Predictions and correlations of structure activity relationship of some aminoantipyrine derivatives on the basis of theoretical and experimental ground

Article abstract of DOI:10.1007/s00044-010-9505-0

A series of 4-aminoantipyrine derivatives were produced by condensing aromatic primary amine, namely, 4-aminoantipyrine with different aryl carbonyls which occurred cleanly and efficiently without using any catalyst at room temperature. Their structures w

Full text of DOI:10.1007/s00044-010-9505-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:157–164
DOI 10.1007/s00044-010-9505-0
ORIGINAL RESEARCH
Predictions and correlations of structure activity relationship
of some aminoantipyrine derivatives on the basis of theoretical
and experimental ground
•
Parvez Ali Jyotsna Meshram Javed Sheikh
•
•
•
Vandana Tiwari Rajendra Dongre Taibi Ben Hadda
•
Received: 1 February 2010 / Accepted: 3 November 2010 / Published online: 7 December 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of 4-aminoantipyrine derivatives were
produced by condensing aromatic primary amine, namely,
4-aminoantipyrine with different aryl carbonyls which
occurred cleanly and efficiently without using any catalyst
at room temperature. Their structures were confirmed on
Keywords Azomethines Á Synthesis Á
Molecular properties Á Screening
Introduction
1
the basis of H NMR, IR, Mass spectra, and elemental
analysis. The synthesized library was screened virtually
using versatile bioinformatics parameters owing to the
quick access, biological response, and utility of the pro-
duced moieties. The virtually screened molecules were
subjected to screen practically against certain some strain
of microorganisms: Staphylococcus aureus (Gram posi-
tive), Pseudomonas vulgaris (Gram positive), Pseudomo-
nas Aeruginosa (Gram negative), and Escherichia coli
(Gram negative). A correlation of structure and activities
relationship of these compounds with respect to molecular
modeling, Lipinski rule of five, drug-likeness, toxicity
profiles, and other physico-chemical properties of drugs is
described and verified experimentally.
Pyrazolone moiety is a five-membered lactam ring
containing two nitrogens and ketone in the same molecule
or alternatively a derivative of pyrazole possessing an
additional carbonyl/hydroxy group. It has been the focus
of medicinal chemists over the past ten decades because
of the outstanding pharmacological properties shown by
several of its derivatives (Kees et al., 1996), e.g., ampy-
rone, metamizole, etc. Ludwig Knorr discovered antipy-
rine. Owing to its promising antipyretic and analgesic
activities antipyrine was launched by Hoechst Pharma-
ceuticals. For the next 20 years, antipyrine became the
most widely used drug in the world, proving highly
successful for treating fever and flu-like infections, until
acetylsalicylic acid (aspirin) began to outsell it (Goder,
1985). Recently, a new pyrazolone compound, edarav-
one (3-methyl-1-phenyl-2-pyrazolin-5-one, also known as
MCI-186), has been developed as a promising drug for
brain ischemia and has also been reported to be effective
for myocardial ischemia (Watanabe et al., 1994; Kawai
et al., 1997). More recently, a series of pyrazolone
derivatives have been synthesized as potent inhibitors of
protease-resistant prion protein accumulation for the
treatment of fatal neurodegenerative diseases (Tarafder
et al., 2002). Antipyrine shows minimal protein binding
and is rapidly and completely absorbed from the gastro-
intestinal tract and extensively metabolized by the cyto-
chrome P450 liver enzymes. Estimates of half-life and
systemic clearance of antipyrine have been used for the
in vivo assessment of hepatic drug oxidation in different
P. Ali (&) Á J. Meshram Á V. Tiwari Á R. Dongre
Department of Chemistry, Rashtrasant Tukadoji Maharaj,
Nagpur University, Nagpur 440033, India
e-mail: parvezali_81@yahoo.com
J. Meshram
e-mail: drjsmeshram@rediffmail.com
J. Sheikh
National Environmental Engineering and Research Institute,
CSIR, Nagpur 440010, India
T. B. Hadda
Laboratoire de Chimie des Materiaux, Universite Mohammed
´
Premier, 60000 Oujda, Morocco
´
123

158
Med Chem Res (2012) 21:157–164
species (Kimata et al., 2007). Owing to its low pKa value
and small degree of plasma protein binding, antipyrine is
distributed in total body water. In view of their high
medicinal value and due to our interest in the synthesis of
compounds of potential pharmacological interest (Peri-
cherla et al., 2007; Pal et al., 2007; Jayaselli et al., 2008),
we became interested in constructing a library based on
pyrazolone scaffold. Azomethine belong to a widely used
group of organic intermediates important for production
of specialty chemicals, e.g., pharmaceuticals, or rubber
additives (Macho et al., 2004) and as amino protective
groups in organic synthesis (Bey and Vevert, 1977; Lucas
et al., 1960; Bezas and Zervas, 1961). They also used as
liquid crystals, (Adams, 2000) and in analytical (Layer,
1963) medicinal (Jarrahpour et al., 2004) and polymer
chemistry (Higuchi and Yamamoto, 1999). Based on the
significant biological and pharmacological properties the
pyrazolone moiety possesses a new class of such com-
pounds is reported by combining the chemistry of anti-
pyrine with azomethine with varying functionalities and
to explore their biological activities with the aim of
obtaining more potent antibacterial compounds. These
reported molecules in this article formulate a new class of
antibacterial agents that may become excellent candidates
for globally alarming drug resistance issues in clinically
used therapeutics. There is considerable interest in these
compounds as combined antibacterial agents, exhibiting
potency similar pharmacophore pockets to that observed
for Ampicillin. Several groups have reported on the
failed attempts to get a clear idea concerning the origin
of each activity in this standard reference, casting doubt
over the structural needs assignment. We present here
the results of our virtual screening investigation into
possible alternative structures for these compounds.
A
comparison between experiment and theoretical
predictions of the antibacterial activity has enabled us to
identify alternative combined pharmacophore sites struc-
tures. The structural assignment of the synthesized
compounds was based on its 1H NMR, IR, Mass, and
Elemental analysis.
Result and discussions
Chemistry
The azomethine derivatives 2a–2i were synthesized in
good yields (85–95%) by condensation of 4-aminoantipy-
rine with various substituted aromatic aldehydes in solid
state solvent less or minimum solvent conditions as shown
in Scheme 1. The structures of the title compounds were
1
determined by IR, H NMR, mass spectrometry, and ele-
mental data. The spectroscopic properties and analytical
1
data were in accord with the proposed structures. The H
NMR spectrum for compounds 2a–2i showed a single peak
for the azomethine –CH=N proton, which varied from 9.65
up to 9.77 ppm. Such values are very similar to those found
1
in the literature for the azomethine proton. The H NMR
spectra of 2a–i contained multiplet signals due to aromatic
protons in the 6.93–7.90 ppm regions. The IR spectra
provide valuable information regarding the nature of
functionalities present in the compounds. The bands around
1,600–1,610 cm-1 suggested the presence of azomethine
linkage in the compounds. The other signals and peaks of
1H NMR and IR are in complete agreement with the
assigned structures, and they are listed in the experimental
section.
Scheme 1 Solvent-free
synthesis of Antipyrine
derivatives
H
N
C
R
R
N
O
N
OHC
Where R:
2a: H,
2b: 2-OH
NH2
2 (a)-(h)
2c: 4-OH, 2d: 2-NO2
2e: 3-NO2, 2e: 2-Cl
2f: 4-Cl, 2g: 4-OMe
N
40-50 Secs., RT
O
N
1
Solventless/Minimum
EtOH
H
N
C
O
N
O
N
OHC
O
2 (i)
123

Med Chem Res (2012) 21:157–164
159
Virtual screenings and molecular properties
calculations
PSA. This is also supported by the antibacterial screening
data of compounds 2b and 2i in terms of maximum zone of
inhibitions. It has to be kept in mind that log P and PSA
values are only two important, although not sufficient cri-
teria for predicting oral absorption of a drug. To support this
contention, note that all the compounds have zero violations
of the Rule of 5. The Rule of 5 is a set of parameters devised
to aid the screening of potential drug ‘‘hits’’ identified
through processes such as high throughput screening
(Lipinski et al., 2001). Applying the Rule of 5 increases the
probability that a potential chemotherapeutic will have
favorable bioavailability. The criteria are as follows
(Lipinski et al., 2001): (A) Not more than 5 hydrogen bond
donors; (B) Not more than 10 hydrogen bond acceptors; (C)
Formula weight less than 500; and (D) Log P less than 5.
Two or more violations of the Rule of 5 suggest the prob-
ability of problems in bioavailability (Lipinski et al., 2001).
All the compounds have zero violations of the Rule of 5.
Drug-likeness of compounds 3a–3i is tabulated in Table 4.
Drug-likeness may be defined as a complex balance of
various molecular properties and structure features which
determine whether particular molecule is similar to the
known drugs. These properties, mainly Hydrophobicity,
electronic distribution, hydrogen bonding characteristics,
molecule size and flexibility and presence of various phar-
macophores features influence the behavior of molecule in a
living organism, including bioavailability, transport prop-
erties, affinity to proteins, reactivity, toxicity, metabolic
stability, and many others. Activity of all nine compounds
and standard drugs were rigorously analyzed under four
criteria of known successful drug activity in the areas of
GPCR ligand activity, ion channel modulation, kinase
inhibition activity, and nuclear receptor ligand activity.
Results are shown for all compounds in Tables 1 and 2 by
means of numerical assignment. Likewise all compounds
have consistent negative values in all categories and
Molinspiration calculations (Parvez et al., 2010a)
CLogP (octanol/water partition coefficient) is calculated by
the methodology developed by Molinspiration as a sum of
fragment-based contributions and correction factors. The
method is very robust and is able to process practically all
organic and most organometallic molecules. Molecular
polar surface area TPSA is calculated based on the meth-
odology as a sum of fragment contributions. O– and N–
centered polar fragments are considered. PSA has been
shown to be a very good descriptor characterizing drug
absorption, including intestinal absorption, bioavailability,
Caco-2 permeability and blood–brain barrier penetration.
Prediction results of compounds and molecular properties
(TPSA, GPCR ligand, and ICM) are valued (Tables 1, 2).
Lipophilicity (log P value) and polar surface area (PSA)
values are two important predictors of per oral bioavail-
ability of drug molecules (Clark, 1999; Chang et al., 2004).
Therefore, we calculated log P and PSA values for com-
pounds 2a–2i using mol inspiration software programs and
compared them to the values obtained for standard market
available drugs. For all compounds the calculated log P
values were lower than 5, which is the upper limit for drugs
to be able to penetrate through biomembranes according to
Lipinski’s rules. The polar surface area (PSA) is calculated
from the surface areas that are occupied by oxygen and
nitrogen atoms and by hydrogen atoms attached to them.
Thus, the PSA is closely related to the hydrogen bonding
potential of a compound (Clark, 1999). Molecules with
˚
PSAs of 140 A or more are expected to exhibit poor
intestinal absorption (Clark, 1999). Table 1 show that all
the compounds are within this limit with compounds 2b, 2c,
and 2i is having minimum comparable values of log P and
Table 1 Molinspiration calculations of molecular properties and drug-likeness of compounds (2a–2i)
Compd.
Molecular properties calculations
Drug-likeness
MW (g/mol)
cLogP
TPSA
OH–NH interract.
N violation
Volume
GPCRL
ICM
KI
NRL
2a
2b
2c
2d
2e
2f
291
307
307
336
336
326
326
321
281
2.86
2.80
2.38
2.767
2.79
3.49
3.54
2.91
2.12
39
60
60
85
85
39
39
49
52
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
273
281
281
296
296
286
286
298
254
-1.05
-0.97
-0.97
-1.22
-1.08
-1.05
-1.00
-0.96
-1.07
-1.24
-1.27
-1.15
-1.24
-1.22
-1.25
-1.17
-1.21
-1.35
-1.29
-1.32
-1.21
-1.44
-1.27
-1.32
-1.23
-1.19
-1.54
-1.27
-1.09
-1.03
-1.14
-1.22
-1.24
-1.29
-1.14
-2.18
2g
2h
2i
GPCRL GPCR ligand, ICM Ion channel modulator, KI Kinase inhibitor, NRL Nuclear receptor ligand
123

160
Med Chem Res (2012) 21:157–164
numerical values conforming and comparable to that of
standard drugs used for comparison. Therefore, it is readily
seen that all the analogs are expected to have near similar
activity to standard drugs used based upon these four rig-
orous criteria (GPCR ligand, ion channel modulator, kinase
inhibitor, and nuclear receptor ligand).
compound’s Hydrophilicity. Low Hydrophilicity and
therefore high log P values may cause poor absorption or
permeation. It has been shown for compounds to have a
reasonable probability of being well absorb their log P
value must not be greater than 5.0. On this basis, all the
compounds 2a–2i is having log P values under the
acceptable criteria. Along with this, compound 2b and 2i
which have shown good antibacterial screening results is
having low log p values as compared to other compounds
in the series. The aqueous solubility of a compound sig-
nificantly affects its absorption and distribution character-
istics. Typically, a low solubility goes along with a bad
absorption and therefore the general aim is to avoid poorly
soluble compounds. Our estimated log S value is a unit
stripped logarithm (base 10) of a compound’s solubility
measured in mol/liter. There are more than 80% of the
drugs on the market have an (estimated) log S value greater
than -4. In case of compounds 2b and 2i, values of log S
are low as compared to others in the series. Further, the
Table 3 shows drug-likeness of compounds 2a–2i which is
in the comparable zone with that of standard drugs used.
We have calculated overall drug-score (DS) for the com-
pounds 2a–2i and compared with that of standard drugs
Ampicillin and streptomycin used as shown in Table 3 and
4. The DS combines drug-likeness, ClogP, logs, molecular
weight, and toxicity risks in one handy value that may be
used to judge the compound’s overall potential to qualify
for a drug. The reported compounds 2a–2i showed mod-
erate to good DS as compared with standard drugs used.
Osiris calculations (Parvez et al., 2010b) Structure based
design is now fairly routine but many potential drugs fail to
reach the clinic because of ADME-Tox liabilities. One very
important class of enzymes, responsible for many ADMET
problems, is the cytochromes P450. Inhibition of these or
production of unwanted metabolites can result in many
adverse drug reactions. Of the most important program,
Osiris is already available online. With our recent publi-
cation of the drug design combination of various pharma-
cophore sites by using heterocyclic structure Parvez et al.,
(2010a, b) it is now possible to predict activity and/or
inhibition with increasing success in two targets (bacteria
and HIV virus). This is done using a combined electronic/
structure docking procedure and an example will be given
here. The remarkably well behaved mutagenicity of divers
synthetic molecules classified in data base of CELERON
Company of Switzerland can be used to quantify the role
played by various organic groups in promoting or inter-
fering with the way a drug can associate with DNA. Tox-
icity risks (mutagenicity, tumorogenicity, irritation,
reproduction) and physicochemical properties (ClogP,
solubility, drug-likeness and drug-score) of compounds
(2a–2i) are calculated by the methodology developed by
Osiris as a sum of fragment-based contributions and cor-
rection factors (Tables 3, 4). The toxicity risk predictor
locates fragments within a molecule which indicate a
potential toxicity risk. Toxicity risk alerts are an indication
that the drawn structure may be harmful concerning the
risk category specified. From the data evaluated in Tables 3
and 4 indicates that, all structures are supposed to be
mutagenic when run through the mutagenicity assessment
system but as far as irritating and reproductive effects are
concerned, all the compounds are at low risk comparable
with standard drugs used. The log P value of a compound,
which is the logarithm of its partition coefficient between
n-octanol and water, is a well-established measure of the
Pharmacology
Antibacterial activity (in vitro) (Parvez et al., 2010a) The
antibacterial activity of the series (2a)–(2i) has been carried
out against some strain of bacteria. To determine the
antibacterial activity of these agents, Agar cup plate
method was used, with Ampicillin and Streptomycin as
the reference antibiotics. The prepared compounds were
examined against two strains each of Gram-positive and
Gram-negative bacteria. The test results, presented in
Table 5, suggest that compounds 2a, 2c, and 2i are highly
active against two strains each of Gram-positive and Gram-
negative bacteria showing the broadest spectrum of
Table 2 Molinspiration calculations of molecular properties and drug-likeness of Ampicillin and Streptomycin
Compd.
Molinspiration calculations
Drug-likeness
MW g/mol
cLogP
TPSA
OH–NH interract.
N violation
Volume
GPCRL
ICM
KI
NRL
AMP
349
582
-0.87
-5.35
112.73
336
4
0
3
299
497
-0.56
-0.67
-0.55
-1.15
-0.90
-0.76
-0.87
-1.11
STREP
16
123

Med Chem Res (2012) 21:157–164
161
Table 3 Osiris calculations of compounds (2a–2i)
Compd.
Toxicity risks
MUT
Osiris calculations
TUMO
IRRI
REP
MW
CLP
Log S
DL
5.05
D-S
2a
2b
2c
2d
2e
2f
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
291
307
307
336
336
325
325
321
281
1.96
1.66
1.66
1.83
1.82
2.57
2.57
1.85
1.06
-3.24
-2.94
-2.94
-3.70
-3.7
0.31
0.32
0.32
0.16
-0.22
0.28
0.28
0.31
0.32
5.00
5.26
-2.10
-0.11
5.44
-3.98
-3.98
-3.25
-2.92
2g
2h
2i
5.83
5.23
5.00
Active risk = -, Non-active risk = ?
Table 4 Osiris calculations of Ampicillin and Streptomycin
Compd.
Toxicity risks
MUT
Osiris calculations
TUMO
IRRI
REP
MW
CLP
Log S
DL
D-S
AMP
?
?
?
?
?
?
?
349
581
20.04
27.83
21.57
20.96
10.72
0.83
0.91
0.43
STREP
AMP Ampicillin, STREP Streptomycin, MUT Mutagenic, TUMO Tumorogenic, IRR Irritant, REP Reproductive Effective, MW Molecular
Weight in g/mol, CLP ClogP, S Solubility, DL Drug-Likeness, D-S Drug-Score
Non-active risk = ?, Average =
Table 6 MIC of selected compounds
Table 5 Antibacterial activity of compounds (2a–2i)
*Compd.
Gram (?) bacteria
Gram (-) bacteria
Compd. MW (g/mol) Gram (?) bacteria
Gram (-) bacteria
A
B
C
D
A
B
C
D
2b
50
75
50
25
75
75
100
100
75
2a
2b
2c
368
384
384
413
413
402
402
398
358
349
???
???
??
??
???
-
-
-
2f
100
75
100
75
???
?
??
?
2i
AMP
25
25
25
2d
2e
??
-
-
?
AMP Ampicillin, STREP Streptomycin, A S.aureus, B P.vulgaris,
C E.coli, D P.aeruginosa
?
-
?
-
2f
???
??
???
-
???
-
???
?
* Concentrations were in lg/ml
2g
2h
2i
?
??
???
??
???
?
-
Minimum inhibitory concentration (MIC) was defined
as the lowest compound concentration preventing visible
bacterial growth. MICs of selected compounds (activity
over 80%) 2b, 2f, and 2i were determined by taking dif-
ferent concentrations of the compound in DMF. The dif-
ferent concentrations were added by using sterilized
pipettes to different test tubes containing sterilized broth
medium inoculated with test organism. Then all the test
tubes were incubated at 37°C for 24 h. Then after incu-
bation period, the presence of growth (turbidity) was
observed. It was observed that the MIC of selected com-
pounds was in the range 50–100 lg/ml. This is the MIC of
the compounds. Out of three selected compounds, 2i was
shown to have least MIC values as tabulated in Table 6.
???
???
???
???
??
???
???
???
???
AMP
STREP 581
AMP Ampicillin, STREP Streptomycin, A S.aureus, B P.vulgaris,
C E.coli, D P.aeruginosa. Inactive = -(inhibition zone \ 5 mm),
slightly active = ? (inhibition zone 5–10 mm), moderately active =
? ? (inhibition zone 10–15 mm), highly active = ? ? ? (inhibition
zone [ 15 mm)
antibacterial activity. The rest of the compounds were
found to be moderately active, slightly active, or inactive
against the tested microorganisms. The results show that
the prepared compounds are toxic against the bacteria.
123

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Med Chem Res (2012) 21:157–164
Experimental
General
(0.1 M) contained in a beaker and the mixture was scrat-
ched with glass rod (ca. 10 s.), affording an oil (ranging
from cream to dark brown in color). On further scratching
(ca. 30 s.) the dark yellow solid azomethine was formed
Parvez et al. 2010b, c. If required, analytically pure product
can be obtained by recrystallization (from methanol). Same
process was followed for the generation of other azo-
methines except for compound 2c, 2d, 2e, and 2g where
aldehydes were dissolved in a minimum amount of ethanol
followed by the addition of 4-aminoantipyrine. This com-
pound was obtained as light brown solid, Yield: (85%),
M.P 195°C. IR (KBr, cm-1): 1650 (C=O), 1600 (C=N),
1034 (N–N). 1H NMR (CDCl3): 2.60 (s, 3H, C–CH3), 3.20
(s, 3H, N–CH3),6.33 (d, 1H, C–H, Furan), 6.30 (m, 3H,
C–H, Furan), 7.40 (d, 1H, C–H, Furan), 7.12–7.55 (m, 5H,
Phenyl H), 9.65 (s, 1H, –CH=N). MS: m/z: 304 (M?23).
Anal. calcd. for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94;
O, 11.37. Found: C, 68.34; H, 5.40; N, 14.96; O, 11.35.
The solvents and reagents used in the synthetic work were
of laboratory grade purchased from Qualigens, India and
were purified by distillation or crystallization where nec-
essary and their boiling or melting points were compared
with the available literature values. Melting points were
determined in open capillaries and are uncorrected. 1H
NMR spectra were recorded on a Perkin–Elmer FT-NMR
Cryo-magnet Spectrometer 400 MHz (Bruker) instrument
using tetramethylsilane (TMS) as an internal standard and
CDCl3 as a solvent. Chemical shifts are given in parts per
million (ppm). Infrared spectra were recorded on Schi-
madzu-IR Prestige 21 in the range 400–4,000 cm-1. Mass
spectra were recorded on a Waters Micromass Q-T of
Micro spectrometer. The purity of products was checked
out on pre-coated TLC plates (Silica gel 60 F254, Merck),
visualizing the spots under ultraviolet light and iodine
chamber. Elemental analyses were carried out using a
Perkin–Elmer, CHNS/O elemental analyzer model 2400.
Data
4-((Benzylidineamino-2-yl) methyleneamino)-1,2-
Antimicrobial screening
dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (2a)
The agar cup plate method using Hi-Media agar medium
was employed to study the antibacterial activity of 2a–2i
against S. aureus, p. vulgaris, P. aeruginosa, and E. coli.
Preparation of nutrient broth, subculture, base layer med-
ium, agar medium, and peptone water was done as the
standard procedure. 10 mg of the test compound was dis-
solved in 10 ml of DMF. From this 10 ml of solution was
taken and diluted to 100 ml with DMF. Now the concen-
tration of the test compound is 100 lg/ml. These sample
solutions were made in suitably labeled sterilized test
tubes. The standard drugs used in this testing were Ampi-
cillin and Streptomycin. The concentrations of these drugs
were adjusted so as to contain 100 lg/ml. The tests results
are shown in Table 5.
Light yellow solid, Yield: (90%)., M.P 162°C.IR (KBr,
1
cm-1): 1660 (C=O), 1610 (C=N), 1040 (N–N). H NMR
(CDCl3): 2.50 (s, 3H, C–CH3), 3.20 (s, 3H, N–CH3),
6.98–7.20 (m, 10H, Phenyl), 9.70 (s, 1H, –CH=N). MS: m/z:
291 (M?23). Anal. Calcd. for C18H17N3O: C, 74.20; H, 5.88;
N, 14.42; O, 5.49. Found: C, 74.24; H, 5.35; N, 14.45; O, 5.50.
4-((2-Hydroxybenzylidineamino-2-yl)
methyleneamino)-1,2-dihydro-2,3-dimethyl-1-
phenylpyrazol-5-one (2b)
Light orange solid, Yield: (92%). M.P 220°C. IR (KBr,
cm-1): 1658 (C=O), 1609 (C=N), 3200 (–O–H), N–N
1
(1040). H NMR (CDCl3): 1.72 (s, 3H, C–CH3), 2.55 (s,
Minimum inhibitory concentrations of selected com-
pounds were determined by taking different concentrations
of the compound in DMF. The different concentrations
were added by using sterilized pipettes to different test
tubes containing sterilized broth medium inoculated with
test organism. Then all the test tubes were incubated at
37°C for 24 h. Then after incubation period, the presence
of growth (turbidity) was observed. The results obtained
are tabulated in Table 6.
3H, N–CH3), 6.65–7.20 (m, 5H, N–Phenyl), 7.35–7.70 (m,
4H, C–Phenyl), 8.25 (s, 1H, –CH=N), 11.45 (s, 1H, –OH).
MS: m/z: 325 (M?23). Anal. calcd. for C18H17N3O2: C,
70.34; H, 5.58; N, 13.67; O, 10.41. Found: C, 70.35; H,
5.60; N, 13.70; O, 10.45.
4-((4-Hydroxybenzylidineamino-2-yl)
methyleneamino)-1,2-dihydro-2,3-dimethyl-1-
phenylpyrazol-5-one (2c)
General procedure for the synthesis of azomethines
Light orange solid, Yield: (90%). M.P 190°C. IR (KBr,
cm-1): 1658 (C=O), 1609 (C=N), 3200 (–O–H), N–N
1
(1040). H NMR (CDCl3): 1.72 (s, 3H, C–CH3), 2.55 (s,
In a typical solvent less experiment, the aldehyde, namely
(0.1 M) furfuraldehyde was added to 4-aminoantipyrine
3H, N–CH3), 6.65–7.20 (m, 5H, N–Phenyl), 7.35–7.70 (m,
123

Med Chem Res (2012) 21:157–164
163
4H, C–Phenyl), 8.25 (s, 1H, –CH=N), 11.45 (s, 1H, –OH).
MS: m/z: 325 (M?23). Anal. calcd. for C18H17N3O2: C,
70.34; H, 5.58; N, 13.67; O, 10.41. Found: C, 70.35; H,
5.60; N, 13.70; O, 10.45.
(CDCl3): 2.50 (s, 3H, C–CH3), 3.13 (s, 3H, N–CH3), 3.85
(s, 3H, O–CH3), 6.93–7.87 (m, 9H, Phenyl), 9.69 (s, 1H,
–CH=N),. MS: m/z: 344 (M?23). Anal. Calcd. for
C19H19N3O2: C, 71.01; H, 5.96; N, 13.08; O, 9.96. Found:
C, 71.04; H, 5.99; N, 13.10; O, 9.98.
4-((2-NitroBenzylidineamino-2-yl) methyleneamino)-
1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (2d)
Orange solid, Yield: (88%). M.P 158°C. IR (KBr, cm-1):
1660 (C=O), 1614 (C=N), 1040 (N–N). 1H NMR (CDCl3):
2.45 (s, 3H, C–CH3), 3.18 (s, 3H, N–CH3), 7.30–7.90 (m,
10H, Aromatic H), 9.85 (s, 1H, –CH=N). Mass (m/z):
[M?23]; 359 (100%). Anal. calcd. for C18H16N4O3: C,
64.28; H, 4.79; N, 16.66; O, 14.27. Found: C, 64.30; H,
4.82; N, 16.70; O, 14.30.
Conclusions
The functionalized compounds 2a–2i can easily be pre-
pared. The compounds were varied to possess a broad
range of lipophilicity character, revealed by Log P values
less than 5. All compounds were determined to express
zero violations to the Rule of 5, hence an indication
of favorable bioavailability based on drug-likeness.
The considerable number of hydrogen donor/acceptor
atoms incurred significant hydrophilic character into the
majority of these drugs (supported by low CLP values).
Comparing relative activity scores of Ampicillin and
streptomycin to those of standard drugs utilizing four
drug classes (GPCR ligand, ion channel modulator
(kinase inhibitor, and nuclear receptor ligand) showed all
compounds are very highly correlated with expected
similar bio-activity. In general, these compounds typi-
cally could form the highly interesting combined two or
more pharmacophore sites in one molecule. It has been
suggested that some functional groups along with het-
erocyclic system present in these compounds displayed
role of biological activity that may be responsible for
the increase of hydrophobic character and liposolubility
of the molecules. This in turn enhances activity of the
compounds and biological absorbance, so as, all the
Synthesized compounds have good antibacterial proper-
ties with compounds 2b and 2i shows highest screening
points with 2i is shown to have least MIC values. These
results prompt several pertinent observations (Pal et al.,
2007; Parvez et al., 2010b): (i) This type of derivatives
can furnish an interesting model for studying the inter-
action of antibiotics with viral target because the possi-
ble charge modification of substituent and O/N/S of
pharmacophore groups; (ii) The future flexible pharma-
cophore site (s) geometric conformation enables us to
prepare molecules for multi-therapeutic materials with
high selectivity.
4-((3-NitroBenzylidineamino-2-yl) methyleneamino)-
1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (2e)
Orange Solid, Yield: (91%). M.P 162°C. IR (KBr, cm-1):
1658 (C=O), 1615 (C=N), 1040 (N–N). 1H NMR (CDCl3):
2.40 (s, 3H, C–CH3), 3.15 (s, 3H, N–CH3), 7.30–7.89 (m,
10H, Aromatic H), 9.85 (s, 1H, –CH=N). Mass (m/z):
[M?23]; 359 (100%). Anal. calcd. for C18H16N4O3: C,
64.28; H, 4.79; N, 16.66; O, 14.27. Found: C, 64.34; H,
4.85; N, 16.75; O, 14.35.
4-((2-ChloroBenzylidineamino-2-yl) methyleneamino)-
1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (2f)
Yellow solid, Yield: (89%). M.P 165°C. IR (KBr, cm-1):
1655 (C=O), 1605 (C=N), N–N (1038).1H NMR (CDCl3):
2.47 (s, 3H, C–CH3), 3.18 (s, 3H, N–CH3), 6.97–7.82 (m,
9H, Phenyl), 9.77 (s, 1H, –CH=N). MS: m/z: 348 (M?23).
Anal. Calcd. for C18H16ClN3O: C, 66.36; H, 4.95; N,
12.90; O, 4.91. Found: C, 66.43; H, 4.98; N, 12.99; O, 4.97.
4-((4-Chlorobenzylidineamino-2-yl) methyleneamino)-
1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (2g)
Lightorangesolid,Yield:(92%).M.P230°C.IR(KBr,cm-1):
1652 (C=O), 1608 (C=N), 1038 (N–N). H NMR (CDCl3):
1
2.45 (s, 3H, C–CH3), 3.15 (s, 3H, N–CH3), 6.95–7.85 (m, 9H,
Phenyl), 9.70 (s, 1H, –CH=N). MS: m/z: 348 (M?23). Anal.
Calcd. for C18H16ClN3O: C, 66.36; H, 4.95; N, 12.90; O, 4.91.
Found: C, 66.40; H, 4.99; N, 12.98; O, 4.98.
Acknowledgments Authors are thankful to UGC [F-33-301/
2007(SR)], New Delhi for financial assistance to carry out this study.
We are grateful to SAIF Punjab University, Chandigarh for the help in
undertaking NMR, Mass spectra and Dr. Reddy’s Laboratory for
undertaking IR spectra. Special thanks are due to the Head, Depart-
ment of Microbiology, Rashtrasant Tukadoji Maharaj Nagpur Uni-
versity, Nagpur for antimicrobial screening. Prof. Jyotsna Meshram
would like to thank in particularly Dr. Johann Gasteiger for the online
molecular properties calculations.
4-((4-Methoxybenzylidineamino-2-yl)
methyleneamino)-1,2-dihydro-2,3-dimethyl-1-
phenylpyrazol-5-one (2h)
Yellow solid, Yield: (94%). IR (KBr, cm-1): 1660 (C=O),
1610 (C=N), 3200 (O–CH3), N–N (1045).1H NMR
123

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