Synthesis, antibacterial screening, and POM analyses of novel bis-isoxazolyl/pyrazolyl-1,3-diols

Article abstract of DOI:10.1007/s00044-013-0755-5

This research article reports the synthesis of 4,6-bis(5-aryl/heteroaryl-1, 2-oxazol-3-yl)benzene-1,3-diol 4a-4f and 4,6-bis(5-aryl/heteroaryl-1H-pyrazol-3- yl)benzene-1,3-diol 5a-5f from 1,1′-(4,6-dihydroxybenzene-1,3-diyl)bis(3- aryl/heteroarylpropane-1

Full text of DOI:10.1007/s00044-013-0755-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0755-5
ORIGINAL RESEARCH
Synthesis, antibacterial screening, and POM analyses
of novel bis-isoxazolyl/pyrazolyl-1,3-diols
•
Harjeet Juneja Dhanashri Panchbhai
•
•
Javed Sheikh Vishwas Ingle Taibi Ben Hadda
•
Received: 20 March 2013 / Accepted: 20 August 2013
Ó Springer Science+Business Media New York 2013
Abstract This research article reports the synthesis of
4,6-bis(5-aryl/heteroaryl-1,2-oxazol-3-yl)benzene-1,3-diol
4a–4f and 4,6-bis(5-aryl/heteroaryl-1H-pyrazol-3-yl)ben-
zene-1,3-diol 5a–5f from 1,10-(4,6-dihydroxybenzene-1,
3-diyl)bis(3-aryl/heteroarylpropane-1,3-dione) 3a–3f. The
compounds were fully characterized using spectroscopic
analyses and tested for their antibacterial activity. A cor-
relation 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 are described and
verified experimentally.
empirical therapy, delay in starting effective treatment, and
the use of less effective, more toxic, and more expensive
drugs. Although studies are not always consistent, antimi-
crobial resistance in the infecting organisms is associated
with treatment failure, prolonged or additional hospital-
ization, increased costs of care, and increased mortality.
Additional costs and lost bed days are incurred by the need
to control the spread of antimicrobial-resistant organisms
within hospitals. All this has significant direct impact on
patients and their families and also secondary effects on the
cost effectiveness of healthcare delivery. Hence, there is a
foremost urgent need to control antimicrobial resistance by
preparing improved antibiotic drugs.
Keywords Bis-isoxazole/pyrazole derivatives ꢀ
Antibacterial activity ꢀ Virtual screening ꢀ
This work reports the synthesis, antimicrobial activity,
and POM analyses of bis-isoxazole/pyrazole derivatives.
Pyrazoles and isoxazoles; and their variously substituted
derivatives are important biological agents and a significant
amount of research activity has been directed toward this
class. A numerous reports have appeared in the literature,
which highlighted their chemistry and use. Pyrazole
derivatives, in particular, are used as an antitumor (Taylor
et al., 1992), antibacterial and antifungal, antiviral, anti-
parasitic, anti-tubercular, and insecticidal agents (Abdel-
Rahman et al., 2007; Bhat et al., 2005; Holla et al., 2000;
Maggio et al., 2001; Michael et al., 1990; Sharshira and
Hamada, 2011; Rashad et al., 2005, 2008). Some of these
compounds also have anti-inflammatory, anti-diabetic,
anesthetic, and analgesic properties (Clinton et al., 1959;
Urmila et al., 2005; Vibhute and Basser, 2003). In similar
way, the isoxazole nucleus is well known for its medicinal
importance and a number of related compounds are known
to exhibit antifungal (Santos et al., 2010), antimicrobial
(Ravi et al., 2009), anticancer (Kamal et al., 2010), anal-
gesic, anti-inflammatory (Jayashankar et al., 2009), anti-
tuberculine (Kini et al., 2009), antiviral (Mazzei et al.,
Petra, Osiris, Molinspiration (POM) ꢀ Bioinformatics
Introduction
The increasing antimicrobial and multiple resistances have
resulted in increasing difficulties in the treatment of
bacterial infections. Resistance leads to inappropriate
H. Juneja ꢀ D. Panchbhai ꢀ J. Sheikh (&) ꢀ V. Ingle
Department of Chemistry, RTM Nagpur University,
Nagpur 440033, India
e-mail: sheikhchemie@gmail.com
J. Sheikh
Department of Chemistry, Dhote Bandhu Science College,
Gondia 441614, India
T. B. Hadda
Laboratoire Chimie Materiaux, FSO, Universite Mohammed I,
60000 Oujda, Morocco
´
´
123

Med Chem Res
´
1993), antipsychotic (Barcelo et al., 2007), and hypogly-
Mass spectroscopic analysis. All the compounds were
obtained in good to excellent yield.
cemic (Kumar et al., 2009) activities.
In appraisal of the aforementioned facts we describe herein
the synthesis of some new bis-pyrazole and bis-isoxazole
derivatives bearing 1,2-dihydroxyphenyl moiety in a goal to
get some new more active antimicrobial agents (Fig. 1).
In IR spectra of 4,6-bis(5-aryl/heteroaryl-1,2-oxazol-
3-yl)benzene-1,3-diol (4a–4f), the stretching frequency
from 3,406 to 3,597 cm-1 corresponds to the presence of
phenolic-OH in the skeleton. The presence of C=N and C–
O stretch was shown by the bands at 1,631–1,656 and
1,412–1,452 cm-1, respectively. The IR spectra of these
compounds reveal a characteristic aromatic stretch at
2,925–3,119 cm-1. Similarly, in IR spectra of 4,6-bis
(5-aryl/heteroaryl-1H-pyrazol-3-yl)benzene-1,3-diol (5a–5f),
the stretching frequency from 3,412 to 3,557 cm-1 corre-
sponds to the presence of phenolic-OH in the skeleton.
The presence of C=N and C–N stretch was shown by the
bands at 1,629–1,666 and 1,425–1,460 cm-1, respectively.
The IR spectra of these compounds reveal a characteristic
aromatic stretch at 2,950–3,153 cm-1. In both, bis-isoxazole
and bis-pyrazole derivatives C=O stretch is absent. All other
peaks in the spectra are in well agreement with the contents
of functionalities in the synthesized 4a–4f and 5a–5f
compounds.
Results and discussion
Chemistry
In this study six of each bis-isoxazole and bis-pyrazole
derivatives have been prepared and evaluated for their
antimicrobial activity.
In first step, 1,3-diaroyloxy/heteroaroyloxy-4,6-diace-
tylbenzene 2a–2f were prepared from 4,6-diacetylresor-
cinol 1. In second step, 1,10-(4,6-dihydroxybenzene-1,
3-diyl)bis(3-aryl/heteroarylpropane-1,3-dione) 3a–3f were
obtained by base catalyzed Baker–Venkataraman trans-
formation of 2a–2f. Bis-isoxazoles 4a–4f and bis-pyrazoles
5a–5f have been achieved by interaction of 3a–3f with
hydroxylamine hydrochloride and hydrazine hydrate in
presence of KOH in ethanol, respectively (Scheme l).
1
The H NMR spectra were recorded in DMSO-d6 at
1
room temperature using TMS as internal standard. The H
NMR data of compounds 4a–4f and 5a–5f reveal multiplet
peaks between 6.32 and 8.73 ppm owing to the presence of
aromatic protons. The absence of enolic proton at
15.89–15.99 ppm and existence of Ar–OH peak at
Spectral studies of 4a–4f and 5a–5f
1
The synthesized bis-isoxazole and bis-pyrazole derivatives
were characterized by FTIR, 1H-NMR, 13C-NMR, and
5.21–5.46 ppm rather than at 12.01–12.11 ppm as in H
NMR spectra of 3a–3f are in complete agreement with the
Fig. 1 Chemical structure
of clinical standard drugs
and candidates 3–5
Neomycin
Erythromycin
O
X
Ar
N
Ar
O
OH
OH
OH
OH
Ar
O
N
O
Ar
X
4 (X = O); 5 (X =NH)
3
123

Med Chem Res
Scheme 1 Synthesis of 4,
6-bis(5-aryl/heteroaryl-1,
2-oxazol-3-yl)benzene-1,3-diol
4a–4f and 4,6-bis(5-aryl/
heteroaryl-1H-pyrazol-
HO
O
OH
O
Ar
(a)
(b)
(1)
3-yl)benzene-1,3-diol 5a–5f
OCH3
ArCOOH/POCl3,
Pyridine
(c)
(d)
(e)
Cl
O
O
Ar
Ar
O
O
O
O
CH3
H3C
CH3
S
(f)
(2a-2f)
N
NaOH/DMSO
OH
HO
O
Ar
Ar
NH2OH.HCl/
KOH in EtOH
NH2NH2.H2O/
KOH in EtOH
O
O
O
(3a-3f)
HO
OH
HO
OH
N
O
N
N
N
O
NH
HN
Ar
Ar
Ar
Ar
(4a-4f)
(5a-5f)
assigned structure of 4a–4f and 5a–5f. All the compounds
have given the satisfactory elemental analysis.
like compounds. Various investigators have used compu-
tational methods in understanding efficacy and efficiency
of natural products and other sources of drug leads. We
have analyzed known standard references (neomycin and
erythromycin) for drug-like and lead-like properties which
would establish a strategy in designing specific drug-like or
lead-like armed bis-isoxazole/bis-pyrazole products.
Antibacterial activity of compounds 3–5
The antibacterial activities of the compounds 4a–4f and
5a–5f were carried out against some strain of bacteria as
mentioned in the method. The test results presented in
Table 1 suggest that compounds 4b, 4c, 4f, 5a, 5c, and 5f
are found active against all the bacterial strain. Most of the
compounds are found active against two of the four strains.
The excellent antibacterial activity of 4b, 4c, 5a, and 5c
compounds is due to the substituents bearing electro-
withdrawing groups. The increased activity of 4f and 5f
compounds is due to the introduction of nitrogen atom
(pyridyl ring) in the bis-pyrazole and bis-isoxazole
derivatives.
Tautomerism is an important and under-appreciated
phenomenon in the drug design process. Therefore, the
purpose of this study is important and has a potential to
improve how the descriptor-based QSAR studies are per-
formed. So, we have to avoid choosing a simplistic
approach to the problem. Tautomer equilibria in homolo-
gous structures depend on structure and the fractions of
individual tautomers in the equilibrium mixture will vary
from compound to compound in the set. These fractions are
a key component in the correct correlation equation. The
fractions can be obtained using publicly available resour-
ces, e.g., SPARC web server. It has been shown (Natesan
et al., 2012) that the drug-receptor binding constant is the
sum of the binding constants for individual tautomers
Modern drug discovery is largely based on screening of
small molecules against macromolecular disease targets
requiring molecular screening libraries of drug-like or lead-
123

Med Chem Res
Table 1 Antibacterial activity
of compounds 3–5. Minimum
inhibitory concentration (MICs,
Compounds
Aryl
Gram-positive
Gram-negative
M. albus
B. substilis
E. coli
P. vulgaris
mg mL-1
)
3a
Ph
15.15
16.12
14.98
13.14
14.95
15.67
–
15.78
14.90
13.23
16.24
15.54
11.90
11.23
16.48
13.65
12.66
13.21
15.75
12.25
15. 54
16.25
12.45
–
12.45
11.40
–
13.30
–
3b
4-CH3O-Ph
4-Cl-Ph
4-CH3-Ph
2-Thiophenyl
3-Pyridyl
Ph
3c
10.99
12.55
14.90
14.25
15.25
15.45
13.25
11.43
–
3d
13.75
15.50
16.45
16.98
14.33
12.66
–
3e
3f
4a
4b
4-CH3O-Ph
4-Cl-Ph
4-CH3-Ph
2-Thiophenyl
3-Pyridyl
Ph
15.87
15.03
14.65
15.98
16.09
13.98
14.40
15.66
–
4c
4d
4e
12.50
12.44
15.19
12.12
15.03
14.65
15.36
15.19
26.12
27.45
4f
11.9
5a
15.24
–
5b
4-CH3O-Ph
4-Cl-Ph
4-CH3-Ph
2-Thiophenyl
3-Pyridyl
–
5c
15.74
15.68
15.29
15.44
25.29
25.10
5d
5e
11.65
15.28
25.78
26.11
5f
14.20
26.12
27.12
Neomycin
Erythromycin
Diameter of inhibition zone in
mm; (–): no zone of inhibition
–
multiplied by the fractions of individual tautomers. This
makes the correlation equation nonlinear in coefficients so
a nonlinear regression technique must be used to optimize
the coefficients. Although more complicated than the use of
linear techniques, this is the price of treating the system
with a realistic approach. The used data sets contain cell-
level bioactivities, so the intracellular disposition also
needs to be considered. So we suggest that the study is re-
worked with the multi-species formalism (Fig. 2). The
‘‘Tauto-01’’ is attributed to the most predominant and
stable tautomeric form of series 3–5.
as biological activity in the form of pharmacophore site,
which gives key features on not only the ligand–receptor
interaction but also on the topology of the receptor
(Alafeefy et al., 2012; Chohan et al., 2010; Hadda et al.,
2012a, b, c, d; Jarrahpour et al., 2012; Mahajan et al.,
2012; Masand et al., 2012; Ozcelik et al., 2013; Parvez
et al., 2010; Sheikh et al., 2011; Sheikh and Hadda, 2013).
Hence to find out the structural features for the bacteria
inhibitory activity, we have carried out POM analysis of
series 3–5.
Osiris calculations
POM analyses of compounds 3–5
Structure-based design is now fairly routine but many
potential drugs fail to reach the clinic because of ADMET
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. To assess the
possible toxicity risks associated with 3–5, Osiris a freely
available online program was used (Htskuldsson, 1988).
Petra/Osiris/Molinspiration analysis (POM) is one of the
well-known approaches that have been used regularly to
produce the two dimensional models to identify, and to
indicate the type of pharmacophore site that affects bio-
logical activity with a change in the chemical substitution
(Alafeefy et al., 2012; Chohan et al., 2010; Hadda et al.,
2012a, b, c, d; Jarrahpour et al., 2012; Mahajan et al.,
2012; Masand et al., 2012; Ozcelik et al., 2013; Parvez
et al., 2010; Sheikh et al., 2011; Sheikh and Hadda, 2013).
The advantages of POM are the ability to predict the bio-
logical activities of the molecules and to represent the
relationships between steric/electrostatic property as well
Molinspiration calculations
CLogP (octanol/water partition coefficient) is calculated by
the methodology developed by Molinspiration as a sum of
fragment based contributions and correction factors
123

Med Chem Res
Ar
Ar
Ar
pyrazolyl-1,3-diols (BISOD) family. Indeed, this study
proved that a simple control of nature of few numbers of
substitutions leads to compounds with encouraging activi-
ties against both Gram positive and Gram negative bacteria
with reduced cytotoxicities.
δ-
-
O
O
O
δ
O
O
δ+
H
δ+
H
-
-
HO
HO
O
HO
HO
δ
δ
HO
HO
POM analyses of the BISOD compounds 3–5 showed
that lipophilic substituents bearing electro-withdrawing
groups could be introduced in benzene-1,3-diol moiety
maintaining a good antibacterial activity. Introduction of
nitrogen atom (1-H-pyrazol-3-yl) instead of oxygen atom
(1-oxazol-3-yl) on the BISOD template provided three
additional compounds 5a–5f with similar antibacterial
activity. The BISOD-molecules bearing (NHd?/Od-) and
(Nd-/HOd?) pharmacophore sites in equilibrium constitute
potential antibacterial drugs.
δ-
O
O
δ-
O
O
O
δ+
H
+
H
δ
O δ-
-
δ
Ar
Ar
Ar
3a-3f
3a-3f
3a-3f
(Tauto-01)
(Tauto-02)
(Tauto-03)
δ+ δ-
δ-
Ar
O
δ-
Ar
O
δ+
Ar
O
N
H
N
H
N
O
δ-
O
O
O
δ-
δ-
O
Experimental
O
H
H
N
δ+
N
δ+
H
N
δ+
δ-
Ar
Ar
Ar
O
O
Ar
Ar
O
Materials and methods
4a-4f
4a-4f
4a-4f
The solvents and reagents used in the synthetic work were
of analytical grade obtained from Qualigens India and were
purified by distillation or crystallization where necessary
and their boiling or melting points were compared with the
available literature values. Melting points were determined
(Tauto-02)
(Tauto-01)
(Tauto-03)
H
N
H
N
H
N
δ-
N
δ-
N
δ-
N
Ar
H
H
δ-
O
O
O
O
O
O
1
in open capillaries and are uncorrected. H NMR spectra
were recorded on a Perkin Elmer FTNMR Cryo-magnet
Spectrometer 400 MHz (Bruker) instrument using tetra-
methylsilane (TMS) as an internal standard and DMSO-d6
as a solvent. Chemical shifts are given in parts per million
(ppm). Infrared spectra were recorded on Shimadzu-IR
Prestige 21. Mass spectra were recorded on a Waters Micro
Mass Q–T of Micro Spectrometer. The reactions were
monitored and the purity of products was checked on pre-
coated TLC plates (silica gel 60 F254, Merck), visualizing
the spots under ultraviolet light and iodine chamber. The
purifying and drying of compounds and solvents were done
by usual process.
δ-
δ-
H
N
H
H
N
N
Ar
N
H
δ-
Ar
N
H
Ar
N
H
5a-5f
5a-5f
5a-5f
(Tauto-02)
(Tauto-01)
(Tauto-03)
Fig. 2 Chemical structure of most important tautomers of 3–5
(Table 2). 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 methodology published by Ertl et al. (2000) as a sum of
fragment contributions. O– and N– centered polar frag-
ments 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 3–5 molecular properties (TPSA, GPCR
ligand, and ICM) are valued (Table 3).
General procedure for the synthesis of compounds 2–5
General procedure for the preparation of 1,3-diaroyloxy/
heteroaroyloxy-4,6-diacetylbenzene 2a–2f
4,6-Diacetylresorcinol (1) (0.1 mol) and aromatic carbox-
ylic acids (0.02 mol) were dissolved in 5 mL of redistilled
pyridine and cooled, to that POCl3 1 mL was added
dropwise with constant stirring maintaining the tempera-
ture below 20 °C. The reaction mixture was kept overnight
at room temperature and poured with stirring on ice cold
diluted HCl (1 mol in 50 mL). A white granulated solid
compound 2 separated out which was washed with cold
Conclusion
This work provided us with structure–activity and struc-
ture–cytotoxicity information of a novel bis-isoxazolyl/
123

Med Chem Res
Table 2 Osiris calculations
of compounds 3–5
Compounds
MW
Toxicity risk
Osiris calculations
MUT
TUMO
IRRI
REP
CLP
S
D-L
D-S
0.36
3a
402
462
470
430
414
404
396
456
464
424
408
398
394
454
462
422
406
396
614
719
???
??
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
??
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
3.00
-4.54
-4.57
-6.01
-5.23
-4.56
-2.95
-6.33
-6.37
-7.8
-0.62
-0.35
0.59
3b
??
2.79
4.22
3.63
2.68
0.84
4.76
4.55
5.98
5.39
5.00
2.60
4.25
4.04
5.47
4.88
4.49
2.09
-10.03
2.02
0.28
0.28
0.26
0.4
3c
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
???
??
3d
??
-1.44
0.00
3e
??
3f
??
0.05
0.5
4a
???
???
???
???
???
???
???
???
???
???
???
???
???
???
-2.91
-2.22
-1.26
-4.15
-2.06
-1.72
-2.91
-2.22
-1.26
-4.15
-2.06
-1.72
2.61
0.22
0.22
-0.16
0.17
0.23
0.38
0.28
0.27
0.20
0.21
0.29
0.45
0.58
0.47
4b
4c
4d
-7.02
-6.17
-4.74
-5.28
-5.32
-6.75
-5.97
-5.12
-3.69
0.06
4e
4f
5a
5b
5c
???, not toxic; ??, slightly
toxic; -, highly toxic
5d
5e
MUT mutagenic, TUMO
5f
tumorigenic, IRRI irritant, REP
reproductive effective, CLP
cLogP, S solubility, DL drug
likeness, DS drug-score
Neomycin
Erythromycin
-3.49
11.29
Table 3 Molinspiration
calculations of compounds 3–5
Compounds
Molinspiration calculations
Drug-likeness
TPSA NONI NV nrotb VOL GPCRL ICM
KI
NRL
PI
EI
3a
115
134
115
115
115
141
93
4
4
1
1
1
1
1
0
1
1
1
1
1
0
0
0
1
1
0
0
3
2
6
8
6
6
6
6
4
6
4
4
4
4
4
6
4
4
4
4
9
7
352
403
379
385
333
343
341
392
368
374
322
332
347
398
374
380
329
339
534
693
-0.25
-0.26
-0.24
-0.27
-0.37
-0.17
0.06
-0.16 -0.37 -0.09 -0.22
-0.19 -0.36 -0.10 -0.24
-0.15 -0.36 -0.10 -0.25
-0.21 -0.38 -0.11 -0.26
0.07
0.03
0.04
0.02
3b
3c
4
3d
3e
4
4
-0.39 -0.43 -0.26 -0.33 -0.02
-0.06 -0.19 -0.06 -0.12 0.20
3f
4
4a
2
0.16
0.08
0.14
0.09
0.05
0.01
0.03
0.01
0.25 -0.06 -0.01
0.20 -0.10 -0.05
0.22 -0.10 -0.04
0.21 -0.11 -0.06
0.05 -0.07 -0.12
4b
4c
111
93
2
0.02
2
0.06
4d
4e
93
2
0.02
93
2
-0.02
0.15
0.01 -0.01
4f
118
98
2
0.28
-0.01
-0.06
-0.01
-0.07
-0.09
0.07
0.23
0.27
0.21
0.24
0.22
0.20
0.42
0.26 -0.06
0.12
5a
4
-0.01
-0.04
-0.01
-0.04
-0.12
0.05
0.08 -0.16 -0.01
0.05 -0.19 -0.04
0.06 -0.19 -0.03
0.05 -0.20 -0.05
0.01 -0.27 -0.04
5b
5c
116
98
4
4
TPSA total polar surface area,
VOL volume, ONI OH–NH
interaction, NV number of
violation, GPCRL GPCR
ligand, ICM ion channel
5d
5e
98
4
98
4
5f
124
353
4
0.07 -0.12
0.55
0.09
0.47
Neomycin
19
5
0.03
-0.22 -0.03 -0.13
modulator, KI kinase inhibitor,
NRL nuclear receptor ligand
Erythromycin 194
-0.42
-1.16 -1.14 -0.95 -0.08 -0.42
123

Med Chem Res
water, diluted NaHCO3 solution and again with cold water.
The product was filtered off, dried, and recrystallized from
alcohol. The completion of the reaction was monitored by
TLC.
C-3, C–O), 115.3 (C-2), 124.7 (C-4 & C-6), 128.9 (C-5),
164.9 (C of ester C=O), 122.4 (C-10 & C-100), 131.8 (C-20,
C-60 & C-200, C-600), 115.7 (C-30, C-50 & C-300, C-500), 165.1
(C-40 & C-400, C–O), 25.6 (C of CH3), 199.6 (C of acetyl
C=O), 29.8 (C of acetyl CH3). Anal. Calcd. for C26H22O6
(M?): (430) C, 72.55; H, 5.15. Found: C, 72.58; H, 5.18.
4,6-Diacetylbenzene-1,3-diyl dibenzoate (2a) Yield 74 %;
mp 91 °C; FT-IR (KBr): 1755 (ester C=O), 1692 (C=O),
1601 (aromatic C=C), 1139 (C–O); 1H NMR (DMSO-d6, d,
4,6-Diacetylbenzene-1,3-diyl
dithiophene-2-carboxylate
0
0
00
00
400 MHz) 8.05 (d, 4H, J2 –6 & J2 –6 = 7.8 Hz), 7.01–8.51
(m, 8H, ArH), 2.57 (s, 6H, CH3). 13C NMR (DMSO-d6, d,
400 MHz) 158.1 (C-1 & C-3, C–O), 114.3 (C-2), 124.7 (C-4
& C-6), 128.9 (C-5), 165.9 (C of ester C=O), 130.5 (C-10 &
C-100), 130.4 (C-20, C-60 & C-200, C-600), 128.9 (C-30, C-50 &
C-300, C-500), 134.3 (C-40 & C-400), 199.5 (C of acetyl C=O),
29.6 (C of acetyl CH3). Anal. Calcd. for C24H18O6 (M?):
(402) C, 71.64; H, 4.51. Found: C, 71.69; H, 4.49.
(2e) Yield 72 %; mp 105 °C; FT-IR (KBr): 1753 (ester
C=O), 1689 (C=O), 1597 (aromatic C=C), 1131 (C–O); 1H
NMR (DMSO-d6, d, 400 MHz) 7.09–8.58 (m, 8H, ArH),
2.64 (s, 6H, CH3 of acetyl group). 13C NMR (DMSO-d6, d,
400 MHz) 159.4 (C-1 & C-3, C–O), 114.9 (C-2), 125.4 (C-4
& C-6), 129.5 (C-5), 165.1 (C of ester C=O), 135.8 (C-10 &
C-100), 135.9 (C-30 & C-300), 128.7 (C-40 & C-400), 133.8
(C-50 & C-500), 198.7 (C of acetyl C=O), 28.2 (C of acetyl
CH3). Anal. Calcd. for C20H14O6S2 (M?): (414) C, 57.96;
H, 3.40. Found: C, 57.99; H, 3.48.
4,6-Diacetylbenzene-1,3-diyl bis(4-methoxybenzoate) (2b)
Yield 64 %; mp 95 °C; FT-IR (KBr): 1757 (ester C=O),
1696 (C=O), 1603 (aromatic C=C), 1143 (C–O); H NMR
1
4,6-Diacetylbenzene-1,3-diyl
dipyridine-3-carboxylate
0
0
00
00
(DMSO-d6, d, 400 MHz) 8.09 (d, 4H, J2 –6 & J2 –6
=
(2f) Yield 74 %; mp 120 °C; FT-IR (KBr): 1749 (ester
C=O), 1683 (C=O), 1599 (aromatic C=C), 1143 (C–O); 1H
NMR (DMSO-d6, d, 400 MHz) 6.97–8.23 (m, 10H, ArH),
2.69 (s, 6H, CH3 of acetyl group). 13C NMR (DMSO-d6, d,
400 MHz) 160.7 (C-1 & C-3, C–O), 115.3 (C-2), 124.1
(C-4 & C-6), 128.8 (C-5), 163.9 (C of ester C=O), 135.4
(C-10 & C-100), 135.3 (C-20 & C-200), 127.2 (C-40 & C-400),
132.4 (C-50 & C-500), 135.1 (C-60 & C-600), 197.9 (C of
acetyl C=O), 27.8 (C of acetyl CH3). Anal. Calcd. for
C22H16O6N2 (M?): (404) C, 65.34; H, 3.99. Found: C,
65.38; H, 3.95.
0
7.9 Hz), 7.34–8.61 (m, 2H, ArH), 7.01 (d, 4H, J3 –5
J3 –5 = 7.9 Hz), 3.71 (s, 6H, OCH3), 2.51 (s, 6H, CH3). 13
0
&
00
00
C
NMR (DMSO-d6, d, 400 MHz) 157.9 (C-1 & C-3, C–O),
114.6 (C-2), 124.1 (C-4 & C-6), 128.4 (C-5), 165.4 (C of
ester C=O), 122.8 (C-10 & C-100), 131.6 (C-20, C-60 & C-200,
C-600), 115.2 (C-30, C-50 & C-300, C-500), 165.7 (C-40 & C-400,
C–O), 56.1 (C of OCH3), 199.9 (C of acetyl C=O), 29.4 (C of
acetyl CH3). Anal. Calcd. for C26H22O8 (M?): (462) C, 67.
53; H, 4.80. Found: C, 67.59; H, 4.78.
4,6-Diacetylbenzene-1,3-diyl bis(4-chlorobenzoate) (2c)
Yield 63 %; mp 115 °C; FT-IR (KBr): 1761 (ester C=O),
1699 (C=O), 1606 (aromatic C=C), 1149 (C–O); H NMR
General procedure for the preparation of 1,10-(4,6-
dihydroxybenzene-1,3-diyl)bis(3-aryl/heteroarylpropane-
1,3-dione) (3a–3f)
1
0
0
00
00
=
(DMSO-d6, d, 400 MHz) 8.11 (d, 4H, J2 –6 & J2 –6
0
0
00
00
8.0 Hz), 7.41 (d, 4H, J3 –5 & J3 –5 = 8.0 Hz), 7.29–8.56
(m, 2H, ArH), 2.61 (s, 6H, CH3). 13C NMR (DMSO-d6, d,
400 MHz) 157.8 (C-1 & C-3, C–O), 114.5 (C-2), 124.3 (C-4
& C-6), 128.4 (C-5), 165.5 (C of ester C=O), 130.9 (C-10 &
C-100), 130.7 (C-20, C-60 & C-200, C-600), 129.2 (C-30, C-50 &
C-300, C-500), 139.9 (C-40 & C-400), 199.9 (C of acetyl C=O),
29.1 (C of acetyl CH3). Anal. Calcd. for C24H16Cl2O6 (M?):
(470) C, 61.16; H, 3.42. Found: C, 61.22; H, 3.43.
1,3-Diaroyloxy/heteroaroyloxy-4,6-diacetylbenzene 2a–2f
(0.005 mol) was dissolved in 4 mL of DMSO. To that
solution powdered NaOH (2 g) was added with vigorous
stirring for about 5 min. The stirring was continued for
5 min further. The reaction mixture was then cooled and
poured on cold water. The pale yellow solid product
obtained was washed with water, dried, and recrystallized
from alcohol.
4,6-Diacetylbenzene-1,3-diyl bis(4-methylbenzoate) (2d)
Yield 69 %; mp 110 °C; FT-IR (KBr): 1751 (ester C=O),
1699 (C=O), 1609 (aromatic C=C), 1151 (C–O); H NMR
1,10-(4,6-Dihydroxybenzene-1,3-diyl)bis(3-phenylpropane-
1,3-dione) (3a) Yield 74 %; mp 121 °C; FT-IR (KBr):
3425 (OH), 1740 (C=O), 1601 (aromatic C=C), 1139
1
0
0
00
00
(DMSO-d6, d, 400 MHz) 8.11 (d, 4H, J2 –6 & J2 –6
=
1
0
0
7.9 Hz), 7.44–8.65 (m, 2H, ArH), 7.18 (d, 4H, J3 –5
&
(C–O); H NMR (DMSO-d6, d, 400 MHz) 15.89 (s, 2H,
enolic OH), 12.01 (s, 2H, 4-OH, 6-OH), 8.43 (s, 2H,–CH=),
J3 –5 = 7.9 Hz), 2.37 (s, 6H, CH3 at C-40 and C-400
position in phenyl ring), 2.59 (s, 6H, CH3 of acetyl
group). 13C NMR (DMSO-d6, d, 400 MHz) 158.5 (C-1 &
00
00
0
0
00
00
7.48 (d, 4H, J2 –6 & J2 –6 = 8.4 Hz), 6.59–7.89 (m, 8H,
ArH). 13C NMR (DMSO-d6, d, 400 MHz) 189.1 (C-1 &
123

Med Chem Res
C-3), 133.3 (C-2), 170.6 (C-4 & C-6), 105.8 (C-5), 190.4 (C
of C=O), 185.5 (C of enolic C–O), 93.5 (C of –C=H), 130.4
(C-10 & C-100), 127.1 (C-20, C-60 & C-200, C-600), 128.9 (C-30,
C-50 & C-300, C-500), 129.3 (C-40 & C-400). Anal. Calcd. for
C24H18O6 (M?): (402) C, 71.64; H, 4.51. Found: C, 71.66; H,
4.54.
NMR (DMSO-d6, d, 400 MHz) 157.4 (C-1 & C-3, C–O),
104.9 (C-2), 114.5 (C-4 & C-6), 129.4 (C-5), 162.6 (C of
C=N, oxazole), 98.8 (C of –C=H), 170.6 (C of C–O, oxa-
zole), 131.6 (C-10 & C-100), 128.7 (C-20, C-60 & C-200, C-600),
130.3 (C-30, C-50 & C-300, C-500), 129.4 (C-40 & C-400). Anal.
Calcd. for C24H16N2O4 (M?): (396) C, 72.72; H, 4.07.
Found: C, 72.69; H, 4.13.
1,10-(4,6-Dihydroxybenzene-1,3-diyl)bis[3-(4-methoxyphenyl)
propane-1,3-dione] (3b) Yield 64 %; mp 155 °C; FT-IR
(KBr): 3429 (OH), 1747 (C=O), 1604 (aromatic C=C), 1146
4,6-Bis[5-(4-methoxyphenyl)-1,2-oxazol-3-yl]benzene-1,3-
diol (4b) Yield 65 %; mp 175 °C; FT-IR (KBr): 3412
(OH), 1714 (C=N), 1603 (aromatic C=C), 1159 (C–O); H
1
1
(C–O); H NMR (DMSO-d6, d, 400 MHz) 15.91 (s, 2H,
enolic OH), 12.08 (s, 2H, 4-OH, 6-OH), 8.39 (s, 2H,–CH=),
NMR (DMSO-d6, d, 400 MHz) 5.32 (s, 2H, OH), 6.39–8.
41 (m, 12H, ArH), 3.76 (s, 6H, OCH3). 13C NMR (DMSO-
d6, d, 400 MHz) 158.2 (C-1 & C-3, C–O), 105.2 (C-2),
115.3 (C-4 & C-6), 130.3 (C-5), 161.8 (C of C=N, oxa-
zole), 98.9 (C of –C=H), 170.5 (C of C–O, oxazole), 131.8
(C-10 & C-100), 128.7 (C-20, C-60 & C-200, C-600), 115.3
(C-30, C-50 & C-300, C-500), 161.4 (C-40 & C-400), 56.9 (C of
OCH3). Anal. Calcd. for C26H20N2O6 (M?): (456) C, 68.
42; H, 4.42. Found: C, 68.49; H, 4.44.
0
0
00
00
0
0
&
7.59 (d, 4H, J2 –6 & J2 –6 = 8.1 Hz), 7.16 (d, 4H, J3 –5
00
00
J3 –5 = 8.1 Hz), 7.31–8.59 (m, 2H, ArH), 3.81 (s, 6H,
OCH3). 13C NMR (DMSO-d6, d, 400 MHz) 189.8 (C-1 &
C-3), 134.1 (C-2), 169.5 (C-4 & C-6), 104.5 (C-5), 189.6 (C
of C=O), 184.6 (C of enolic C–O), 94.2 (C of –C=H), 131.2
(C-10 & C-100), 128.7 (C-20, C-60 & C-200, C-600), 128.6 (C-30,
C-50 & C-300, C-500), 160.2 (C-40 & C-400), 55.9 (C of CH3).
Anal. Calcd. for C26H22O8 (M?): (462) C, 67.53; H, 4.80.
Found: C, 67.56; H, 4.81.
4,6-Bis[5-(4-chlorophenyl)-1,2-oxazol-3-yl]benzene-1,3-
1,10-(4,6-Dihydroxybenzene-1,3-diyl)bis[3-(4-chlorophenyl)
propane-1,3-dione] (3c) Yield 69 %; mp 135 °C; FT-IR
(KBr): 3434 (OH), 1740 (C=O), 1602 (aromatic C=C), 1141
diol (4c) Yield 64 %; mp 180 °C; FT-IR (KBr): 3415
(OH), 1707 (C=N), 1601 (aromatic C=C), 1161 (C–O); H
1
1
NMR (DMSO-d6, d, 400 MHz) 5.29 (s, 2H, OH), 6.43–8.
59 (m, 12H, ArH). 13C NMR (DMSO-d6, d, 400 MHz)
158.6 (C-1 & C-3, C–O), 105.3 (C-2), 115.7 (C-4 & C-6),
130.2 (C-5), 161.8 (C of C=N, oxazole), 99.9 (C of –C=H),
171.5 (C of C–O, oxazole), 132.7 (C-10 & C-100), 129.8 (C-
20, C-60 & C-200, C-600), 131.2 (C-30, C-50 & C-300, C-500),
135.6 (C-40 & C-400). Anal. Calcd. for C24H14Cl2N2O4
(M?): (465) C, 61.95; H, 3.03. Found: C, 61.98; H, 3.08.
(C–O); H NMR (DMSO-d6, d, 400 MHz) 15.99 (s, 2H,
enolic OH), 12.11 (s, 2H, 4-OH, 6-OH), 8.31 (s, 2H,–CH=),
0
0
00
00
0
0
8.13 (d, 4H, J2 –6 & J2 –6 = 8.0 Hz), 7.49 (d, 4H, J3 –5 &
J3 –5 = 8.0 Hz), 7.48–8.31 (m, 2H, ArH). 13C NMR
(DMSO-d6, d, 400 MHz) 190.2 (C-1 & C-3), 134.5 (C-2),
169.8 (C-4 & C-6), 105.9 (C-5), 190.4 (C of C=O), 186.3 (C
of enolic C–O), 95.4 (C of –C=H), 132.4 (C-10 & C-100), 129.4
(C-20, C-60 & C-200, C-600), 128.9 (C-30, C-50 & C-300, C-500),
134.2 (C-40 & C-400). Anal. Calcd. for C24H16Cl2O6 (M?):
(470) C, 61.16; H, 3.42. Found: C, 61.20; H, 3.45.
00
00
4,6-Bis[5-(4-methylphenyl)-1,2-oxazol-3-yl]benzene-1,3-
diol (4d) Yield 71 %; mp 150 °C; FT-IR (KBr): 3419
(OH), 1712 (C=N), 1599 (aromatic C=C), 1157 (C–O); H
1
General procedure for the preparation of 4,6-bis(5-aryl/
heteroaryl-1,2-oxazol-3-yl)benzene-1,3-diol (4a–4f)
NMR (DMSO-d6, d, 400 MHz) 5.21 (s, 2H, OH), 6.41–8.
51 (m, 12H, ArH), 2.39 (s, 6H, CH3). 13C NMR (DMSO-
d6, d, 400 MHz) 159.2 (C-1 & C-3, C–O), 105.8 (C-2),
115.9 (C-4 & C-6), 131.6 (C-5), 162.6 (C of C=N, oxa-
zole), 100.2 (C of –C=H), 169.5 (C of C–O, oxazole), 132.1
(C-10 & C-100), 129.6 (C-20, C-60 & C-200, C-600), 128.3
(C-30, C-50 & C-300, C-500), 139.8 (C-40 & C-400), 25.3 (C of
CH3). Anal. Calcd. for C26H20N2O4 (M?): (424) C, 73.57; H,
4.75. Found: C, 73.60; H, 4.74.
The mixture of 1,10-(4,6-dihydroxybenzene-1,3-diyl)bis
(3-aryl/heteroarylpropane-1,3-dione) 3a–3f (0.1 mol),
hydroxylamine hydrochloride (0.004 mol), KOH (1 g), and
ethanol (30 mL) was refluxed for 5 h. It was cooled to
room temperature and poured onto ice cold water and
acidified with diluted HCl. A solid slowly separated out, it
was crystallized from ethanol.
4,6-Bis(5-phenyl-1,2-oxazol-3-yl)benzene-1,3-diol (4a) Yield
75 %; mp 165 °C; FT-IR (KBr): 3401 (OH), 1712 (C=N),
1608 (aromatic C=C), 1154 (C–O). 1H NMR (DMSO-d6, d,
4,6-Bis[5-(thiophen-2-yl)-1,2-oxazol-3-yl]benzene-1,3-diol
(4e) Yield 73 %; mp 169 °C; FT-IR (KBr): 3423 (OH),
1602 (aromatic C=C), 1153 (C–O), 1716 (C=N); H NMR
1
400 MHz) 6.32–8.49 (m, 14H, ArH), 5.23 (s, 2H, OH). 13
C
(DMSO-d6, d, 400 MHz) 5.25 (s, 2H, OH), 6.53–8.69
123

Med Chem Res
(m, 10H, ArH); 13C NMR (DMSO-d6, d, 400 MHz) 158.2
(C-1 & C-3, C–O), 105.2 (C-2), 115.3 (C-4 & C-6), 130.3
(C-5), 161.8 (C of C=N, oxazole), 98.9 (C of –C=H), 170.5
(C of C–O, oxazole), 134.8 (C-10 & C-100), 136.9 (C-30 &
C-300), 129.4 (C-40 & C-400), 134.3 (C-50 & C-500). Anal.
Calcd. for C20H12N2O4S2 (M?): (408) C, 58.81; H, 2.96.
Found: C, 58.84; H, 2.99.
C-300, C-500), 161.3 (C-40 & C-400), 57.1 (C of OCH3). Anal.
Calcd. for C26H22N4O4 (M?): (454) C, 68.71; H, 4.88.
Found: C, 68.69; H, 4.89.
4,6-Bis[5-(4-chlorophenyl)-1H-pyrazol-3-yl]benzene-1,3-
diol (5c) Yield 64 %; mp 185 °C; FT-IR (KBr): 3417
(OH), 1713 (C=N), 1606 (aromatic C=C); 1H NMR
(DMSO-d6, d, 400 MHz) 6.41–8.56 (m, 12H, ArH), 5.34
(s, 2H, OH). 13C NMR (DMSO-d6, d, 400 MHz) 158.2 (C-1
& C-3, C–O), 105.9 (C-2), 114.8 (C-4 & C-6), 128.8 (C-5),
148.9 (C of C=N, pyrazole), 99.3 (C of –C=H), 148.5 (C of
C–N, pyrazole), 132.4 (C-10 & C-100), 128.3 (C-20, C-60 &
C-200, C-600), 129.3 (C-30, C-50 & C-300, C-500), 135.6 (C-40 &
C-400). Anal. Calcd. for C24H16Cl2N4O2 (M?): (463) C, 62.
22; H, 3.48. Found: C, 62.25; H, 3.45.
4,6-Bis[5-(pyridin-3-yl)-1,2-oxazol-3-yl]benzene-1,3-diol
(4f) Yield 75 %; mp 170 °C; FT-IR (KBr): 3429 (OH),
1718 (C=N), 1606 (aromatic C=C), 1157 (C–O); H NMR
1
(DMSO-d6, d, 400 MHz) 6.49–8.63 (m, 12H, ArH), 5.30
(s, 2H, OH). 13C NMR (DMSO-d6, d, 400 MHz) 155.8
(C-1 & C-3, C–O), 105.8 (C-2), 115.8 (C-4 & C-6), 131.7
(C-5), 162.5 (C of C=N, oxazole), 99.8 (C of –C=H), 171.2
(C of C–O, oxazole), 135.4 (C-10 & C-100), 150.6 (C-20 &
C-200), 149.2 (C-40 & C-400), 125.4 (C-50 & C-500), 135.9
(C-6 & C-600). Anal. Calcd. for C22H14N4O4 (M?): (398) C,
66.33; H, 3.54. Found: C, 66.35; H, 3.56.
4,6-Bis[5-(4-methylphenyl)-1H-pyrazol-3-yl]benzene-1,3-
diol (5d) Yield 70 %; mp 190 °C; FT-IR (KBr): 3421
(OH), 1719 (C=N), 1604 (aromatic C=C). 1H NMR (DMSO-
d6, d, 400 MHz) 5.31 (s, 2H, OH), 6.44–8.56 (m, 12H, ArH),
2.36 (s, 6H, CH3). 13C NMR (DMSO-d6, d, 400 MHz) 158.7
(C-1 & C-3, C–O), 106.4 (C-2), 115.9 (C-4 & C-6), 130.3
(C-5), 149.3 (C of C=N, pyrazole), 98.7 (C of –C=H), 150.6
(C of C–N, pyrazole), 127.4 (C-10 & C-100), 129.7 (C-20, C-60
& C-200, C-600), 128.5(C-30, C-50 & C-300, C-500), 139.7 (C-40 &
C-400), 25.7 (C of CH3). Anal. Calcd. for C26H22N4O2 (M?):
(422) C, 73.92; H, 5.25. Found: C, 73.90; H, 5.21.
General procedure for the preparation of 4,6-bis(5-aryl/
heteroaryl-1H-pyrazol-3-yl)benzene-1,3-diol (5a–5f)
The mixture of 1,10-(4,6-dihydroxybenzene-1,3-diyl)bis(3-
aryl/heteroarylpropane-1,3-dione) 3a–3f (0.1 mol), hydra-
zine hydrate (0.004 mol), KOH (1 g), and ethanol (30 mL)
was refluxed for 5 h. It was cooled to room temperature
and poured onto ice cold water and acidified with diluted
HCl. A solid slowly separated out, it was crystallized from
ethanol.
4,6-Bis[5-(thiophen-2-yl)-1H-pyrazol-3-yl]benzene-1,3-
diol (5e) Yield 73 %; mp 180 °C; FT-IR (KBr): 3425
(OH), 1721 (C=N), 1600 (aromatic C=C). 1H NMR
(DMSO-d6, d, 400 MHz) 6.66–8.59 (m, 10H, ArH), 5.39
(s, 2H, OH); 13C NMR (DMSO-d6, d, 400 MHz) 159.2
(C-1 & C-3, C–O), 105.8 (C-2), 115.6 (C-4 & C-6), 131.4
(C-5), 150.4 (C of C=N, pyrazole), 100.9 (C of –C=H),
137.6 (C of C–N, pyrazole), 140.8 (C-10 & C-100), 126.9
(C-30 & C-300), 128.1 (C-40 & C-400), 127.1 (C-50 & C-500).
Anal. Calcd. for C20H14N4O2S2 (M?): (406) C, 59.10; H,
3.47. Found: C, 59.16; H, 3.51.
4,6-Bis(5-phenyl-1H-pyrazol-3-yl)benzene-1,3-diol (5a)
Yield 76 %; mp 195 °C; FT-IR (KBr): 3419 (OH), 1718
(C=N), 1611 (aromatic C=C); 1H NMR (DMSO-d6, d,
400 MHz) 6.47–8.39 (m, 14H, ArH), 5.46 (s, 2H, OH). 13
C
NMR (DMSO-d6, d, 400 MHz) 158.9 (C-1 & C-3, C–O),
105.3 (C-2), 115.3 (C-4 & C-6), 128.7 (C-5), 148.9 (C of
C=N, pyrazole), 100.1 (C of –C=H), 150.9 (C of C–N,
pyrazole), 134.2 (C-10 & C-100), 129.2 (C-20, C-60 & C-200,
C-600), 131.1 (C-30, C-50 & C-300, C-500), 129.2 (C-40 &
C-400). Anal. Calcd. for C24H18N4O2 (M?): (394) C, 73.08;
H, 4.60. Found: C, 73.10; H, 4.61.
4,6-Bis[5-(pyridin-3-yl)-1H-pyrazol-3-yl]benzene-1,3-diol
(5f) Yield 75 %; mp 175 °C; FT-IR (KBr): 3435 (OH),
1721 (C=N), 1604 (aromatic C=C); H NMR (DMSO-d6,
1
4,6-Bis[5-(4-methoxyphenyl)-1H-pyrazol-3-yl]benzene-
1,3-diol (5b) Yield 68 %; mp 180 °C; FT-IR (KBr):
3415 (OH), 1718 (C=N), 1609 (aromatic C=C); H NMR
d, 400 MHz) 5.33 (s, 2H, OH), 6.68–8.73 (m, 12H, ArH).
13C NMR (DMSO-d6, d, 400 MHz) 157.6 (C-1 & C-3,
C–O), 105.3 (C-2), 114.5 (C-4 & C-6), 129.3 (C-5), 148.7
(C of C=N, pyrazole), 99.2 (C of –C=H), 149.6 (C of C–N,
pyrazole), 134.6 (C-10 & C-100), 149.5 (C-20 & C-200), 148.5
(C-40 & C-400), 125.3 (C-50 & C-500), 136.4 (C-6 & C-600).
Anal. Calcd. for C22H16N6O2 (M?): (396) C, 66.66; H,
4.07. Found: C, 66.69; H, 4.10.
1
(DMSO-d6, d, 400 MHz) 6.49–8.53 (m, 12H, ArH), 5.38
(s, 2H, OH), 3.69 (s, 6H, OCH3). 13C NMR (DMSO-d6, d,
400 MHz) 157.5 (C-1 & C-3, C–O), 105.1 (C-2), 115.4
(C-4 & C-6), 129.2 (C-5), 149.3 (C of C=N, pyrazole), 99.5
(C of –C=H), 149.8 (C of C–N, pyrazole), 126.2 (C-10 &
C-100), 128.7 (C-20, C-60 & C-200, C-600), 115.5 (C-30, C-50 &
123

Med Chem Res
its application to the prediction of drug transport properties.
J Med Chem 43:3714–3717
In vitro antimicrobial screening
Hadda TB, Mouhoub R, Jawarkar R, Masand V, Warad I (2012a)
POM analyses of antitrypanosomal activity of 2-iminobenzim-
idazoles: favorable and unfavorable parameters for drugs
optimization. Med Chem Res. doi:10.1007/s00044-012-0238-0
Hadda TB, Ali MA, Masand V, Gharby S, Fergoug T, Warad I
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bacterial and viral strains: POM analyses as new efficient
bioinformatics’ platform to predict and optimize bioactivity of
drugs. Med Chem Res. doi:10.1007/s00044-012-0143-6
Hadda TB, Fathi J, Chafchaouni I, Masand V, Charrouf Z, Chohan
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doi:10.1007/s00044-012-0120-0
Hadda TB, Kerbal A, Bennani B, Al Houari G, Daoudi M, Leite ACL,
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All the operations were carried out under aseptic condi-
tions. The well diffusion method was employed in the
antibacterial screening procedure with methanol extract of
synthesized compounds 3a–3f, 4a–4f, and 5a–5f. The
cultures of bacterial strains were inoculated in 10 mL
nutrient agar medium and was sterilized by autoclaving. To
this sterilized nutrient medium, 1 mL of 1-day-old bacte-
rial culture was added and stirred well; this medium was
poured into Petri dishes. The well impregnated with
100 lg mL-1 of the newly synthesized compounds were
introduced aseptically in the nutrient agar plate. The neo-
mycin and erythromycin were used as a control. All the
nutrient agar plates were incubated at 37 °C for 24 h after
which the plates were observed for clear zone of inhibition.
The results are listed in Table 1.
Minimum inhibitory concentration (MIC, mg mL-1
)
Htskuldsson A (1988) PLS regression methods. J Chemometr
2:211–228
The MICs of the chemical compounds assays were carried
out as described by Clause (1989). The MICs of the
chemical compounds were recorded as the lowest con-
centration of each chemical compounds in the tubes with
no growth (i.e., no turbidity) of inoculated bacteria.
Jarrahpour A, Fathi J, Mimouni M, Hadda TB, Sheikh J, Chohan ZH,
Parvez A (2012) Petra, Osiris and Molinspiration (POM)
together as a successful support in drug design: antibacterial
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and pharmacological evaluation of 1,3,4-oxadiazole bearing
bis(heterocycle) derivatives as anti-inflammatory and analgesic
agents. Eur J Med Chem 44:3898–3902
Acknowledgments Dr. J. Sheikh and Prof. T. B. Hadda would like
to thank ACTELION; the Biopharmaceutical Company of Swiss, for
the molecular properties calculations.
Kamal A, Reddy JS, Ramaiah MJ, Dastagiri D, Bharathi EV, Azhar
MA, Sultana F, Pushpavalli SN, Pal-Bhadra M, Juvekar A, Sen
S, Zingde S (2010) Design, synthesis and biological evaluation
of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine con-
jugates as potential anticancer agents. Eur J Med Chem 45:
3924–3937
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Synthesis, antitubercular activity and docking study of novel
cyclic azole substituted diphenyl ether derivatives. Eur J Med
Chem 44:492–500
Kumar A, Maurya RA, Sharma S, Ahmad P, Singh AB, Tamrakar
AK, Srivastava AK (2009) Design and synthesis of 3,5-
diarylisoxazole derivatives as novel class of antihyperglycemic
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SD, Rastija V (2012) CoMSIA and POM analyses of anti-
malarial activity of synthetic prodiginines. Bioorg Med Chem
Lett 22:4827–4835
Masand VH, Mahajan DT, Patil KN, Hadda TB, Rastija V (2012)
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activity of synthetic prodiginines against multi drug resistant
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