Synthesis and Pharmacological Activity of 3-Phenoxybenzoic Acid Derivatives

Article abstract of DOI:10.1007/s11094-020-02185-z

3-Phenoxybenzoic acid derivatives were synthesized. Their pharmacological activity was studied. Several compounds, in particular 2-cyanoprop-2-yl 3-phenoxybenzoate, were found to exhibit peroxisome proliferator-activated receptor γ agonist activity and to

Full text of DOI:10.1007/s11094-020-02185-z

DOI 10.1007/s11094-020-02185-z
Pharmaceutical Chemistry Journal, Vol. 54, No. 3, June, 2020 (Russian Original Vol. 54, No. 3, March, 2020)
SYNTHESIS AND PHARMACOLOGICAL ACTIVITY
OF 3-PHENOXYBENZOIC ACID DERIVATIVES
A. A. Spasov,1,* V. S. Lobasenko,1 V. A. Kosolapov,1 D. A. Babkov,1
V. A. Kuznetsova,1 O. Yu. Maika,1 Yu. V. Popov,1 and T. K. Korchagina2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 3, pp. 20 – 26, March, 2020.
Original article submitted November 30, 2016.
3-Phenoxybenzoic acid derivatives were synthesized. Their pharmacological activity was studied. Several
compounds, in particular 2-cyanoprop-2-yl 3-phenoxybenzoate, were found to exhibit peroxisome
proliferator-activated receptor g agonist activity and to be capable of activating glucokinase and inhibiting
protein glycation. The studied compounds did not influence dipeptidyl peptidase-4 activity.
Keywords: synthesis, 3-phenoxybenzoic acid derivatives, peroxisome proliferator-activated receptor g,
glucokinase, dipeptidyl peptidase-4, protein glycation.
Scheme 1
The broad spectrum of indications for compounds con-
taining a diphenyloxide fragment is a result of their structural
features and properties [1].
Compounds in this series possess high biological activity
and include highly efficacious antioxidant, marginally toxic
nonsteroidal anti-inflammatory, anti-allergic, immunomodu-
lating, cardiologic, and antimicrobial drugs.
Substituted hydrazones exhibited spasmolytic and hypo-
tensive activity and were active against leukemia, sarcoma,
and other malignant neoplasms [2]. They were also used to
treat schizophrenia, leprosy, and other diseases [3].
It seemed worthwhile to synthesize and study the activity
of 3-phenoxybenzoic acid derivatives for diabetes develop-
ment targets such as peroxisome proliferator-activated recep-
tor ((PPAR-() and AMP-activated kinase (AMPK) and their
antiglycating properties.
I, Ia
R =
(I),
(Ia),
The aromatic nitriles reacted with alcohols and HCl un-
der Pinner conditions to form imidate hydrochlorides.
Scheme 2
2-Cyanoprop-2-yl 3-phenoxybenzoate (I) and 2-cyano-
prop-2-yl benzoate (Ia) were synthesized via reaction of
3-phenoxybenzoylchloride and benzoylchloride with acetone
cyanohydrin in anhydrous Et O in the presence of Et N as an
2
3
HCl acceptor (Scheme 1).
The synthesis was carried out at room temperature
(20 – 25°C) with vigorous stirring for 1 h. A quantitative
·
yield of Et N·HCl was already obtained 1 h after mixing the
3
starting reagents. The yields of the nitriles were 90 – 95%.
Ib, Ic
1
Volgogard State Medical University, Volgograd, 400131 Russia.
2
R1 = C2H5 (Ib); CH(CH3)2 (Ic).
Volgograd State Technical University, Volgograd, 400005 Russia.
*
e-mail: vad-ak@mail.ru
229
0091-150X/20/5403-0229 © 2020 Springer Science+Business Media, LLC

230
A. A. Spasov et al.
The reaction of 2-cyanoprop-2-yl 3-phenoxybenzoate
Esters of N-substituted 3-phenoxyphenylcarboximidic
acid (If and IIa-IIf) were prepared via sequential hydrochlo-
rination of 3-phenoxybenzonitrile under Pinner conditions
and acylation of the resulting imidate hydrochlorides by
carboxylic acid chlorides (Scheme 4).
with aliphatic alcohols and HCl (Scheme 2) produced ethyl-
and isopropylimidates of 2-methyl-2-(3-phenoxybenzoate)-
propionic acid (Ib and Ic).
The reaction was carried out with an equimolar ratio of
reagents and stirring at 0 – 5°C for 1 – 2 h. The reaction was
considered to have ended when the mixture gained weight
and crystallized. The yields were 94 – 95%.
The HCl acceptor was Et N. The reactions were carried
3
out with a molar ratio of the reagents and a two-fold excess
of Et N in anhydrous 1,4-dioxane at 60 – 65°C for 2 h.
3
Ethyl and butyl N-(benzoyl)-2-methyl-2-(3-phenoxyben-
zoate)propiocarboximidates (Id and Ie) were synthesized via
acylation of 2-(3-phenoxybenzoate)propionic acid imidate
hydrochlorides by benzoylchloride (Scheme 3).
EXPERIMENTAL CHEMICAL PART
IR spectra (n, cm–1) of liquid compounds were taken
from thin layers (films); of solids, from mineral-oil mulls on
Specord M82 (Germany) and PerkinElmer instruments
(USA).
Scheme 3
·
PMR spectra (d, ppm) were recorded in DMSO-d with
6
hexamethyldisiloxane internal standard on a Varian Mercury
300BB instrument (USA, operating frequency 300 MHz).
GC-MS were obtained on a Varian MAT-11 instrument
(USA) at ionizing potential 70 eV and cathode emission cur-
rent 240 mA. Samples were directly introduced into the ion
source.
·
The structures of the obtained compounds were eluci-
dated using elemental analyses and IR and PMR spectros-
copy. Table 1 presents the results.
2-Cyanoprop-2-yl 3-phenoxybenzoate (I). A three-nec-
ked reactor equipped with a mechanical stirrer and reflux
condenser was charged with 3-phenoxybenzoylchloride
(10.00 g, 46.2 mmol) and anhydrous Et O. Et N (5.60 g,
Id, Ie
2
3
55.4 mmol) in anhydrous Et O was added dropwise. The
2
Scheme 4
'
If, IIa – f
'
IIa, IIc
If, IId
If
IIc
IIa, IIb

Synthesis and Pharmacological Activity of 3-Phenoxybenzoic Acid Derivatives
231
mixture was treated dropwise with acetone cyanohydrin
Butyl N-(benzoyl)-2-(3-phenoxybenzoate)propiocar-
boxyimidate (Ie). A four-necked reactor equipped with a
mechanical stirrer, thermometer, and reflux condenser was
charged with 2-cyanoprop-2-yl 3-phenoxybenzoate hydro-
chloride (5.00 g, 13.2 mmol) in anhydrous dioxane. The
mixture was stirred, cooled to 5 – 10°C in an ice bath, treated
(4.71 g, 55.4 mmol) in anhydrous Et O. The reaction was
2
carried out at 20 – 25°C for 1 h. The precipitate of Et N·HCl
3
was filtered off. The filtrate was evaporated first at atmo-
spheric pressure and then under vacuum. The product was
purified by vacuum distillation. Yield 11.10 g (95%). bp
190 – 192°C (2 mm Hg). Mass spectrum, m/z: 281 [M+]: 50
(12%), 77 (15%), 115.2 (17%), 169 (35%), 197 (53%), 214
(25%), 281 (100%). C H O N.
dropwise with Et N (2.67 g, 26.4 mmol) in anhydrous
3
dioxane and benzoylchloride (1.85 g, 13.2 mmol) in anhy-
drous dioxane, and stirred for 30 min at room temperature
17 15
3
2-Cyanoprop-2-yl benzoate (Ia). A three-necked reac-
tor equipped with a mechanical stirrer and reflux condenser
was charged with benzoylchloride (10.00 g, 70.7 mmol) in
anhydrous Et O. Et N (7.15 g, 70.7 mmol) in anhydrous
and 2 h at 60 – 65°C. The precipitate of Et N·HCl was fil-
3
tered off. The filtrate was evaporated first at atmospheric
pressure and then under vacuum. Crystals formed as the sol-
vent was removed. The product was purified by recrystalliza-
tion from anhydrous Et O. Yield 82%, C H O N.
2
3
Et O was added dropwise. The mixture was treated dropwise
2
2
28 29
5
with acetone cyanohydrin (6.00 g, 70.7 mmol) in anhydrous
Ethyl N-(methacryloyl)-3-phenoxyphenylcarboximi-
date (If). A four-necked reactor equipped with a mechanical
stirrer, thermometer, and reflux condenser was charged with
3-phenoxybenzoic acid ethylimidate hydrochloride (5.00 g,
24.3 mmol) in anhydrous dioxane. The mixture was stirred,
Et O. The synthesis was carried out at 20 – 25°C for 1 h. The
2
precipitate of Et N·HCl was filtered off. The filtrate was
3
evaporated first at atmospheric pressure and then under vac-
uum. The product was purified by vacuum distillation. Yield
11.10 g (90%). bp = 180 – 185°C (2 mm Hg) Mass spectrum,
m/z: 189 [M+]: 30 (10%), 71 (13%), 98.3 (20%), 123 (31%),
165 (55%), 174 (22%), 189 (100%). C H O N.
cooled to 5 – 10°C in an ice bath, treated dropwise with Et N
3
(4.92 g, 48.6 mmol) in anhydrous dioxane and methacryloyl
chloride (2.54 g, 24.3 mmol) in anhydrous dioxane, and
stirred for 30 min at room temperature and 2 h at 60 – 65°C.
11 11
2
2-methyl-2-(3-phenoxybenzoate)propionic acid ethyl-
imidate hydrochloride (Ib). A tared reactor was loaded
with 2-methyl-2-(3-phenoxybenzoate)propionitrile (6.00 g,
20.9 mmol) and anhydrous EtOH (0.96 g, 20.9 mmol). The
mixture was cooled to 0 – 5°C in an ice bath and saturated
with dry HCl with stirring for 1 – 1.5 h. The end of the reac-
tion was inferred from the weight gain of the mixture and its
crystallization. The mixture was left overnight at 5°C. Yield
8.10 g (94%), C H O NCl.
The precipitate of Et N·HCl was filtered off. The filtrate was
3
evaporated first at atmospheric pressure and then under vac-
uum. Crystals formed as the solvent was removed. The prod-
uct was purified by recrystallization from anhydrous CCl .
4
Yield 4.60 g (82%), C H O N.
19 19
3
3,5-Dimethylphenyl N-(benzoyl)-3-phenoxyphenyl-
carboximidate (IIa). A four-necked reactor equipped with a
mechanical stirrer, thermometer, and reflux condenser was
charged with 3-phenoxybenzoic acid 3,5-dimethylphenyl-
imidate hydrochloride (5.00 g, 14.3 mmol) in anhydrous
dioxane. The mixture was stirred, cooled to 5 – 10°C in an
19 22
4
2-Methyl-2-(3-phenoxybenzoate)propionic acid iso-
propylimidate hydrochloride (Ic). A tared reactor was
loaded with 2-methyl-2-(3-phenoxybenzoate)propionitrile
(6.00 g, 20.9 mmol) and anhydrous i-PrOH (1.25 g,
20.9 mmol). The mixture was cooled to 0 – 5°C in an ice
bath and saturated with dry HCl with stirring for 1 – 1.5 h.
The end of the reaction was inferred from the weight gain of
the mixture and its crystallization. The mixture was left over-
night at 5°C. Yield 8.40 g (94%), C H O NCl.
ice bath, treated dropwise with Et N (2.89 g, 28.6 mmol) in
3
anhydrous dioxane and benzoylchloride (2.00 g, 14.3 mmol)
in anhydrous dioxane, and stirred for 30 min at room temper-
ature and 2 h at 60 – 65°C. The precipitate of Et N·HCl was
3
filtered off. The filtrate was evaporated first at atmospheric
pressure and then under vacuum. Crystals formed as the sol-
vent was removed. The product was purified by recrystalliza-
tion from anhydrous CCl . Yield 83%, C H O N.
20 24
4
Ethyl N-(benzoyl) -(3-phenoxybenzoate)propiocarbo-
2
ximidate (Id). A four-necked reactor equipped with a me-
chanical stirrer, thermometer, and reflux condenser was
charged with ethyl 2-(3-phenoxybenzoate)propiocarboxi-
midic acid hydrochloride (5.00 g, 14.2 mmol) in anhydrous
dioxane. The mixture was stirred, cooled to 5 – 10°C in an
4
28 23
3
3,4-Dimethylphenyl N-(3-phenoxyphenyl)-3-pheno-
xyphenylcarboximidate (IIb). four-necked reactor
A
equipped with a mechanical stirrer, thermometer, and reflux
condenser was charged with 3-phenoxybenzoic acid 3,4-di-
methylphenylimidate hydrochloride (5.00 g, 14.3 mmol) in
anhydrous dioxane. The mixture was stirred, cooled to
ice bath, treated dropwise with Et N (2.87 g, 28.4 mmol) in
3
anhydrous dioxane and benzoylchloride (1.99 g 14.2 mmol)
in anhydrous dioxane, and stirred for 30 min at room temper-
5 – 10°C in an ice bath, treated dropwise with Et N (2.89 g,
3
ature and 2 h at 60 – 65°C. The precipitate of Et N·HCl was
28.6 mmol) in anhydrous dioxane and 3-phenoxyphe-
nylchloride (3.32 g, 14.3 mmol) in anhydrous dioxane, and
stirred for 30 min at room temperature and 2 h at 60 – 65°C.
3
filtered off. The filtrate was evaporated first at atmospheric
pressure and then under vacuum. Crystals formed as the sol-
vent was removed. The product was purified by recrystalli-
The precipitate of Et N·HCl was filtered off. The filtrate was
3
zation from anhydrous Et O. Yield 4.80 g (85%),
evaporated first at atmospheric pressure and then under vac-
uum. Crystals formed as the solvent was removed. The prod-
2
C H O N.
26 26
5

232
A. A. Spasov et al.
TABLE 1. Structures and IR and PMR Spectra of Synthesized Compounds
IR spectrum, n, cm–1
No.
Compound
PMR spectrum, d, ppm
I
1.85 (6H, s, CH3), 6.56 – 7.69
(9H, m, C6H5ÎC6H4)
1600 – 700 (Ar), 2224 (CºN),
2938 (CH), 1287 (CH3), 1732
(C=O)
Ia
Ib
Ic
1.72 (6H, s, CH3), 6.4 – 6.8 (5H,
m, C6H5)
1600 – 700 (Ar), 2224 (CºN),
2938 (CH), 1287 (CH3), 1732
(C=O)
11.1 (s, 1H, HCl), 6.94 – 7.21 (m, 1630 (C=N), 1294 – 970 (C-O-C),
9H, m, C6H5OC6H4), 1.2 s (6H,
CH3), 1.4 – 1.5 (m, 3H, CH3),
4.1 – 4.3 (m, 2H, CH2)
3400, 1830 – 1690 (N-H)
10.8 (s, 1H, HCl), 6.94 – 7.21 (m, 1650 (C=N), 1300 – 980 (C-O-C),
9H, m, C6H5OC6H4), 6.90 – 7.08 3450, 3490, 1810 – 1690 (N-H)
(m, 1H, NH), 1.27 – 1.36 (m, 3H,
CH3), 4.26 (m, 2H, CH2)
Id
Ie
1.05 – 1.37 (9H, m, CH3),
4.25 – 4.27 (2H, d, CH2),
6.89 – 7.56 (14H, m, C6H5OC6H4,
C6H5)
1702 (C=O), 1648 (C=N),
1246 – 1072 (Ñ-O-C)
1.09 – 1.14 (9H, m, CH3),
2.38 – 2.51 (m, 2H, CH2),
3.01 – 3.05 (m, 2H, CH2),
3.23 – 3.37 (t, 2H, CH2),
6.67 – 7.98 (14H, m, C6H5OC6H4,
C6H5)
1750 (C=O), 1678 (C=N),
1266 – 1350 (C-O-C)
If
0.83 – 1.20 (6H, m, 2CH3),
2.22 – 3.15 (2H, m, CH2), 5.13
(2H, s, =CH2), 6.78 – 7.76 (9H, m,
C6H5OC6H4)
1732 (C=O), 1650 (C=N), 1620
(C=C), 1072 – 1246 (C-O-C)
IIa
1.89 (6H, s, 2CH3), 6.68 – 7.32
(17H, m, C6H5OC6H4, C6H3,
C6H5)
1689 (C=O), 1654 (C=N),
1246 – 1272 (C-O-C)
IIb
1.83 (6H, s, 2CH3), 6.95 – 7.78
(21H, m, C6H5OC6H4,
C6H5OC6H4, C6H3)
1716 (C=O), 1653 (C=N),
1041 – 1072 (C-O-C)
IIc
2.92 (2H, s, CH2), 6.9 – 7.8 (23H, 1748 – 1760 (C=O), 1660 (C=N),
m, C6H5OC6H4, C6H5OC6H4, 1235 – 1326 (C-O-C)
C6H5)

Synthesis and Pharmacological Activity of 3-Phenoxybenzoic Acid Derivatives
233
IR spectrum, n, cm–1
1780 – 1793 (C=O), 1660 – 1640
(C=C), 1648 (C=N), 1246 – 1072
No.
Compound
PMR spectrum, d, ppm
IId
0.98 – 1.13 (3H, t, 2CH3),
2.22 – 3.13 (2H, m, CH2),
6.91 – 7.87 (9H, m, C6H5OC6H4), (C-O-C), 1800 – 1770 (C-Cl)
(3H, m, C5H3NCl)
IIe
6.82 – 7.76 (m, 19H, Ar), 3.61 (s, 1290 – 1072 (C-O-C), 1648
1H, NH)
(C=N), 1702 (C=O),
3430 – 3394.1204 (N-H, C-N)
IIf
6.89 – 7.82 (m, 14H, Ar), 4.17 (s, 1290 – 1100 (C-O-C), 1634
1H, NH), 2.62 – 2.73 (m, 1H,
CH), 1.42 – 1.72 (m, 6H, CH2),
1.1 – 1.2 (m, 4H, CH2)
(C=N), 1780 – 1670 (C=O),
1360 – 1000 (C-N), 3430 – 3394
(N-H)
uct was purified by recrystallization from anhydrous CCl .
benzene. The mixture was stirred, cooled to 15 – 20°C in a
water bath, treated dropwise with aniline (5.44 g, 17 mmol),
and held for 2 h at 75 – 80°C. The solvent was evaporated.
The solid crystallized. The product was purified by recrys-
4
Yield 88%, C H O N.
34 27
4
3-Phenoxybenzyl N-(benzoyl)-3-phenoxyphenylcar-
boximidate (IIc). A four-necked reactor equipped with a
mechanical stirrer, thermometer, and reflux condenser was
charged with 3-phenoxybenzoic acid 3-phenoxyphenyl-
imidate hydrochloride (5.00 g, 11.6 mmol) in anhydrous
dioxane. The mixture was stirred, cooled to 5 – 10°C in an
tallization from anhydrous CCl . Yield 80%, mp
4
127 – 128°C, C H O N .
26 23
2
2
N-Benzoyl-N¢-cyclohexyl-3-phenoxybenzamidine (IIf).
A reactor was charged with ethyl N-(benzoyl)-3-phenoxy-
phenylcarboximidate (5.00 g, 13 mmol) in anhydrous ben-
zene. The mixture was stirred, cooled to 15 – 20°C in a water
bath, treated dropwise with cyclohexylamine (5.60 g,
17 mmol), and held for 2 h at 75 – 80°C. Th solvent was
evaporated. The solid crystallized. The product was purified
ice bath, treated dropwise with Et N (2.89 g, 28.6 mmol) in
3
anhydrous dioxane and benzoylchloride (2.00 g, 14.3 mmol)
in anhydrous dioxane, and stirred for 30 min at room temper-
ature and 2 h at 60 – 65°C. The precipitate of Et N·HCl was
3
filtered off. The filtrate was evaporated first at atmospheric
pressure and then under vacuum. Crystals formed as the sol-
vent was removed. The product was purified by recrystalli-
zation from anhydrous CCl . Yield 84%, C H O N.
by recrystallization from anhydrous CCl . Yield 85%, mp
4
115 – 120°C, C H O N .
26 25
2
2
4
33 25
4
Ethyl N-(chloronicotinoyl)-3-phenoxyphenylcarboxi-
midate (IId). A four-necked reactor equipped with a me-
chanical stirrer, thermometer, and reflux condenser was
charged with 3-phenoxybenzoic acid ethylimidate hydro-
chloride (5.00 g, 24.3 mmol) in anhydrous dioxane. The
mixture was stirred, cooled to 5 – 10°C in an ice bath, treated
EXPERIMENTAL PHARMACOLOGICAL PART
The compounds and reference drug pioglitazone were
studied at a concentration of 10–5 M in the in vitro test of
PPARg (Eurofins Cerep, France) activation using the litera-
ture method [4]. Agonist activity of the compounds was cal-
culated from the ratio to the control agonist activity.
dropwise with Et N (4.92 g, 48.6 mmol) in anhydrous
3
dioxane and 2-chloronicotinoylchloride (4.28 g, 24.3 mmol)
in anhydrous dioxane, and stirred for 30 min at room temper-
Activity in vitro of glucokinase (GK). The activity of
recombinant human liver GK expressed in E. coli (Sigma
#SRP6045, USA) was determined using the coupled forma-
tion of glucoso-6-phosphate with NADN generation and
glucoso-6-phosphate dehydrogenase (G6PDH, L. mesentero-
ides, 550 – 1100 U/mg, Sigma #G2921, USA). The analysis
was performed at 37°C in flat-bottomed transparent polysty-
rene 96-well plates (Costar 9018, USA) with a final incu-
bated volume of 210 mL. The incubation mixture contained
HEPES (25 mM, pH 7.2), KCl (25 mM), D-glucose (5 mM),
ature and 2 h at 60 – 65°C. The precipitate of Et N·HCl was
3
filtered off. The filtrate was evaporated first at atmospheric
pressure and then under vacuum. Crystals formed as the sol-
vent was removed. The product was purified by recrystalli-
zation from anhydrous CCl . Yield 87%, C H O N Cl.
4
21 17
3
2
N-Benzoyl-N¢-phenyl-3-phenoxybenzamidine (IIe). A
reactor was charged with N-benzoyl-substituted 3-phenoxy-
benzoic acid ethylimidate (4.80 g, 14 mmol) in anhydrous

234
A. A. Spasov et al.
ATP (1 mM), NAD (1.8 mM), MgCl (2 mM), DTT (1 mM),
microplate reader (Tecan, Austria). The positive control was
vildagliptin (Sigma, USA) [8].
2
test compound or DMSO (5%), G6PDH (1.8 U/mg), and GK
(2 mg/mL). The compounds being tested were dissolved
(5%) in DMSO and incubated beforehand with GK in a
PST-60HL thermostatted shaker (Biosan, Latvia) for10 min
to equilibrate the temperature. Then, the reaction was initi-
The in vitro antiglycating activity of the compounds was
determined by the literature method [9]. Glycation of pro-
teins was modeled in a reaction mixture containing glucose
(500 mM) and bovine serum albumin (BSA, 1 mg/mL) dis-
solved in phosphate buffer solution (pH 7.4). Compounds
were dissolved in DMSO (Fisher Scientific, USA). Experi-
mental samples were treated with solutions of the tested
compounds at a final concentration of 1 mM; control sam-
ples, with an equivalent volume of DMSO. The reference
drug was aminoguanidine. Samples were incubated at 60°C
for 1 d. The specific fluorescence of glycated BSA after incu-
bation was determined on an MPF-400 fluorescence spec-
trometer (Hitachi, Japan) at excitation wavelength 370 nm
and emission wavelength 440 nm. The antiglycating activity
of the compounds was calculated from the ratio to the fluo-
rescence of control samples.
ated by adding D-glucose solution (10 mL) [5]. GK activity
was measured using the increase of optical density at 340 nm
during incubation for 20 min after the reaction started. The
measurements were made using an Infinite M200 PRO
microplate reader (Tecan, Austria). The positive control was
MBX-2982 experimental GK activator [6].
Activity in vitro of dipeptidyl peptidase-4 (DPP-4).
The inhibitory activity of the compounds for DPP-4 was as-
sessed by placing healthy volunteer blood plasma (40 mL)
into Tris-HCl buffer solution (50 mL, 0.1 M, pH 8.0), treating
the mixture with a solution (10 mL) of the tested compound
at the given concentration in Tris buffer, incubating before-
hand at 37°C for 5 min, treating the reaction mixture with
DPP-4 substrate solution (Gly-Pro-p-nitroanilide, 100 mL,
1 mM; Sigma, USA), incubating at 37°C for 15 min, and re-
cording the formation of p-nitroaniline from the increase of
optical density at 405 nm [7] using an Infinite M200 PRO
Data were statistically processed using the Student t-cri-
terion (T).
RESULTS AND DISCUSSION
Table 2 presents results from the experimental studies.
TABLE 2. PPARg-Agonist, Glucokinase, DPP-4-Inhibitory, and Antiglycation Activity of Ia-f and IIa-f
Glucokinase activation,
10–4 M, % (M ± m)
DPP-4 inhibition,
10–4 M, % (M ± m)
Antiglycation activity,
10–3 M, % (M ± m)
PPARg activation,
10–5 M, %
Compound
I
44.6 ± 4.32*
21.77 ± 0.52*
3.42 ± 0.39**
6.13 ± 0.89**
2.24 ± 1.69**
3.06 ± 1.31**
– 0.72 ± 1.55**
6.4 ± 2.00**
0.53 ± 0.91
24.27 ± 2.04*
– 0.75 ± 1.41
0.99 ± 1.41
1.74 ± 0.73
1.63 ± 1.82
…
– 6.1 ± 1.33**
0.65 ± 2.63**
– 4.49 ± 2.74**
– 3.69 ± 1.96**
5.42 ± 1.14**
– 5.11 ± 1.06**
– 1.67 ± 2.08**
– 8.09 ± 2.29**
– 36.7 ± 5.82**
0.46 ± 3.37**
4.38 ± 3.37**
– 2.41 ± 2.8**
– 13.84 ± 2.63**
…
29.10 ± 2.98*
– 20.32 ± 5.08
– 24.88 ± 6.82
– 35.84 ± 12.58
2.34 ± 8.20
…
Ia
0.5 ± 0.02**
Ib
0.3 ± 0.01**
Ic
0.6 ± 0.02**
Id
– 0.1 ± 0.02**
Ie
0.1 ± 0.01**
If
– 0.1 ± 0.02**
– 2.63 ± 0.02
– 1.55 ± 2.78
13.37 ± 2.14
– 18.22 ± 7.58
8.89 ± 6.00
– 11.71 ± 6.93
– 10.61 ± 0.34
…
IIa
IIb
…
…
…
…
…
…
IIc
IId
IIe
IIf
Pioglitazone
MBX-2982
Vildagliptin
Aminoguanidine
68.9 ± 8.58*
…
…
…
…
…
67.76 ± 0.87*
…
…
…
98.69 ± 0.42*
…
57.83 ± 0.58*
*
Data statistically significant (T) vs. control (p < 0.05);
**
data statistically significant (T) vs.
…, compound not studied.

Synthesis and Pharmacological Activity of 3-Phenoxybenzoic Acid Derivatives
235
Compound I had the highest PPAR agonist activity of the
ACKNOWLEDGMENTS
(
3-phenoxybenzoic acid derivatives and activated this type of
nuclear receptor by 44.6% (p < 0.05). The activity of refer-
ence drug pioglitazone was slightly greater although the dif-
ference was not statistically significant. The other com-
The research was sponsored by a Russian Science Foun-
dation Grant (Project No. 14-25-00139).
REFERENCES
pounds did not demonstrate activity for PPAR .
(
Compounds I and IIb showed the ability to activate GK,
increased its activity by 21.8 and 24.3%, respectively
(p < 0.05), and were inferior to the standard compound
MBX-2982 (67.7%, p < 0.05). The other 3-phenoxybenzoic
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acid derivatives were inactive for GK.
None of the studied compounds were capable of inhibit-
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ing DPP-4 activity.
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Compound I possessed moderate antiglycating activity
and inhibited statistically significantly fluorescence of
glycated BSA by 29.1%, which was inferior to the reference
drug aminoguanidine. Compound IIb of the other com-
pounds showed a tendency to decrease glycation. The others
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In summary, it was concluded that the most promising of
8. F. X. Pi-Sunyer, A. Schweizer, D. Mills, et al., Diabetes Res.
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the synthesized 3-phenoxybenzoic acid derivatives for fur-
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