
838 Qi et al.
Asian J. Chem.
TABLE-2
PHARMACODYNAMIC PARAMETERS OF COUMARIN SULFONYLUREA
COMPOUNDS ON BLOOD GLUCOSE LEVEL OF NORMAL MICE (x ± s,n = 10)
Emax
%)
9.49
48.05
20.00
15.02
D50
D50
(mg/kg)
13.26
40.09
8.04
Drugs
R
R1
R2
K
PD2
(
(mol/L)
0.0017
0.0050
0.0010
0.0046
BSU-1
BSU-2
BSU-3
BSU-4
-CH
-CH (CH
-CH CH(CH
-CH (CH CH
2
CH
2
CH
3
H
H
H
H
H
H
H
H
0.0017
0.0050
0.0010
0.0046
2.77
2.30
3.00
2.34
)
2
CH
2
2
3
)
3 2
2
)
3
38.42
2
2
3
CH3
BSU-5
H
-CH3
30.30
0.0067
0.0067
60.73
2.17
BSU-6
BSU-7
H
H
-CH3
-CH3
51.28
13.66
0.0015
0.0091
0.0015
0.0091
13.09
84.88
2.82
2.04
H3C
CH3
BSU-8
BSU-9
BSU-10
BSU-11
-CH
-CH
-CH
-CH
2
(CH
CH(CH
(CH CH
(CH CH
2
)
2
CH
)
3 2
3
H
H
H
H
-CH3
-CH3
-CH3
-CH3
20.41
50.00
12.66
55.87
0.0010
0.0072
0.0020
0.0025
0.0010
0.0072
0.0020
0.0025
8.735
60.25
17.59
24.02
3.00
2.14
2.70
2.60
1.97
2
)
2
2
3
3
)
6
2
2
3
95.31
BSU-12
-CH3
-CH3
23.15
0.0106
0.0106
BSU-13
BSU-14
-CH
CH (CH ) CH
3
2
(CH
2
)
2
CH
3
-CH3
-CH3
-CH3
-CH3
12.15
9.55
0.0112
0.0111
0.0112
0.0111
96.07
98.51
1.95
1.95
2
2
3
Emax = Maximum hypoglycemic effect of the dose; K = the drug dose of dose response got 50 % total intensity; D50 = the actuating quantity of half
effect; PD = Avidity index, the negative logarithm of K value.
2
structure used "ChemNote" as subroutine, the computer
numbered each atom automatically and the established X, Y,
Z coordinates and the file (Residue Topology File, RTF) of
molecular residue topology.And then the energy optimization
of molecular structure was carried out by using the subroutine of
charge of urea; X22-the included angle between sulfonyl and
parent nucleus (°); X23-the dihedral angle between the perssad
of sulfonyl urea and the parent nucleus (DEG); X24-the distance
between the carbon atoms of mother nucleus of 7 position
with carbon atomic connected to the perssad of urea; X25-the
farthest distance between the carbon atom of mother nucleus
of 7 position with the carbon atom connected to the substituted
perssad of urea.
"CHARMm", which used RTF as the data structure of CHARM
(
CHARMm Date Structure) to carry on structural search and
analysis (Search andAnalysis). The computer performed opti-
mization program continuously to make the force field of RMS
close to or equal to zero, finding the lowest energy of three-
dimensional molecular structure, namely the preferred confor-
mation of compound. Twenty three parameters of molecular
mechanics structure of the target compounds were calculated
based on the obtained preferred conformation of compounds
by using MM2 molecular mechanics program, which involved
the stereo factor, power factor and the hydrophobic factor, of
the compound. The parts of molecular mechanics structure
RESULTS AND DISCUSSION
The equation (QSAR) between molecular mechanics
parameters and the quantitative structure-activity relationship
of hypoglycemic activity was obtained by using the mechanics
structure parameter of molecular as a variable and the stepwise
multiple linear regressions for hypoglycemic activity:
Y = 3.0726 – 0.0299X1
N = 15, R = 0.977041, S = 0.302434, F = 11.00224
Y: refers to the avidity index of hypoglycemic activity
parameters of target compounds (X
-the lowest energy of molecular (Kcal/mol ); X
total bond energy of molecular (Kcal/mol); X -the total bond
angle of molecular (Kcal/mol); X -the total dihedral angle
energy of molecular (Kcal/mol); X -the total non regular
energy of molecular (Kcal/mol); X -the total Lennard-Jones
energy of molecular (Kcal/mol); X -the total electrostatic
energy of molecular (Kcal/mol); X -the dipole moment of
molecular (D); X -the van der Waals volume of molecular
1
-X25) were shown in Table-3.
X
1
2
-the
2
PD : This equation showed that the hypoglycemic activity of
3
3-bromocoumarin sulfonylurea compound was negatively
related to the minimum energy of compound. The preliminary
conclusion was obtained by the comparison of the changes of
compound structure: when the substituent group of the perssad
of urea was fatty group, the energy of compound was low
energy and the activity was high. In addition, the following
preliminary conclusion also was got according to the hypogly-
cemic activity data of measured compounds: the substituent
group of the perssad of urea should have a certain size and
lipophilic ability; when the number of carbon atoms was 3-8,
the compound generally had the obvious hypoglycemic
activity and the compound had higher activity as the amount
of substituent group was 4; comparing the hypoglycemic
activity of the coumarin sulphonyl urea compound substituted
by bromine atoms with non substitutional compound, intro-
4
5
6
7
8
9
3
2
(
Å ); X10-the affinity surface area of molecular (Å ); X11-the
2
hydrophobic surface area of molecular (Å ); X12-the total surface
area of molecular (Å ); X13-the total volume of molecular (Å );
14-solvent accessible affinity surface area (Å ); X15-solvent
accessible hydrophobic surface area (Å ); X16-solvent acces-
2
3
2
X
2
2
sible total surface area (Å ); X17-solvent accessible total volume
3
(
Å ); X18-the carbon atomic charge of mother nucleus of 2
position; X19-the carbon atomic charge of mother nucleus of 3
position; X20-the charge of sulfur atom; X21-the nitrogen atom
ducing bromine could enhance activity and the PD value
2

Vol. 25, No. 17 (2013)
Synthesis of New Coumarin Compounds and Its Hypoglycemic Activity 9839
TABLE-3
STRUCTURAL PARAMETERS OF SELECTED COMPOUNDS BASED ON MM2 PROGRAM CALCULATION
X1
X2
X3
X4
X5
X6
X7
X8
X21
6.812
X9
X22
266.06
X10
X23
195
X11
X12
X13
Compd.
X14
1.2227
X15
1.418
383
1.564
414
1.843
407
1.697
444
3.135
470
2.603
445
4.072
499
1.853
415
2.206
433
2.033
469
2.383
555
3.118
447
2.383
456
2.495
484
X16
2.329
551
2.795
583
3.515
562
3.076
612
7.332
610
5.669
594
7.688
642
2.866
570
2.707
587
2.999
627
3.571
714
6.262
603
4.203
613
4.532
642
X17
X18
X19
X20
X24
98
6.465
103
6.465
102
6.465
285
6.638
305
7.351
292
6.365
321
6.614
264
6.465
109
6.708
295
6.697
132
6.686
122
6.365
290
6.679
117
X25
294
8.800
311
9.814
304
8.800
331
11.49
343
10.18
332
9.108
360
10.04
306
8.800
318
9.067
338
11.52
386
15.16
340
9.108
334
10.08
347
Y
268.2
2.77
286.8
2.30
284.6
3.00
304.6
2.34
338.2
2.17
319.8
2.82
361.5
2.04
284.0
3.00
301.8
2.14
316.4
2.70
365.5
2.60
335.7
1.97
317.6
1.95
330.3
1.95
1
0.3428 0.6871
861.2 0.589
0.1753 0.3326
915.0 0.578
0.6148 0.5661
894.8 0.582
0.1762 0.0252
963.5
4.659
995.1
3.391
954.3
11.57
1065.5
6.899
-0.151
7.505
-0.162
7.467
-0.157
7.828
-0.164
15.41
-0.164
14.28
-0.162
17.48
-0.170
8.253
-0.154
8.180
-0.160
8.458
-0.166
9.529
-0.170
16.23
-0.166
10.11
-0.168
10.43
-0.170
-0.453
0.389
-0.653
0.378
-5.947
0.382
1.723
0.376
-7.919
0.376
-6.278
0.378
-3.934
0.370
-1.444
0.386
3.021
0.380
2.225
0.374
5.541
0.370
-3.323
0.374
-0.174
0.372
1.448
0.370
BSU-1
BSU-2
BSU-3
BSU-4
BSU-5
BSU-6
BSU-7
BSU-8
BSU-9
BSU-10
BSU-11
BSU-12
BSU-13
BSU-14
1
67
1.7191
69
.0596
55
4.5257
69
3.7672
40
1.4361
49
0.3544
44
2.2593
56
4.5562
54
3.1076
58
7.8884
58
2.1900
56
4.7998
58
6.7433
58
-0.311 137.90 48.15
9.093 270.62 207
-0.322 137.90 48.15
7.579 273.63 201
-0.317 137.90 48.15
9.885
-o.324 122.06
6.612 318.67
-0.324 120.01 97.89
6.244 306.18 40
-0.322 137.90 48.15
7.626 339.63 39
-0.330 155.98 33.97
5.540 272.41 42
-0.314 137.90 48.15
7.814 291.95 209
-0.320 168.64 45.09
9.559 301.19 43
-0.326 164.07 41.55
11.68 342.47 254
-0.330 158.73 35.24
6.840 313.82 218
-0.326 137.90 48.15
8.120 300.20 44
-0.328 153.60 29.62
8.654 312.49 230
-0.330 150.90 27.38
1
1
8
1
1
2
2
4
1
2
2
2
3
2
2
185.49
46
7.96
38
1
0.576
1.148
0.576
1.775
0.578
3.478
0.570
1
1
1
0.4876 0.2440
1
901.1
7.524
937.5
6.618
999.1
5.796
1141.0
7.819
980.1
6.010
983.5
5.543
1031.4
0.586
0.9175
0.580
0.7753
0.574
1.069
0.570
2.084
0.574
2.271
0.572
2.295
0.570
1
1
1
1
1
1
6.695
11.51
2
3
4
5
.
.
.
.
F.Z. Shen, Q.M. Chen, H.F. Liu and M.Z. Xie, Acta Pharm. Sinica,
4, 391 (1989).
J.S. Mishkinsky, A. Goldschmied, B. Joseph, Z. Ahronson and F.G.
Sulman, Arch. Int. Pharmacodyn. Ther., 210, 27 (1974).
S.Y. Xu, H.P. Zeng and C.W. Wei, Chinese J. Synthetic Chem., 12,
was relatively high; the space structure of active compounds
showed "U " type.
2
ACKNOWLEDGEMENTS
3
40 (2004).
The authors thank research fund of Key Laboratory for
Advanced Technology in Environmental Protection of Jiangsu
Province (No. AE201127) for the financial support.
S. Sethna and R. Phadke, The Pechmann reaction. In: Organic
Reaction, Volume VII, Chapter 1 (1953).
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(
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