Synthesis and anti-bacterial activities of some novel schiff bases derived from aminophenazone

Article abstract of DOI:10.3390/molecules15106850

A series of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one-containing Schiff bases were synthesized, characterized and screened for their antibacterial activities. The structures of the synthesized compounds were established by spectroscopic (FT-IR, <

Full text of DOI:10.3390/molecules15106850

Molecules 2010, 15, 6850-6858; doi:10.3390/molecules15106850
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Synthesis and Anti-Bacterial Activities of Some Novel Schiff
Bases Derived from Aminophenazone
Abdullah M. Asiri 1,2 and Salman A Khan 1,*
1
Chemistry Department, Faculty of Science, King Abdul Aziz University, P.O. Box 80203, Jeddah
21589, Saudi Arabia
2
The Center of Excellence for Advanced Materials, King Abdul Aziz University, Jeddah 21589, P.O.
Box 80203, Saudi Arabia
* Author to whom correspondence should be addressed; E-Mail: sahmad_phd@yahoo.co.in.
Received: 20 July 2010; in revised form: 16 August 2010 / Accepted: 18 August 2010 /
Published: 8 October 2010
Abstract: A series of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one-containing
Schiff bases were synthesized, characterized and screened for their antibacterial activities.
The structures of the synthesized compounds were established by spectroscopic (FT-IR,
13
1H-NMR, C-NMR, MS) and elemental analyses. The anti-bacterial activities (with MIC
values) of compounds were evaluated. The anti-bacterial screening results reveal that
among the six compounds screened, four compounds showed moderate to good anti-
bacterial activity. Among the tested compounds, the most effective compounds against four
bacterial strains, viz. Escherichia coli, Staphylococcus aureus, Salmonella typhimurium
and Streptococcus pyogenes, are [(2-Chlorobenzylidene)amino]-1,5-dimethyl-2-phenyl-
1,2-dihydropyrazol-3-one (4) and [(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-ylimino)methyl]benzonitrile (5) with MIC values of 6.25 μg/mL.
Keywords: Schiff bases; aminophenazone; antibacterial activity; ciprofloxacin
1. Introduction
Compounds containing the -C=N- (azomethine group) structure are known as Schiff bases, usually
synthesized from the condensation of primary amines and active carbonyl groups. Schiff bases are well
known for their biological applications as antibacterial, antifungal, anticancer and antiviral agents

Molecules 2010, 15
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[1,2]. Chloro and cyano groups containing Schiff bases at the C-2 position may display enhanced
antibacterial effects [3,4]. Pyrazol-3-ones are found in numerous biologically active molecules
recognized as having an important role in the animal and plant kingdoms. Different pyrazol-3-one-
bearing compounds possess antibacterial [5], antifungal [6], antiinflammatory [7], antihypertensive [8],
anti-HIV [9], antitumor [10], antifilarial [11] and anticonvulsant activities [12]. Recently, 4,5-diaryl-
1H-pyrazole-3-ols were utilized as a versatile template for synthesizing compounds that act as
potential cyclooxygenase-2 (COX-2) inhibitors and also show good selectivity for COX-2 versus
COX-1 enzymes [13]. Some pyrazolones showed inhibition of TNF-α production in response to the
tumor promotor TPA on HL-60 cells [4]. The pyrazol-3-one nucleus is known as an estrogen receptor
ligand [14] and also as a novel class of antagonists for adenosine receptors [15]. Thus both the pyrazol-
3-one nucleus and Schiff bases have attracted much interest in the development of pharmacologically
active compounds. Since the pyrazol-3-one Schiff base moiety seemed to be a possible pharmacophore
in various pharmacologically active agents, we decided to synthesize new pyrazol-3-one-containing
Schiff bases as possible antimicrobial agents which might furnish better therapeutic results.
2. Results and Discussion
2.1. Chemistry
In the present work, 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one Schiff base derivatives
1-6 were prepared by the reaction of 4-aminophenazone and the corresponding active aldehydes in
accordance with the method described in the literature [16]. The synthetic route is outlined in Scheme 1.
Scheme 1. Synthesis of novel pyrazol-3-one derived Schiff bases.
H
R
H2N
CH3
N
reflux, 5h
Ethanol
CH3
H
O
+
O
N
CH3
N
R
O
N
CH3
N
The chemical structures of the synthesized compounds were established by spectroscopic (FT-IR,
1H-NMR, 13C-NMR, MS) and elemental analyses. The FT-IR spectra of the pyrazol-3-one Schiff bases
showed absorption bands at 2,830–2,940 cm-1 for aliphatic C–H and at 1,560–1,670 cm-1 for the
azomethine group (–CH=N–). The nuclear magnetic resonance (1H-NMR) spectra of the compounds
were recorded in CDCl3 and the structural assignments are given in Section 6. The 600 MHz 1H-NMR
spectra of hydrazones 1-6 showed peaks of aromatic, methyl, and olefinic (–N=CH–) protons. These
1
were all one proton singlets. The H NMR spectrum of Schiff bases (1-6) showed sharp singlet at δ
9.25–10.18 indicating the presence of azomethine (–CH=N–) proton. The sharp singlet at δ
3.11–3.22 indicated the presence of -CH3 group attached to the Nitrogen. The appearance of multiplets
13
at δ 7.26–8.21 was due to aromatic protons. Moreover, the C-NMR spectra showed signals in the

Molecules 2010, 15
6852
range of δ 109.14–111.75 ppm and at δ 134.61–135.28 ppm due to aryl and azomethine carbons,
respectively. In the mass spectrum, compound 1 showed a peak at m/z 335 (M 1, 100%), which
matches its molecular formula C20H22N4O. A peak at m/z 409 (M 1, 100%) was observed for
compound 2 which is in conformity with the molecular formula C26H24N4O. Physicochemical data and
elemental analysis results of the compounds are listed in Table 1. The spectral data of all the
compounds are given in Section 4.
Table 1. Physicochemical data of the synthesized compounds.
Compound no.
Molecular
formula
M.p. oC/
Crystallization
% Yield
R
1
C20H22N4O
226/CHCl3
191/CHOH
82
N
2
C26H24N4O
76.5
N
3
4
OMe
C19H19N3O2
222 /CH3Cl
258 /CHCl3
76.8
78.5
Cl
C18H16N3OCl
CN
5
6
C19H16N4O
308/CH3OH
381/CHCl3
86.4
72.8
OMe
C21H23N3O4
MeO
OMe

Molecules 2010, 15
6853
2.2. Anti-bacterial activity
The anti-bacterial activity of the newly synthesized compounds 1-6 was evaluated against various
pathogenic (Gram-negative and Gram-positive) bacterial strains viz., Escherichia coli (E. coli),
Staphylococcus aureus (S. aureus), Salmonella typhimurium (S. typhi), Streptococcus pyogenes
(S. pyogenes). The anti-bacterial activities were evaluated by the agar disc diffusion method as per the
guidelines of the National Committee for Clinical Laboratory. Standards (NCCLS, 1997) [17]. The
solvent used for the preparation of compound solutions (DMSO) did not show inhibition against the
tested organisms (negative control).
The results of anti-bacterial screening of all the newly synthesized compounds are presented in
Table 2. Most of the compounds showed moderate to good activity with MIC value in the range of
6.25 μg/mL in DMSO. Particularly, cyano and chloro derivative of Schiff base (4&5) showed good
activity (zone of inhibition up to 19–28 mm at concentration of 6.25 μg/mL) against Escherichia coli,
Staphylococcus aureus, Salmonella typhimurium and Streptococcus pyogenes. Compound 1 showed
good activity against, Staphylococcus aureus, Salmonella typhimurium and Streptococcus pyogenes.
(zone of inhibition up to 17–19 mm at concentration of 6.25 μg/mL).
Table 2. Antibacterial activities of the compounds 1-6.
Product
E. coli
12 (25)
S.aureus
17 (6.25)
14 (25)
S.typhinurium
19 (6.25)
S. pyogenes
18 (6.25)
1
2
16 (6.25)
21 (6.25)
17 (6.25)
3
4
16 (6.25)
21 (6.25)
12 (25)
28 (6.25)
<10 (50)
25 (6.25)
<10 (50)
19 (6.25)
5
6
28 (6.25)
15 (25)
20 (6.25
13 (25)
26 (6.25)
<10 (50)
22 (6.25)
<10 (50)
Ciprofloxacin
32 (6.25)
23 (6.25)
28 (6.25)
24 (6.25)
MIC values are given in brackets. MIC (μg/mL) = Minimum inhibitory concentration, i.e. the
lowest concentration of drug which completely inhibit bacterial growth. Ciprofloxacin was used as
standard drug for anti-bacterial activity. Diameter of inhibition zone was measured in mm.
3. Experimental
3.1. General
All the chemicals and solvents used for this work were obtained from Merck (Germany) and
Aldrich Chemical Company (U.S.A.). Melting points of the synthesized compounds were determined
in open-glass capillaries on a Stuart-SMP10 melting point apparatus and are uncorrected. IR
absorption spectra were recorded on a Shimadzu FTIR-8400s using KBr pellets in the range of
1
4,000–400 cm-1, H-NMR and 13C-NMR spectra were recorded on a JEOL AL600 FTNMR
spectrometer operating at 600 MHz using. The 1H-NMR and 13C-NMR chemical shifts are reported as
parts per million (ppm) downfield from TMS (Me4Si) used as an internal standard The splitting
patterns are designated as follows; s, singlet; d, doublet; m, multiplet. Mass spectra were recorded on
1
VG-AUTOSPEC spectrometer. IR, H-NMR, 13C-NMR and MS were consistent with the assigned

Molecules 2010, 15
6854
structures. Elemental analyses (C, H, N) were done on a CHN Rapid analyzer. All the new compounds
gave C, H and N analysis within ±0.03% of the theoretical values. Purity of the compounds was
checked by thin layer chromatography (TLC) on Merck silica gel 60 F254 precoated sheets in
chloroform/methanol mixture and spots were developed using iodine vapours/ultraviolet light as
visualizing agents.
3.2. General procedure for the synthesis of Schiff Bases
A mixture of 4-aminophenazone (0.0058 mol, 0.5 g) and the corresponding active aldehyde.
(0.0058 mol) in anhydrous methanol (15 mL) was refluxed at 80 ºC for 5 h with continuous stirring in
the presence of few drop of acetic acid. Progress of the reaction was monitored by TLC. After
completion of the reaction the solution was cooled. The heavy precipitate thus obtained was collected
by filtration and purified by recrystallization from methanol and chloroform.
4-[(4-Dimethylaminobenzylidene)-amino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one
(1).
C20H22N4O; IR vmax cm-1: 2893 (C-H), 1644 (C=C), 1656 (C=O), 1578 (C=N), 1133 (N-N); H-NMR
(CDCl3) δ: 9.65 (s, 1H, CH olefinic), 7.78 (d, CHaromatic, J = 2.4 Hz), 6.72 (d, CHaromatic,
J = 3.00 Hz), 7.26-7.48 (m, 5H, CHaromatic), 3.20, (s, N-CH3), 2.98 (s, N-CH3), 2.56 (s, N-CH3), 1.25
1
13
(s, CH3); C-NMR (CDCl3) δ: 190.38, 161.31, 157.93, 151.87, 138.10, 135.05, 129.30, 129.06,
126.48, 125.87, 123.99, 122.80, 119.94, 111.81, 110.95, 40.24, 37.84, 10.24; MS (m/z, %): 335 (M+1,
45); Anal. Calc. for C20H22N4O: C, 71.58; H, 6.48; N, 16.75, Found: C, 71.83; H, 6.63; N, 16.75.
4-[(9-Ethyl-9H-carbazol-2-ylmethylene)-amino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one (2).
C26H24N4O; IR vmax cm-1: 2976 (C-H), 1651 (C=C), 1675(C=O), 1566 (C=N), 1132 (N-N); 1H-NMR
(CDCl3) δ: 10.02 (s, 1H, CH olefinic), 8.67 (s, H3, CHaromatic), 8.24 (dd, H1, CHaromatic,
J = 11.58 Hz), 8.13 (dd, H2, CHaromatic J = 12.72 Hz), 7.32-7.58 (m, 5H, CHaromatic), 4.47 (q,
CH3-CH2-N, J = 10.74 Hz), 1.55 (t, CH3-CH2-N, J = 10.684 Hz ), 3.22 (s, N-CH3), 2.62 (s,-CH3); 13C-
NMR (CDCl3)δ: 162.02, 158.53, 151.47, 143.56, 141.46, 138.10, 135.28, 134.97, 129.24, 129.04,
128.44, 125.91, 124.15, 123.16, 122.03, 120.80, 120.30, 119.36, 118.93, 109.14, 37.93, 37.71, 36.14,
13.86, 10.29; MS (m/z, %): 409 (M+1, 52); Anal. Calc. for C26H24N4O: C, 76.45; H, 5.92; N, 13.92,
Found: C, 76.35; H, 5.85; N, 13.82.
4-[(2-Methoxybenzylidene)-amino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one (3). C19H19N3O2;
1
IR vmax cm-1: 2830 (C-H), 1646 (C=C), 1691 (C=O), 1572 (C=N), 1135 (N- N); H-NMR (CDCl3) δ:
10.18 ((s, 1H, CH olefinic), 8.22(d, H3, CHaromatic, J = 2.58 Hz), 8.20 (dd, H4, CHaromatic,
J = 11.22 Hz), 6.99 (dd, H5, CHaromatic, J = 12.42 Hz), 8.20 (d, H6 CHaromatic, J = 2.64 Hz),
7.39-7.56 (m, 5H, CHaromatic), 3.92 (s, O-CH3), 3.21 (s, N-CH3), 2.56 (s,-CH3); 13C-NMR (CDCl3) δ:
190.10, 160.92, 159.21, 153.55, 151.93, 134.90, 131.42, 129.09, 126.64, 126.38 125.90, 124.17,
120.44, 119.58, 113.08, 111.04, 55.48, 35.96, 10.16; MS (m/z, %): 322 (M+1, 58); Anal. Calc. for
C19H19N3O2: C, 71.01; H, 5.96; N, 13.07, Found: C, 70.85; H, 5.88; N, 12.98.
4-[(2-Chlorobenzylidene)amino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one (4). C18H16N3OCl;
1
IR vmax cm-1: 2939 (C-H), 1664 (C=C), 1678 (C=O), 1570 (C=N), 1132 (N-N), 718(C-Cl); H-NMR

Molecules 2010, 15
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(CDCl3) δ: 9.71 ((s, 1H, CH olefinic), 7.79 (d, H3, CHaromatic, J = 1.80 Hz), 7.34 (dd, H4,
CHaromatic, J = 1.20 Hz), 7.32 (dd, H5, CHaromatic, J = 1.2 Hz), 7.78 (d, H6 CHaromatic,
13
J = 1.8 Hz), 7.35-7.50 (m, 5H, CHaromatic), 3.16 (s, N-CH3), 2.49 (s,-CH3); C-NMR (CDCl3) δ:
190.94, 160.72, 155.53, 152.04, 136.41, 135.87, 134.61, 130.93, 129.47,128.86, 127.05, 125.89,
124.48, 122.82, 118.31, 110.35, 37.85, 35.74, 10.24; MS (m/z, %): 326, 327 (M+1, 38, 56); Anal.
Calc. for C18H16N4O: C, 66.36; H, 4.95; N, 12.90, Found: C, 66.10; H, 4.85; N, 12.82.
2-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)methyl]benzonitrile
(5).
C19H16N4O; IR vmax cm-1: 2940 (C-H), 1645 (C=C), 1672 (C=O), 1563 (C=N), 1139 (N-N); H-NMR
(CDCl3) δ: 9.76 ((s, 1H, CH olefinic), 7.93 (d, H3, CHaromatic, J = 1.2 Hz), 7.39 (dd, H4,
CHaromatic, J = 1.20 Hz), 7.35(dd, H5, CHaromatic, J = 7.2 Hz), 7.92 (d, H6, CHaromatic,
J = 1.8 Hz), 7.69-8.21 (m, 5H, CHaromatic), 3.22(s, N-CH3), 2.51 (s,-CH3); 13C-NMR (CDCl3) δ:
190.08, 160.33, 154.05, 152.28, 141.98, 134.33, 132.32, 129.33, 129.05, 127.91, 127.41, 124.82,
122.84, 118.99, 117.84, 111.75, 35.48, 10.07; MS (m/z, %): 316 (M+1, 32); Anal. Calc. for
C19H16N4O: C, 72.14; H, 5.10; N, 17.17, Found: C, 72.08; H, 5.05; N, 17.08.
1
1,5-Dimethyl-2-phenyl-4-[(2,4,5-trimethoxybenzylidene)amino]-1,2-dihydropyrazol-3-one
(6).
C21H23N3O4; IR vmax cm-1: 2937 (C-H), 1644 (C=C), 1658 (C=O), 1591 (C=N), 1122 (N-N); 1H-NMR
(CDCl3) δ: 10.02 (s, 1H, CH olefinic), 7.67 (s, H3, CHaromatic), 6.49 (s, H6, CHaromatic), 7.47-7.86
(m, 5H, CHaromatic), 3.93 (s, OCH3), 3.93 (s, OCH3), 3.84 (s, OCH3), 3.11(s, N-CH3), 2.48 (s,-CH3);
13C-NMR (CDCl3) δ: 188.07, 161.09, 154.92, 153.38, 151.31, 143.44, 134.99, 129.08, 128.89, 126.58,
124.10, 122.80, 117.23, 109.88, 96.88, 95.83, 56.70, 55.98, 37.85, 14.73, 10.27; MS (m/z, %): 382
(M1, 52); Anal. Calc. for C21H23N3O4: C, 66.13; H, 6.07; N, 11.02, Found: C, 65.95; H, 5.86; N, 10.93.
3.3. Antimicrobial activity assay procedure
3.3.1. Disc diffusion method
The antimicrobial activity of newly synthesized compounds was evaluated according to the
guidelines of the National Committee for Clinical Laboratory Standards (NCCLS, 1997) using the agar
disc diffusion method [18]. Briefly, a 24/48 h-old culture of selected bacteria was mixed with sterile
physiological saline (0.85%) and the turbidity was adjusted to the standard inoculum of McFarland
scale 0.5 [~106 colony forming units (CFU) per milliliter]. Petri plates containing 20 mL of Mueller
Hinton Agar (MHA, Hi- Media) were used for all the bacteria tested. The inoculums was spread on the
surface of the solidified media and Whatman no. 1 filter paper discs (6 mm in diameter) impregnated
with the test compound (20 μL/disc) were placed on the plates. Ciprofloxacin (5 μg/disc, Hi-Media)
was used as positive control for bacteria. A paper disc impregnated with dimethylsulfoxide (DMSO)
was used as negative control. Plates inoculated with the bacteria were incubated for 24 h at 37 ºC and
the fungal culture was incubated for 72 h at 25 ºC. The inhibition zone diameters were measured in
millimeters. All the tests were performed in triplicate and the average was taken as final reading.

Molecules 2010, 15
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3.3.2. Determination of MIC
Minimum inhibitory concentration (MIC) of any compound is defined as the lowest concentration
which completely inhibits visible growth (turbidity on liquid media). MIC values were determined by
testing performed according to the guidelines of NCCLS document M27-A [19]. Solutions of the test
compounds, ciprofloxacin were prepared in DMSO at a concentration of 100 μg/mL. From this stock
solution, serial dilutions of the compounds and ciprofloxacin (50, 25. 6.25 μg/mL) 50 (1 μL stock
solution  1 μL solvent), 25 (1 μL stock solution  3 μL solvent), 6.25 (1 μL stock solution  15 μL
solvent), were prepared to determine the MIC. All determinations were done in triplicate and found the
same result. The standard antibiotic, ciprofloxacin for bacteria was used as positive control and
100 μL of DMSO were used as a negative control. At the end of the incubation period, the MIC values
were determined.
4. Conclusions
Some novel Schiff bases containing a pyrazol-3-one nucleus were synthesized by the reaction of
4-aminophenazone with the corresponding active aldehydes and were studied for their antimicrobial
activity. The anti-bacterial screening results reveal that among all the compounds screened,
compounds 1 and 2 showed moderate anti-bacterial activity, while compounds 4 and 5, which bear
chloro and cyano substituents, displayed good anti-bacterial activity (zone of inhibition up to
19–28 mm at concentration of 6.25 μg/mL) against Staphylococcus aureus, Salmonella typhimurium
and Streptococcus pyogenes when compared with ciprofloxacin, used as standard.
Acknowledgements
The authors would like to thank the Chemistry Department, King Abdul Aziz University, Jeddah,
Saudi Arabia for providing the research facilities.
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Sample Availability: Samples of the compounds are available from the authors.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).