Pharmaceutical Chemistry Journal Vol. 32, No.

6, 1998

SYNTHESIS AND ANTIMICROBIAL ACTIVITY

OF 4-FORMYLPYRAZOLE N-ACYLHYDRAZONES

M. IC Bratenko, I N. P. Voloshin, 1 I. O. Petrunik, 2 D. M. Livak, 2

and M. V. Vovk 2

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 32, No. 6, pp. 2 9 - 3 0 , June, 1998.

Original article submitted October 23, 1997.

Hydrazones of aliphatic and aromatic carbonyl com- IIio: R = (l-naphthyl)hydroxymethyl; R' = 6-benzodioxanyl;
pounds are known to possess high biological activity [ 1 - 4 ] lllp: R = (l-naphthyl)hydroxymethyl; R' = 9-ethyl-3-e.arbazolyl.

and are used in the production of some pharmaceuticals

[5, 6]. It was reported that 3-bromo-4-alkoxyphenylacetyl hy- Hydrazones Ilia-IIIp were obtained by condensation of
drazones possess mutagenic and antitumor properties [7], the hydrazides of isonicotinic (Ia), 4-chlorophenoxyacetic
while N-isonicotinoyl hydrazones produce antibacterial ef- (Ib), and (1-naphthyl)hydroxyacetie (Ic) acids with pre-
fects [8, 9]. Pharmacological properties of the N-acylhydra- viously synthesized compounds [11], including 1-phenyl-3-
zones of heteroeyclie aldehydes have been studied much less. heteryl-4-formylpyrazoles (IIa-IIe) and their new repre-
Proceeding from the data on the fungicidal and antimi- sentatives (IIf, IIg). Heating hydrazides I a - I c with pyra-
erobial activity of imino derivatives of 4-formylpyrazole zolyl-4-earbaldehydes IIa-IIg for 1 h in boiling glacial ace-
[10], we have synthesized N-acylhydrazones of 1,3-substi- tic acid leads to a high yield of N-acylhydrazones IIIa- IIIp.
tuted 4-formylpyrazoles (Ilia- Hip) and studied their antimi- The latter compounds appear as high-melting colorless (or
crobial properties. light-yellow) substances with limited solubility in most of the
organic solvents. The product compositions were confirmed
by elemental analyses, and the proposed structures by the
CHO data of IR spectroscopy. The IR spectra contain absorption
R' N/ bands at 3 1 8 0 - 3220 cm- t attributed to stretching vibrations
R--C--NH--NH 2 + ~ R--C--NH--N=CH of the NH groups, and bands at 1645 - 1665 cm- I assigned
II N--N II ~ N
O "Ph 0 to vibrations of the C--N and C=O groups.
la - l c lla - llg I l i a -- l l l p R'

EXPERIMENTAL CHEMICAL PART

II: R' = 5-methyl-2-furyl (a), 2-thienyl (b), 5-(4-bromophenyl)-2-fia.,yl (c), 5-
(4-nitrophenyl)-2-furyl (d), 3-coumaryl (e), 6-benzodioxanyl (f), 9-¢thyl-3- The IR spectra were measured on an UR-20 spectro-
carbazolyl (g);
photometer (Germany) using samples prepared by pelletizing
IIIa: R = 4-pyridyl, R' = 5-methyl-2-fia'yl;
IIlb: R = 4-pyridyl, R' = 2-thienyl;
with KBr. The 1H NMR spectra were obtained with a Bruker
IIIc: R = 4-pyridyl, R' = 5-(4-bromophenyl)-2-furyl; WP-200 (200 MHz) spectrometer using deuterated chloro-
IIId: R = 4-pyridyl, R' = 5-(4-nitrophenyl)-2-furyl; form as the solvent and HMDS as the internal standard. The
life: R = 4--pyridyl, R' = 3-coumaryl; course of the reactions was monitored and the purity of prod-
IIIf: R = 4-pyridyl, R' = 6-benzodioxanyl; ucts checked by TLC on Silufol UV-254 plates eluted in the
IIIg: R = 4-chlorophenoxymethyl; R' = 5-methyl-2-furyl;
diethyl ether-chloroform (1 : 2) system and developed in the
IIIh: R = 4-chlorophenoxymethyl; R' = 2-thienyl;
IIli: R = 4-chlorophenoxymethyl; R' = 3-coumaryl;
iodine vapors. The yields and physicochemical characteristics
IIIj: R = 4-chlorophenoxymethyl; R' = 6-benzodioxanyl; of the synthesized compounds are presented in Table 1.
IIIk: R = 4-chlorophenoxymethyl; R' = 9-ethyl-3-carbazolyl; 3-(6-Benzodioxanyi)-l-phenyl-4-formylpyrazole (llf)
II1 h R = (I-naphthyl)oxymethyl; R' = 5-methyl-2-furyl; and 1-phenyl-4-formyl-3-(9-ethyl)-3-carbazolyl)pyrazole
lIIm: R = (l-naphthyl)oxymethyl; R' = 2-thienyl; (Ilg) were synthesized by a procedure similar to that de-
IIIn: R = (I-naphthyl)hydroxymethyl; R' = 3-coumaryl;
scribed in [11]. Compound IIf: yield, 63%; m.p., 118 - 120°C
1 Bukovinian State Medical Academy, Chemovtsy, Ukraine.
(from acetic acid); IR spectrum (Vmax,cm-1): 1690 (CO); IH
2 Institute o f Organic Chemistry, National Academy of Sciences of Ukraine, NMR spectrum (5, ppm): 4.24 (m, 4H, (CH2)2), 7.15-7.84
Kiev, Ukraine. (m, 9H, C6H4, C6H5), 8.54 (s, 1H, CH=), 10.28 (s, IH,
315
0091 - 150X/98/3206-0315520.00 °1999 Kluwer Academic/Plenum Publishers
 316 M . K . B r a t e n k o et al.

TABLE I. Properties of l-Phenyl-3-heteryl--4-formylpyrazoleN-Acylhy- EXPERIMENTAL BIOLOGICAL PART

drazones
MBC, ~tg/ ml The antimicrobial activity with respect to standard strains
Corn o
pound M.p.,°C Yield, Empirical St. Klebsiella o f E. coli, St. aureus 209-P, and Klebsiella pneumoniae was
% formula E. coli
aureus Pneumo- determined using a four-hour-grown suspension o f test cul-
209-P niae
ture in a liquid nutrient medium ( ( 1 - 2 ) x 106 c e l l s / m l ac-
IIla 210-212 76 C21HI7N502 > 500 > 500 > 500
cording to the calibration curve). The activity was evaluated
lIIb 115- 117 84 C20HIsNsOS > 500 > 500 > 500
after a 24-h incubation at 37°C. The minimum bacteriostatic
lllc 283-285 77 C26HtTBrNsO2 > 500 250 500
concentration (MBC) o f a compound tested for each bacterial
llId 270- 273 68 C26HITN604 250 > 500 500
strain was determined from the last dilution o f this com-
llle 276-278 90 C25HtrNsO3 >500 > 125 500
lllf 179- 180 75 C24HIoN503 > 500 > 125 500 pound, for which the visible growth o f the culture was com-
lllg 168 - 170 77 C23H14CIN403 > 500 > 500 > 500 pletely inhibited in contrast to control [12].
lllh 174-176 80 C22HITCIN402S 250 125 500 It was established that the synthesized compounds exhibit
IIli 231-234 86 C27HI9CIN404 500 250 500 a weak bacteriostatic effect (see Table 1). The maximum ac-
llIj 164 66 CqrH21CIN404 500 > 500 > 500 tivity among the compounds studied was observed for N-
lllk 130- ! 33 70 C32H26CIN502 500 > 500 500 acylhydrazone IIIe containing the isonicotinoyl fragment and
IIII 200- 203 76 C27H22N403 < 500 > 500 > 500 the coumaryl substituent in position 3 o f the pyrazole ring.
lllm 193 - 196 82 C26H2oN402S 125 500 500
llln 233 -235 86 C31H22N404 > 500 500 250 REFERENCES
IIio 182- 185 69 C30H24N404 500 > 500 500
lllp 137-140 76 C36H29N502 500 500 500 1. S. A. Giller, M. V. Shimanskaya, V. I~..l~gert, et. al., Zk. Vses.
Khim. o-va ira. D. 1. Mendeleeva, 15, 343 (1970).
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CH=O). Compound IIg: yield, 67%; m.p., 178 - 180°C (from of Hydrazine Derivatives [in Russian], Mariisk. Knizhn. Izdat.
acetic acid); IR spectrum (Vnm, c m - I): 1695 (CO); IH N M R Ioshkar-Ola (1976).
4. A. IC Dimri and S. S. Parmot, J. Heterocycl. Chem., 15, 335 -
spectnun (5, ppm): 1.08 (t, 3H, CH3), 3.98 (q, 2H, CH2), 336 (1978).
7 . 1 8 - 7 . 9 3 (m, 12H, C6H5, C6I-I4, C6H3), 8.76 (s, 1H, CH=), 5. M. S. Mashevskaya, Kkim.-Farm. Zh., 11(7), 3 5 - 37 (1977).
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3-(5-Methyl-2-furyi)-l-phenyipyrazole-4-c.arbaldehyde 7. I~. R. Dikanyan, F. G. Arsenyan, G. M. Stepanyan, and
L. G. Akopyan, Khim.-Farm. Zk., 30(6), 16 - 17 (1996).
4=pyridylcarbonylhydrazone (Ilia). To 10 mmole (2.52 g) 8. H. L. Yale and K. Losase, J. Am. Chem. Soc., 75(8), 1933-
o f 3-(5-methyl-2-furyl)-l-phenyl-4-formylpyrazole (IIa) in 1942 (1953).
7 ml glacial acetic acid was added 10 mmole (1.37 g) o f 4- 9. M. D. Mashkovskii, Drugs [in Russian], Vol. 2, Meditsina,
Moscow (1989), pp. 278 - 282.
pyridinecarboxylic acid hydrazide and the mixture was boiled 10. M. A. Thana and A.-R. E. Abdu, J. Chem. Technol. Biotechnol.,
for 1 h. The precipitate was filtered, washed with ethanol, and 55(2), 157- 161 (1992).
recrystallized from glacial acetic acid to obtain 2.81 g (76%) I1. M. K. Bratenko and M. V. Vovk, Abstracts of Papers. Ukrain-
ian Conf. "Chemistry of Nitrogen-Containing Heterocycles [in
o f compound IIIa.
Ukrainian], Kharkov (1997), p. 190.
Compounds I I I b - IIIp were obtained using similar pro- 12. G.N. Pershin (ed.), Methods of Experimental Chemotherapy [in
cedures (see Table 1). Russian], Moscow (1971).