Synthesis and antimicrobial activity of pyrazole-4-carboxylic acid hydrazides and N-(4-pyrazoyl)hydrazones of aromatic and heteroaromatic aldehydes

Full text of DOI:10.1023/A:1010432029236

Pharmaceutical Chemistry Journal
Vol. 35, No. 4, 2001
SYNTHESIS AND ANTIMICROBIAL ACTIVITY
OF PYRAZOLE-4-CARBOXYLIC ACID HYDRAZIDES
AND N-(4-PYRAZOYL)HYDRAZONES OF AROMATIC
AND HETEROAROMATIC ALDEHYDES
V. A. Chornous,1 M. K. Bratenko,2 M. V. Vovk,1 and I. I. Sidorchuk1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 4, pp. 26 – 28, April, 2001.
Original article submitted September 19, 1990.
Proceeding from the fact that some widely used antibac-
terial preparations (furacilin, furazolidone, ftivazide) contain
hydrazone groups, we decided to synthesize a series of
pyrazole-4-carboxylic acid hydrazides, modify these com-
pounds so as to obtain N-(4-pyrazoyl)hydrazones, and study
the antibacterial properties of the products.
R¢ = 3-(4H-chromenon-4-yl) (b); R = C6H5, R¢ = 5-nitrofur-2-yl (c);
R = 4- FC6H4, R¢ = 3-CH3J-4-HOC6H3 (d); R = 4-FC6H4,
R¢ = 5-nitrofur-2-yl (e); R = 4-C1C6H4, R¢ = 3-CH3O-4-HOC6H3 (f);
R = 4-ClC6H3, R¢ = 5-nitrofur-2-yl (g); R = 4-BrC6H4,
R¢ = 3-CH3O-4-HOC6H3 (h); R = 4-BrC6H4, R¢ = 5-nitrofur-2-yl (i);
R = 4-C2H5C6H4, R¢ = 5-nitrofur-2-yl (j); R = 4-CH3O C6H4,
R¢ = 5-nitrofur-2-yl (k); R = thienyl-2, R¢ = 5-nitrofur-2-yl (l).
Hydrazides IIIa – IIIg were synthesized based on the pre-
viously described pyrazole-4-carboxylic chloroanhydrides
(Ia – Ig) [1]. Treated with methanol in the presence of an or-
ganic base, compounds Ia – Ig converted with a quantitative
yield into the corresponding methyl esters IIa – IIg. Interac-
tion of these intermediates with hydrazine hydrate (on heat-
ing in ethanol) led to a high yield of hydrazides IIIa – IIIg.
The yields and physicochemical characteristics of methyl es-
ters IIa – IIg and hydrazides IIIa – IIIg are listed in Table 1.
The target N-(4-pyrazoyl)hydrazones (Va – Vl) (Table 1)
were obtained by the condensation of hydrazides IIIa – IIIg
with aryl(heteryl)aldehydes (IVa – IVc) in boiling ethanol.
The proposed compositions were confirmed by elemental
analyses and the proposed structures, by the IR spectra of the
products, which displayed absorption bands due to the
stretching vibrations of NH (3200 – 3280 cm – 1), as well as
C=O and C=N (1670 – 1640 cm – 1) groups.
OCH3
NHNH2
Cl
O
O
O
NH2NH2 · H2O
CH3OH
R
R
R
EXPERIMENTAL CHEMICAL PART
N
N
N
N
N
N
Ph
Ph
Ph
IIa – IIg
The IR absorption spectra were measured on an UR-20
spectrophotometer (Germany) using samples pelletized with
KBr. The 1H NMR spectra of esters IIa – IIg and hydrazides
IIIa – IIIg were recorded with a 100-MHz Bruker spectrome-
ter using deuterated DMSO as the solvent and HMDS as the
internal standard. The course of reactions was monitored and
the purity of products checked by TLC on Silufol UV-254
plates (Czech Republic) eluted in an ethyl acetate – diethyl
ether (10 : 1) system and developed by exposure to iodine
vapors.
Ia – Ig
IIIa – IIIg
H
C
H
N
O
R'
N
R'CHO
R
IVa – IVc
N
N
Ph
Va – Vl
I – III: R = C6H5 (a), 4-FC6H4 (b), 4-ClC6H4 (c), 4-BrC6H4 (d),
4-C2H5C6H4 (e), 4-CH3OC6H4 (f), 2-thienyl (g);
IV: R¢ = 3-CH3O-4-HOC6H3 (a), 3-(4H-chromenon-4-yl) (b),
5-nitrofur-2-yl (c);
1,3-Diphenylpyrazole-4-carboxylic acid methyl ester
(IIa). To 10 mmole (2.8 g) of 1,3-diphenylpyrazole-
4-carboxylic acid chloroanhydride (Ia) in 10 ml of anhydrous
methanol was added 10 mmole (1,0 g) triethylamine and the
mixture was boiled for 2 h. Then the solvent was evaporated
and the residue washed with water, filtered, dried, and crys-
tallized from ethanol. Yield of compound IIa, 2.5 g (95%).
V: R = C6H5, R¢ = 3-CH3O-4-HOC6H3 (a); R = C6H5,
1
Bukovinian State Medical Academy, Chernovtsy, Ukraine.
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Kiev, Ukraine
2
203
0091-150X/01/3504-0203$25.00 © 2001 Plenum Publishing Corporation

204
V. A. Chornous et al.
Compounds IIb – IIg were obtained using analogous pro-
cedures (Table 1).
anol was added 1 ml of 85% hydrazine hydrate and the mix-
ture was boiled for 4 h. Then the solvent was evaporated and
the residue washed with water, filtered, dried, and crystal-
lized from 80% ethanol. Yield of compound IIIa, 1.0 g
(75%).
1,3-Diphenylpyrazole-4-carboxylic acid hydrazide
(IIIa). To a suspension of 5 mmole (1.3 g) of 1,3-diphenyl-
pyrazole-4-carboxylic acid methyl ester (IIa) in 10 ml of eth-
TABLE 1. Yields and Physicochemical Characteristics of Methyl Esters (IIa – IIg) and Hydrazides (IIIa – IIIg) of Pyrazole-4-carboxylic
Acids
IR spectrum: n, cm – 1
M.p.,
°C
Yield,
%
Empirical
formula
Compound
1H NMR spectrum: d, ppm
C=O
N–H
IIa
107 – 108
130 – 131
137 – 138
153 – 154
94 – 95
95
96
97
94
96
C17H14N2O2
1740
1735
1735
1745
1740
–
–
–
–
–
9.01 (s, 1H, CH=), 6.42 – 7.70 (m, 10H, Harom), 3.75 (s, 3H, CH3O)
8.82 (s, 1H, CH=), 7.04 – 8.18 (m, 9H, Harom), 3.87 (s, 3H, CH3O)
9.11 (s, 1H, CH=), 7.11 – 7.85 (m, 9H, Harom), 3.54 (s, 3H, CH3O)
9.07 (s, 1H, CH=), 7.21 – 7.94 (m, 9H, Harom), 3.63 (s, 3H, CH3O)
IIb
IIc
IId
IIe
C17H13FN2O2
C17H13ClN2O2
C17H13BrN2O2
C19H18N2O2
8.99 (s, 1H, CH=), 7.15 – 7.63 (m, 9H, Harom), 2.44 (q, 2H, CH2),
1.33 (t, 3H, CH3), 3.70 (s, 3H, CH3O)
IIf
102 – 103
92
C18H16N2O3
1740
–
9.14 (s, 1H, CH=), 7.24 – 7.85 (m, 9H, Harom), 3.84 (s, 3H, CH3O),
3.69 (s, 3H, CH3O)
IIg
82 – 83
98
75
C15H12N2O2S
C16H14N4O
1735
1655
–
8.87 (s, 1H, CH=), 6.99 – 7.83 (m, 8H, Harom), 4.01 (s, 3H, CH3O)
IIIa
157 – 158
3240
9.53 (s, 1H, NH), 8.94 (s, 1H, CH=), 6.54 – 7.79 (m, 10H, Harom.),
4.57 (bs, 2H, NH2)
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
203 – 204
181 – 182
196 – 198
166 – 168
157 – 158
154 – 155
79
81
76
61
72
77
C16H13FN4O
C16H13ClN4O
C16H13BrN4O
C18H18N4O
1660
1665
1660
1670
1665
1660
3240
3230
3260
3240
3250
3260
9.44 (s, 1H, NH), 8.87 (1H, CH=), 7.10 – 8.24 (m, 9H, Harom),
4.64 (bs, 2H, NH2)
9.59 (s, 1H, NH), 9.04 (s, 1H, CH=), 7.17 – 7.90 (m, 9H, Harom),
4.54 (bs, 2H, NH2)
9.37 (s, 1H, NH), 8.92 (s, 1H, CH=), 7.22 – 7.84 (m, 9H, Harom),
4.44 (bs, 2H, NH2)
9.46 (s, 1H, NH), 9.00 (s, 1H, CH=), 7.03 – 7.52 (m, 9H, Harom),
4.55 (bs, 2H, NH2), 2.47 (q, 2H, CH2), l.33 (t, 3H, CH3)
C17H16N4O
9.29 (s, lH, NH), 8.92 (s, lH, CH=), 7.30 – 7.92 (m, 9H, Harom),
4.62 (bs, 2H, NH2), 3.76 (3H, CH3O)
C14H13N4OS
9.50 (s, 1H, NH), 8.86 (1H, CH=), 6.88 – 7.56 (m, 8H, Harom),
4.56 (bs, 2H, NH2)
TABLE 2. Yields, Physicochemical Characteristics, and Antimicrobial Properties of Aromatic and Heteroaromatic Aldehydes
Antimicrobial activity
Compound
Yield, %
M.p., °C
Empirical formula
St. aureus 209-P
MBSC, mg/ml MBCC, mg/ml
E. coli
MBSC, mg/ml MBCC, mg/ml
250
Va
Vb
Vc
Vd
Ve
Ve
Vg
Vh
Vi
77
72
81
84
79
80
74
85
86
73
78
82
261 – 263
201 – 202
227 – 228
279 – 280
252 – 253
270 – 271
263 – 264
256 – 257
258 – 259
205 – 206
240 – 241
234 – 235
C24H20N4O3
C27H18N4O3
C21H15N5O4
C24H19FN4O3
C21H14FN5O4
C24H19ClN4O3
C21H14ClN5O4
C24H19BrN4O3
C21H14BrN5O4
C23H19N5O4
C22H17N5O5
C19H13N5SO4
62.5
62.5
62.5
31.2
31.2
125
125
125
125
62.5
62.5
250
-“-
500
250
250
250
> 500
-“-
125
125
125
> 500
-“-
125
-“-
-“-
125
-“-
-“-
-“-
125
-“-
-“-
-“-
Vj
15.6
62.5
31.2
31.2
125
62.5
-“-
-“-
Vk
Vl
125
250
250
500

Synthesis and Antimicrobial Activity of Pyrazole-4-carboxylic Acid Hydrazides
205
Compounds IIIb – IIIg were obtained using analogous
procedures (Table 1).
after incubation for 20 – 24 h at 37°C by determining the
minimum bacteriostatic concentration (MBSC) inhibiting the
growth and multiplication of the microbes. Then the mini-
mum bactericidal concentration (MBCC) was determined by
inoculating Petri dishes containing a meat-infusion agar with
culture drops from the tubes exhibiting no visible growth of
microbes. The samples of inoculated dense medium were in-
cubated for two days at 37°C. A sector with a minimum con-
centration completely inhibiting the microbial growth was
assumed to represent the MBCC.
3-Methoxy-4-hydroxybenzaldehyde N-[4-(1,3-diphen-
yl)pyrazoyl]hydrazone (Va). A mixture of 2 mmole (0.6 g)
of hydrazide IIIa and 2 mmole (0.32 g) of 3-methoxy-4-hyd-
roxybenzaldehyde (IVa) in 10 ml of ethanol was boiled for
3 h. Then the precipitate was filtered, washed with ethanol,
dried, and crystallized from acetic acid. Yield of compound
Va, 0.64 g (77%).
Compounds Vb – Vl were obtained using analogous pro-
cedures (Table 2).
As seen from the data presented in Table 2, all the syn-
thesized compounds possess moderate bactericidal and
bacteriostatic properties, the effect being more pronounced
with respect to staphylococcal species than to E. coli.
EXPERIMENTAL BIOLOGICAL PART
The antimicrobial activity of hydrazides IIIa – IIIg and
hydrazones (Va – Vl) with respect to standard strains of St.
aureus 209-P and E. coli was determined using a
four-hour-grown suspension of each test culture in a liquid
nutrient medium (microbial load (1 – 2) ´ 106 cells/ml ac-
cording to the turbidity standard). The activity was evaluated
REFERENCES
1. M. K. Bratenko, V. A. Chornous, and M. V. Vovk, Zh. Org.
Khim., 36(5), 849 – 852 (2000).