Synthesis and biological activity of N-acyl-5-bromanthranilic acids

Article abstract of DOI:10.1007/s11094-006-0143-2

Ten N-acyl-5-bromanthranilic acids have been obtained via acylation of 5-bromanthranilic acid with appropriate anhydrides. The antiinflammatory and antibacterial properties of the synthesized compounds have been evaluated. It is established that N-(o-anisoyl)-5-bromanthranilic acid possesses most pronounced antiinflammatory activity (49% inhibition of carrageenan induced paw edema in rat) and antimicrobial properties (MIC = 2.0 μg/ml with respect to St. aureus and E. coli).

Full text of DOI:10.1007/s11094-006-0143-2

Pharmaceutical Chemistry Journal
Vol. 40, No. 8, 2006
SYNTHESIS AND BIOLOGICAL ACTIVITY
OF N-ACYL-5-BROMANTHRANILIC ACIDS
A. V. Dolzhenko,1 L. M. Korkodinova,1 V. P. Kotegov,2
M. V. Vasilyuk,2 and V. V. Novikova1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 8, pp. 12 – 14, August, 2006.
Original article submitted July 30, 2004.
Ten N-acyl-5-bromanthranilic acids have been obtained via acylation of 5-bromanthranilic acid with appro-
priate anhydrides. The antiinflammatory and antibacterial properties of the synthesized compounds have been
evaluated. It is established that N-(o-anisoyl)-5-bromanthranilic acid possesses most pronounced
antiinflammatory activity (49% inhibition of carrageenan induced paw edema in rat) and antimicrobial prop-
erties (MIC = 2.0 mg/ml with respect to St. aureus and E. coli).
O
Halogen-substituted N-acylanthranilic acid amides ex-
Scheme 1
Br
hibit a broad spectrum of biological activity, including anti-
viral [1, 2], antibacterial [3, 4], antifungal [5], anti-inflam-
matory and analgesic [3, 4, 6, 7] properties. In continuation
of the search for biologically active compounds in the class
of 5-bromine-substituted anthranilic acids [8 – 10], we syn-
thesized a series of N-acyl-5-bromanthranilic acids (I – X)
and studied their antiinflammatory and antimicrobial proper-
ties.
OH
O
NH
O
O
O
O
O
HO
Br
OH
OH
Br2
O
O
I
NH2
NH2
Cl
R
The initial 5-bromanthranilic acid was obtained by brom-
inating anthranilic acid according to the well-known classical
method [11]. The subsequent acylation of this brominated
acid with phthalic anhydride in ethyl acetate at room temper-
ature (Scheme 1) using a method described previously [12]
yielded N-phthalyl-5-bromanthranilic acid (I). A series of
N-acyl derivatives (II – X) were obtained via the interaction
of 5-bromanthranilic acid with the corresponding acid
chloroanhydrides in benzene. The reactions were carried out
with heating on a water bath for 30 – 40 min [8].
O
Br
OH
NH
O
R
II – X
R = n-Pr (II); Ph (III); C6H4OMe-2 (IV); C6H4NO2-3 (V); C6H4Cl-4 (VI);
C6H4Br-4 (VII); CH2Ph (VIII); CHPh2 (IX); 2-furyl (X)
The synthesized compounds appeared as white, some-
times with a yellowish tint, crystalline substances insoluble
in water and soluble in organic solvents (DMSO, DMF, etha-
nol, acetone, dioxane). Yields, physicochemical characteris-
EXPERIMENTAL CHEMICAL PART
1
The H NMR spectra were measured on an RYa-2310
1
tics, and parameters of the IR and H NMR spectra of the
spectrometer (Russia) operating at a frequency of 60 Hz. The
samples were dissolved in DMSO-d and the chemical shifts
newly synthesized N-acyl-5-bromanthranilic acids are pre-
sented in Table 1 and in the experimental chemical part be-
low.
6
were calculated relative to HMDS (internal standard). The IR
spectra were recorded with a Specord M-80 spectrophotome-
ter (Germany) using samples prepared as nujol mulls. The
course of reactions was monitored and the purity of the reac-
tion products was checked by TLC on Silufol UV-254 plates
(Chemapol, Czech Republic), which were eluted in an ace-
1
Perm State Pharmaceutical Academy, Perm, Russia.
2
Perm State Medical Academy, Perm, Russia.
418
0091-150X/06/4008-0418 © 2006 Springer Science+Business Media, Inc.

Synthesis and Biological Activity of N-Acyl-5-bromanthranilic Acids
419
tone – benzene (1 : 6) mixture and developed by exposure to
Analogous procedures were used for the synthesis of
iodine vapor and under UV irradiation [13].
compounds II – VII, IX, and X.
N-Phthalyl-5-bromanthranilic acid (I). To a solution
of 1.08 g (0.005 mole) of 5-bromanthranilic acid in 10 ml of
ethyl acetate was gradually added with stirring a solution of
0.74 g (0.005 mole) of phthalic anhydride in 10 ml of the
same solvent. The mixture was stirred and kept at room tem-
perature for 24 h. The precipitate was filtered, dried, and
recrystallized from ethanol; yield of compound I, 0.90 g
(49%); m.p., 194 – 196°C.
N-(3-Nitrobenzoyl)-5-bromanthranilic acid (X). IR
spectrum (n , cm – 1): 3140 (NHCO, COOH), 1704
max
(COOH), 1612 (NHCO), 1540 (NHCO), 1502, 1353, 824,
740 (NO ), 932 (COOH).
2
N-(2-Furanoyl)-5-bromanthranilic acid (X). IR spec-
trum (n , cm – 1): 3180 (NHCO, COOH), 1712 (COOH),
max
1668 (NHCO), 1532 (NHCO), 1554, 1496 (C H O), 884
4
3
(COOH).
N-Phenylacetyl-5-bromanthranilic acid (VIII). To a
suspension of 1.08 g (0.005 mole) of 5-bromanthranilic acid
in 10 ml of benzene was added 0.93 g (0.006 mmole) of
phenylacetic acid chloroanhydride and the mixture was
boiled for 30 min on a water bath, after which excess ben-
zene was distilled off. The reaction mass was cooled, poured
into water (50 ml), and neutralized with sodium carbonate.
The precipitate was separated by filtration, dried, and
recrystallized from acetone to obtain compound VIII with a
EXPERIMENTAL BIOGICAL PART
The antiinflammatory activity of the synthesized com-
pounds was studied on a group of white mongrel rats weigh-
ing 200 – 250 g, bearing a carrageenan-induced foot edema
model [14]. The synthesized compounds (in a dose of
50 mg/kg) and the reference drug diclofenac sodium
(25 mg/kg) were intraperitoneally injected (as aqueous sus-
pensions stabilized with Tween-80) 1 h before carrageenan
injections. Animals in the control group were treated with an
equal volume of Tween-80 solution. The extent of edemation
was estimated oncometrically, by measuring the inflamed
foot volume immediately before and 3 and 5 h after edema
induction. The effect was evaluated by a degree of inhibition
yield of 1.41 g (84%); m.p., 232 – 234°C; IR spectrum (n
,
max
cm – 1): 3332 (COOH), 3248 (NHCO), 1672 (COOH,
NHCO), 1518 (NHCO), 920 (COOH).
TABLE 1. Yields, Physicochemical Characteristics, and Parame-
1
ters of the H NMR Spectra of N-Acyl-5-Bromanthranilic Acids
(I – X)
TABLE 2. Antiinflammatory Activity of N-Acyl-5-Bromanthrani-
Com-
1H NMR spectrum
Yield, M.p.,
Empirical
formula
lic Acids (III – X)
po-
und
%
°C
(DMSO-d6): d, ppm
Percentage foot edema growth
Dose,
Compound1
relative to initial volume (M ± m )
mg/kg
I
49 194 – 196 C15H10BrNO5 7.42 – 8.75 (m, 7H, C6H3,
C6H4), 11.38 (s, 1H, NH)
(i.p.)
3 h
5 h
II
87 242 – 243 C11H12BrNO3 0.95 (t, 3H, CH3), 1.77 (m,
2H, CH2), 2.55 (t, 2H,
III
50
–
54.2 ± 7.10**
90.5 ± 7.80
46.1 ± 6.80**
90.5 ± 7.80
46.9 ± 6.50
66.1 ± 6.30
69.0 ± 12.50
90.5 ± 7.80
78.2 ± 9.8
56.0 ± 5.50**
90.4 ± 6.80
46.0 ± 4.70**
90.4 ± 6.80
48.7 ± 5.80*
69.6 ± 4.60
70.5 ± 8.90
90.4 ± 6.80
79.4 ± 7.30
69.6 ± 4.60
46.6 ± 5.30*
69.6 ± 4.60
64.1 ± 8.20*
90.4 ± 6.80
51.9 ± 7.40
69.6 ± 4.60
23.8 ± 6.00***
76.2 ± 6.00
Control
IV
COCH2), 7.65 – 8.95 (m, 3H,
C6H3), 10.58 (s, 1H, NH),
50
–
11.78 (s, 1H, COOH)
Control
V
III
IV
46 255 – 256 C14H10BrNO3 6.65 – 7.98 (m, 8H, C6H3,
C6H5), 11.05 (s, 1H, NH)
50
–
Control
VI
79 256 – 260 C16H13BrNO3 4.07 (s, 3H, OCH3),
6.80 – 8.83 (m, 7H, C6H3,
50
–
Control
VII
C6H4), 12.27 (bs, 1H, NH)
50
–
V
92 236 – 238 C14H9BrN2O5 7.58 – 8, 85 (m, 7H, C6H3,
C6H4), 10.15 (s, 1H, NH)
Control
VIII
66.1 ± 6.30
46.6 ± 5.30*
66.1 ± 6.30
65.0 ± 9.70
90.5 ± 7.80
48.1 ± 7.70
66.1 ± 6.30
27.7 ± 5.00**
73.0 ± 10.60
VI
VII
90 252 – 253 C15H10BrCINO3 6.88 – 9.05 (m, 7H, C6H3,
C6H4), 12.22 (s, 1H, NH)
50
–
Control
IX
71 252 – 254 C15H10Br2NO3 6.83 – 9.00 (m, 7H, C6H3,
C6H4), 12.17 (bs, 1H, NH)
50
–
Control
X
VIII 84 230 – 232 C15H12BrNO3 3.72 (s, 2H, CH2),
6.85 – 8.72 (m, 8H, C6H3,
50
–
C6H5), 11.21 (s, 1H, NH)
Control
Diclofenac
Control
IX
X
91 225 – 227 C21H16BrNO3 5.12 (s, 1H, CH), 7.00 – 7.88
(m, 13H, C6H3, C6H5, C6H5),
25
–
11.62 (s, 1H, NH)
87 257 – 258 C12H8BrNO4 6.62 – 8.78 (m, 6H, C6H3,
C4H3O), 12.08 (s, 1H, NH)
* p < 0.05, ** p < 0.01, and *** p < 0.001 relative to control; num-
ber of animals in experimental groups, n = 5.

420
A. V. Dolzhenko et al.
TABLE 3. Antimicrobial Activity of N-Acyl-5-Bromanthranilic
than the corresponding acids, in agreement with the estab-
lished general rule [17]. The inverse trend is observed with
respect to the antimicrobial action [10, 17].
Acids (III – V, VII, VIII, X)
MIC, mg/ml
Compound
Thus, the results of this investigation confirmed good
prospects in the search for new antimicrobial agents among
N-acyl-5-bromanthranilic acids and their derivatives.
St. aureus
E. Coli
III
62
2.0
62
2.0
IV
V
VII
250
250
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500
500
VIII
250
250
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