Synthesis, x-ray crystallography, molecular docking and biological screening of 2-aminophenol based Schiff bases

Article abstract of DOI:10.4067/S0717-97072013000300016

Schiff bases, 2-{[(2-hydroxyphenyl)methylidene]amino}phenol (4) and 2-{[3-4-(dimethylamino)phenyl-2-propenylidene]amino}phenol (5), have been synthesized by the condensation of 2-aminophenol (1) with 2-hydroxybenzaldehyde (2) and 4-dimethylaminocinnamalde

Full text of DOI:10.4067/S0717-97072013000300016

J. Chil. Chem. Soc., 58, Nº 3 (2013)
SYNTHESIS, X-RAY CRYSTALLOGRAPHY, MOLECULAR DOCKING AND BIOLOGICAL
SCREENING OF 2-AMINOPHENOL BASED SCHIFF BASES
1
,2*
2
1
3
MUHAMMAD ASLAM , ITRAT ANIS , NIGHAT AFZA , MUHAMMAD TAHIR HUSSAIN , RASHAD
4
*
5
6
1
1
MEHMOOD , AJAZ HUSSAIN , SAMMER YOUSUF , LUBNA IQBAL , SAMINA IQBAL , AND
7
INAMULLAH KHAN
1
Pakistan Council of Scientific and Industrial Research Laboratories Complex, Karachi-75280, Pakistan
2
Department of Chemistry, University of Karachi, Karachi-75270, Pakistan
Department of Applied Sciences, National Textile University, Faisalabad-37610, Pakistan
Department of Conservation Studies, Hazara University, Mansehra-21120, Pakistan
3
4
5
Department of Chemistry, Government College University, Faisalabad-38040, Pakistan
6
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
7
Department of Pharmacy, University of Peshawar, Peshawar-25120, Pakistan
(Received: November 24, 2012 - Accepted: May 9, 2013)
ABSTRACT
Schiff bases, 2-{[(2-hydroxyphenyl)methylidene]amino}phenol (4) and 2-{[3-4-(dimethylamino)phenyl-2-propenylidene]amino}phenol (5), have been
synthesized by the condensation of 2-aminophenol (1) with 2-hydroxybenzaldehyde (2) and 4-dimethylaminocinnamaldehyde (3), respectively. They showed
good lipoxygenase inhibition and antioxidant activities, as compound 4 showed potent antioxidant activity. The products also showed good activities against
Gram-positive: S. intermedius, B. subtilis and S. aureus, and Gram-negative: E. coli and S. typhi bacteria, as compounds 5 and 4 are excellent active against B.
subtilis and S. typhi, respectively. These good to potent activities may be due to the presence of free hydroxyl and amino groups. They showed non-significant
urease inhibition activity.
Key Words: Schiff bases, Synthesis, X-ray diffraction, Molecular docking, Biological activities.
INTRODUCTION
activity. Both target compounds also showed good activities against S.
intermedius, B. subtilis, S. aureus, E. coli, S. typhi but insignificant against P.
aeruginosa bacteria but showed non-significant activity against urease enzyme.
In the pharmaceutical field, study on antioxidants, antibacterial and enzyme
inhibitions remain a vital area of research as these can depreciate human skin,
body, can be the reason of different disease or even can cause death. This
research has led to the discoveries of new drugs useful in different physiological
conditions. Reactive oxygen species (ROS) oxidize the human cell or body
and play an important role in the etiology [1] and pathophysiology such as
coronary heart disease, cancer, Alzheimer’s disease [2], neurodegenerative
disorders, atherosclerosis, cataracts and inflammation [3], and human aging
EXPERIMENTAL
All the chemicals and solvents purchased from E. Merck and used as
obtained. Thin layer chromatography (TLC) was performed on pre-coated
silica gel G-25-UV254 plates (E. Merck), and detection was carried out at 254
and 366 nm. The IR spectra were recorded on Thermo Nicolet Avatar 320 FTIR
spectrometer using KBr pellets. Melting points were measured on a Gallenkamp
apparatus and are uncorrected. Elemental analyses were performed on Perkin
Elmer 2400 Series II elemental analyzer. X-ray diffraction was performed
on Bruker Smart APEX II, CCD 4-K area detector diffractometer, SAINT
program was used for data reduction, structure was solved by direct method
and refined by full-matrix least squares on F2 using SHELXTL-PC package.
The figures were plotted with the help of ORTEP program. The FAB (Fast
Atomic Bombardment) mass spectra were recorded on JEOL SX102/DA-6000
[
4]. Antioxidants fate the ROS and protect the human body. In the world, most
people died due to bacterial infectious diseases [5]. The various species of
Bacillus, Staphylococcus, Salmonella and Pseudomonas can survive in harsh
conditions due to their multiple environmental habitats [6] and cause the severe
infections, which may lead to various fatal diseases. The bacteria can develop
resistance to antibiotics through morphological and biochemical modifications
and need to be developing new drugs that can work in a variety of conditions.
The enzyme have various pathological effects such as lipoxygenase (LOX)
causes inflammation and is also responsible in the growth of cancer cells,
metastasis, invasiveness and tumor necrosis factor (TNF) induction, and urease
enzyme causes gastric ulceration, urinary stone formation, pyelonephritis, and
other dysfunctions [7].
1
mass spectrometer using glycerol as matrix and ions are given in m/z. The H
NMR spectra were recorded on a Bruker AMX-400 spectrometer in DMSO-d6.
The chemical shifts (δ) are given in ppm, relative to tetramethylsilane as an
internal standard, and the scalar coupling constants (J) are reported in Hertz.
GENERAL PROCEDURE FOR THE SYNTHESIS OF SCHIFF
BASES 4-5
The Schiff bases engrossed much attention as they demonstrated
antimicrobial [8], anticancer [9], anticonvulsant [10], diuretic [11], herbicidal
[
12], anti-inflammatory [13], antitumor [14] and anti HIV [15] activities, can
The mixture of solutions of 2-aminophenol (0.01 mole in 50 mL EtOH,
1) and 2-hydroxybenzaldehyde (2) or 4-dimethylaminocinnamaldehyde (3)
(0.01 mole in 50 mL EtOH) along with 3-4 drops of conc. H SO was refluxed
be prepared through condensation of an amine and a carbonyl compound
with good yield. Generally, it is well known that the compounds having
hydroxyl, thiol, carboxylic, amino, thio, etc functional groups are more active.
Due to this reason and versatile biological uses of Schiff bases prompted
us to synthesize the new Schiff bases by condensation of 2-aminophenol
2
4
with stirring at 70 ˚C for 3 hours (Figure 1). After cooling, the mixture
was concentrated to one third of its volume under reduced pressure. The
concentrated mixture kept for overnight at ambient temperature and orange
red crystals were obtained. The crystalline product collected, washed with cold
methanol, dried and recrystallized with methanol. The recrystallize product
was dried over anhydrous calcium hydroxide under the reduced pressure. The
reaction was examined by TLC with time to time till completion. TLC also
used to check the purity of the product.
(
(
1) with free hydroxyl and amino groups containing hydroxybenzaldehyde
2) and 4-dimethylaminocinnamaldehyde (3), respectively. It is expected
that the products will show excellent results as antioxidant, lipoxygenase,
antibacterial and urease activities. Herein, we report the synthesis,
characterization, X-ray crystallography and biological screening of two new
Schiff bases named 2-{[(2-hydroxyphenyl)methylidene]-amino}phenol (4)
and 2-{[3-4-(dimethylamino)phenyl-2-propenylidene]amino}phenol (5).
Biological screening of products exhibited that they have good lipoxygenase
inhibition and antioxidant activities, as compound 4 showed potent antioxidant
2-{[(2-Hydroxyphenyl)methylidene]amino}-phenol (4)
-1
Orange red crystalline solid; Yield 96%. M.p. 186 ˚C. IR (KBr) ν cm :
1
3618, 3045, 1630, 1531. H NMR (400 MHz, DMSO-d ) δ: 14.77 (OH), 8.95
6
(1H, s, H-1”), 7.60 (1H, dd, J = 7.2, 1.6 Hz, H-6), 7.37 (1H, ddd, J = 8.4, 8.0,
e-mail: maslamchemist@hotmail.com, rashadhej@gmail.com
1867

J. Chil. Chem. Soc., 58, Nº 3 (2013)
1
1
.6 Hz, H-4), 7.34 (1H, dd, J = 8.0, 1.2 Hz, H-3’), 7.14 (1H, ddd, J = 8.4, 8.0,
ANTI-BACTERIAL ASSAY
.2 Hz, H-5’), 6.91-6.96 (3H, m, H-3, -5 -6’), 6.87 (1H, ddd, J = 8.4, 8.0, 1.2
Antibacterial activities of compounds 4-5 was carried out against Gram-
positive: S. intermedius, B. subtilis and S. aureus, and Gram-negative: E. coli,
S. typhi and P. aeruginosa bacteria by modified agar well diffusion method
using Mueller Hinton agar medium [17]. Each compound (200 mg) was
dissolved in 10 ml 99.9 % dimethyl sulfoxide (DMSO) to get the concentration
of 20 mg/ml. Test organism were grown individually in tryptic Soya broth for
overnight and subsequently mixed with physiological saline until turbidity
+
Hz, H-4’). FAB-MS (+ve) m/z: 214.1 [M+H] (calcd. 214.1 for C H NO ).
Elemental analysis: found C 73.29, H 5.31, N 6.60; calcd. C 73.23, H 5.20, N
6
1
3
12
2
.57.
8
standard 10 Colony Forming Unit (CFU) per ml was achieved. Molton
Mueller Hinton agar medium was seeded for individual organism with 10
8
ml of prepared inoculums (inoculum size was 10 cells/ml as per McFarland
standard) and after proper homogenization, it was poured into 20×100 mm
petri dishes. After solidification, required numbers of wells were made in the
seeded plates with help of a sterile crock-borer (8.0 mm). The test compound
(100 µl) was introduced into respective well. Positive control (gentamicin
0
.3%) and negative control (DMSO) was also applied in each plate then all the
plates were incubated at 37 ˚C for 24 h. Antibacterial activity was determined
by measuring the diameter of the zone inhibition and percentage of growth
inhibition was calculated by this formula:
Percentage inhibition (%) = (Test sample – Solvent control) / Positive
control × 100
LIPOXYGENASE INHIBITION ASSAY
Figure 1: Synthetic scheme of Schiff bases 4-5.
-{[3-4-(Dimethylamino)phenyl-2-propenylidene]amino}phenol (5)
All the chemicals including linoleic acid and lipoxygenase (EC 1.13.11.12)
purchased from Sigma (St. Louis, Missouri, USA). 160 µL of 100 mM sodium
phosphate buffer (pH 8.0) and 10 µL of test compound solution in methanol
(of concentrations 5-500 µM) was added in each well. 20 µL of lipoxygenase
2
-1
Orange red crystalline solid; Yield 89%. M.p. 147 ˚C. IR (KBr) ν cm :
1
3
1
376, 3050, 1601, 1513. H NMR (400 MHz, DMSO-d ) δ: 8.36 (1H, d, J =
6
(
LOX) solution (enzyme 130 units per well) was added, mixed and incubated
6.0 Hz, H-1”), 7.46 (2H, d, J = 8.8 Hz, H-2’, -6’), 7.19 (1H, d, J = 15.6 Hz,
for 10 min at 25 C. The reaction was then initiated by the addition of 10 µL
̊
H-3”), 7.04 (1H, dd, J = 8.0, 1.6 Hz, H-6), 6.99 (1H, ddd, J = 8.4, 8.0, 1.6
Hz, H-4), 6.89 (1H, d, J = 16.0, 15.6 Hz, H-2”), 6.82 (1H, dd, J = 8.0, 1.6
Hz, H-3), 6.78 (1H, ddd, J = 8.4, 8.0, 1.6 Hz, H-5), 6.73 (2H, d, J = 8.8 Hz,
substrate solution (linoleic acid, 0.5 mM, 0.12 % w/v tween-20 in ratio of 1:2)
in each well. The absorption changed with the formation of (9Z,11E)-13S)-13-
hydroperoxyo-ctadeca-9,11-dienoate and was measured after 15 min at 234
nm. Baicalein was used as standard and IC50 values were determined by EZ-fit
enzyme kinetic program (Pellera Scientific Inc. Amherst, U.S.A).
UREASE INHIBITION ASSAY
+
H-3’, -5’), 2.97 (6H, s, N-CH ). FAB-MS (+ve) m/z: 267.2 [M+H] (calcd.
3
for C H N O). Elemental analysis: found C 76.73, H 6.90, N 10.55; calcd. C
17
19
2
7
6.66, H 6.81, N 10.52.
CRYSTAL DATA OF 4
The urease enzyme solution was prepared by taking 0.125 units in each
well in phosphate buffer (K HPO .3H O, 1 mM EDTA and 0.01M LiCl ).
C H NO , MS: 213.23, triclinic, space group P-1, a = 9.0456(12) Å,
1
3
11
2
°
°
b = 10.1549(14) Å, c = 12.3667(17) Å, α = 69.680(3) , β = 89.897(3) , γ =
6.960(3) , V = 1034.2(2)Å , Z = 4, r = 1.370 mg/m , F(000) = 448, µ(Mo
2
4
2
2
°
3
3
Each well was filled with 80 µL of 0.05 M potassium phosphate buffer (pH
.2), 10 µL of the test compound (concentration range 5 - 500 µM), contents
were mixed and incubated for 15 min at 30 ˚C. 40 µL of substrate solution
urea) (50 mM) was added in each well except B enzyme for initiating reaction.
7
calc
8
Kα = 0.71073 Å, max/min transmission 0.8935/0.6105 crystal dimensions 0.38
°
°
x 0.28 x 0.08, 1.76 < q < 25.5 , 11775 reflections were collected, of which
(
2
3848 reflections were observed (Rint = 0.0307). The R-values were: R =
1
Then, 70 µL alkaline reagent (0.5 % NaOH and 0.1 % active NaOCl) and 40
µL of phenol reagent (1% Phenol & 0.005 % w/v sodium nitroprusside) were
introduced to each well. The reaction mixture containing well plates were
incubated for 50 minutes and absorbance was recorded at 630 nm. IC50 values
were determined by monitoring the effect of increasing concentrations of test
compounds on extent of inhibition [16].
0
.0476, wR = 0.1172 for I > 2s(I), and R = 0.0734, wR = 0.1362 for all data;
2
1
2
−
3
max/min residual electron density: 0.226 / -0.180 e Å .
CRYSTAL DATA OF 5
C H N O, MS: 266.33, monoclinic, space group P21/c, a = 6.3277(4) Å,
17
18
2
°
°
b = 12.8050(8) Å, c = 18.0358(12) Å, α = 90.00 , β = 97.926(2)°, γ = 90.00 ,
V = 1447.41(16)Å , Z = 4, r = 1.222 mg/m , F(000) = 568, µ(Mo Kα =
3
3
calc
0
0
.71073 Å, max/min transmission 0.9893/ 0.9633, crystal dimensions 0.49 x
.14 x 0.14, 1.96 < q< 25.5 , 8436 reflections were collected, of which 2698
°
°
RESULTS AND DISCUSSION
reflections were observed (Rint = 0.0275). The R-values were: R = 0.0436, wR
1
2
Schiff bases
4 and 5 were synthesized through condensation
=
0.1084 for I > 2s(I), and R = 0.0666, wR = 0.1235 for all data; max/min
1 2
−3
of 2-aminophenol (1) with 2-hydroxybenzaldehyde (2) or 4-N,N-
dimethylaminocinnamaldehyde (3), respectively, in ethanol at 70 ˚C followed
by few drops of conc. sulfuric acid as catalyst (Figure 1). Their structures were
determined by spectroscopic data as shown in experimental part.
residual electron density: 0.138 / -0.167e Å .
Supplementary crystallographic data of 4 and 5 have been deposited in
the Cambridge Crystallographic Data Center (CCDC) with the CCDC number
8
79997 and 883324 respectively, and can be obtained via www.ccdc.cam.
X-RAY CRYSTALLOGRAPHY
ac.uk/data request/cif.
The structure of the Schiff base 4 consists of two independent molecules
in the asymmetric units (Figure 2). The planner phenyl rings of both molecules
are twisted by 10.42 (10) (C1--C6 and C8--C13) and 9.92 (11)% (C14--C19
and C21--C26) with respect to each other. The bond lengths and angles are
similar to those in our previously published related compound [18]. In the
crystal, intramolecular N1---H1A...O2 and N12---H2A...O4 hydrogen bonds
form S (6) and adjacent molecules are linked by intermolecular O1---H ...O
ANTIOXIDANT: DPPH RADICAL SCAVENGING ACTIVITY
ASSAY
The solution of DPPH (0.3 mM) was prepared in ethanol. 5 µL methanol
solution of each sample of different concentration (5-500 µg) was mixed with
9
5 µL of DPPH solution in ethanol. The mixture was then dispersed in 96
well plate and incubated at 37° C for 30 min, then absorbance was measured
at 515 nm by microtitre plate reader (Spectramax plus 384 Molecular Device,
U.S.A.). Butylated hydroxyanisole (BHA) was used as standard. The percent
radical scavenging activity was determined in comparison to the methanol
treated control with the following formula:
1B
4
and O ---H ...O2 hydrogen bonds, forming zigzag sheets parallel to the c axis
3
3A
(Figure 3). The crystal data is in Experimental Part (Table 4).
Single-crystal X-ray diffraction analysis was carried out to establish
the structure of the Schiff base 5. The ORTEP diagrams of the Schiff base
showed that mono-substituted N,N-dimethyl phenyl and phenol rings are
connected by aza-butadiene chain (Figure 4). The azomethine (C ═N , 1.278
5
7
1
(
2) Å) and olefinic double bonds (C ═C , 1.335 (2) Å) adopts E-configurations,
8 9
The IC50 value of the compounds was determined by monitoring the
effect of different concentrations (1-1000 µM). The IC50 of the compounds
were calculated using EZ-fit enzyme kinetic program (Pellera Scientific Inc.
Amherst, U.S.A) [16].
further stabilized by O1-H1A….N1 intramolecular hydrogen bond forming a
S(5) ring motif (Figure 4). In the crystal, molecules are linked by C —H ….O
7
7A
1
intermolecular hydrogen bonds to form chains arranged parallel to the b-axis
Figure 5) and crystal data is in Experimental Part (Table 3).
(
1
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J. Chil. Chem. Soc., 58, Nº 3 (2013)
Table 1: Results of antibacterial activities of the Schiff bases 4-5.
4
5
Gentamicin (0.3%)
Bacteria
Zone inhibition (mm)
Zone inhibition (mm)
Inhibition (%)
Zone inhibition (mm)
Inhibition (%)
Gram-positive
S. intermedius
B. subtilis
30
27
30
17
20
19
57
74
63
+
+
25
21
93
70
S. aureus
Gram-negative
E. coli
S. typhi
30
24
25
10
18
+
33
75
+
18
11
+
60
46
+
P. aeruginosa
S. Intermedius (Staphylococcus intermedius), B. subtilis (Bacillus subtilis), S. aureus (Staphylococcus aureus), E. coli (Escherichia coli), S. typhi (Salmonella
typhi) and P. aeruginosa (Pseudomonas aeruginosa); + mean non-significant
Figure 4: The molecular structure of 5 with displacement ellipsoids drawn
at 30% probability level. Dashed lines indicate the intramolecular hydrogen
bonding.
Figure 2: The molecular structure of 4 with displacement ellipsoids drawn
at 30% probability level. Dashed lines show the intramolecular hydrogen
bonding.
Figure 5: The crystal packing of 5, only hydrogen atoms involve in the
intramolecular hydrogen bonding which are shown by dashed lines.
ANTIOXIDANT: DPPH RADICAL SCAVENGING ACTIVITY
The antioxidant activity of compounds 4-5 was carried out with DPPH
by well diffusion method in comparison with the BHA. They showed good
activity against DPPH, as 5 showed comparable activity with the standard and
4
showed more activity than the standard (BHA) (Table 2), which may lead to
the potential antioxidant and it need to be further proceed.
ANTI-BACTERIAL ACTIVITIES
Activities of the products 4 and 5 were investigated against Gram-
positive: Staphylococcus intermedius, Bacillus subtilis, Staphylococcus aureus
and Gram-negative: Escherichia coli, Salmonella typhi and Pseudomonas
Figure 3: The crystal packing of 4, only hydrogen atoms involve in the
intramolecular hydrogen bonding, which are shown by dashed lines.
1
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J. Chil. Chem. Soc., 58, Nº 3 (2013)
aeruginosa bacteria in comparison with gentamicin as reference drug. Both
the compounds are good active against all bacteria except P. aeruginosa. The
results show that both compounds are more active against B. subtilis than
against the others bacteria (Table 1). The results also show that Gram-positive
bacteria are more active than the Gram-negative bacteria for the products.
and consequently block this active site. In the present study, the compound 4
showed the LOX inhibition activity with IC50 59.2 μM. A number of factors
are involve in the low LOX inhibition activity of 4 such as non-existence of
hydrogen bonding between phenolic moiety and the active site (His 518, His
523 and Ile 867), dipole-dipole interactions between nitrogen of imine group
and Ile 557, and charge-dipole interactions: non-hydrophobic interactions with
Phe 576 and Ile 770. The major factors are the defective electrostatic and steric
interactions.
LIPOXYGENASE INHIBITION ACTIVITY AND MOLECULAR
DOCKING
Lipoxygenase inhibition activity of the synthetic compounds 4-5 were
examined with the comparison of baicalein. The results showed that both
compounds are good active against lipoxygenase (Table 2).
The compound 5 showed LOX inhibition activity with IC50 28.9 μM,
which is near to the IC50 value of standard (Baicalein, IC50 22.1 ± 0.03 μM).
The good LOX inhibition of 5 is due to the strong interactions with the active
site of LOX. The molecular docking simulations of 5 showed that it has strong
molecular contacts with the catalytic triad along with iron atom (Figure 6, 7).
The various factors involve in the good LOX inhibition activity of 5 include
hydrogen bonding, dipole-dipole interactions and charge-dipole interactions.
The most important part of the compound 5 is phenolic group, which is
involved in hydrogen bonding with all four components of the active site as
His 518 (3.58 Å), His 523 (2.57 Å) and Ile 867 (3.12 Å). These promising
interactions could be one of the major factors of its good LOX inhibition
activity. The other aspect of its activity is the dipole-dipole interactions of
nitrogen of imine with Ile 557. Alongside with the above factors, N-methyls
also provide the favorable hydrophobic interactions with Phe 576 and Ile
Table 2: Results of antioxidant, lipoxygenase and urease inhibitions
activities of Schiff bases 4-5.
DPPH
Scavenging
Activity
Lipoxygenase
Inhibition
Activity
Urease
Inhibition Activity
IC (μM)
Compound
50
IC50 (μM)
IC (μM)
50
4
+
+
-
32.0
45.5
44.2
-
59.2
28.9
-
5
7
70. All the interactions form the compound 5 a good inhibitor of LOX. The
BHA
good LOX inhibition of 5 showing strong potential to be developed as anti-
inflammatory agent. Therefore, based on present studies, it can be proceeded to
develop a new anti-inflammatory drug.
Baicalein
Thiourea
-
22.6
-
21.6
-
Butylated hydroxyanisole (BHA); + mean non-significant.
Table 3: Crystal data of 4 and 5
5
(C H N O); MS:
17 18 2
Compound
4 (C H NO ); MS: 213.23
1
3
11
2
2
66.33
Geometry
Triclinic
P-1
Monoclinic
P21/c
Space group
a
9.0456(12) Å
10.1549(14) Å
12.3667(17) Å
6.3277(4) Å
12.8050(8) Å
18.0358(12) Å
90.00°
b
c
°
α
69.680(3)
°
β
89.897(3)
97.926(2)°
90.00°
Figure 6: Molecular docking of 5, figure showing the interactions of 5 with
the inside active site of LOX. For clarity, hydrogen atoms were omitted except
polar ones. Yellowish and white dotted lines show the hydrogen bonding and
charge-dipole interactions between LOX and 5, respectively.
°
γ
V
76.960(3)
3
3
1034.2(2)Å
1447.41(16)Å
Z
4
4
3
3
rcalc
F(000)
1.370 mg/m
1.222 mg/m
448
568
0
.49 x 0.14 x 0.14
mm
Crystal dimension
0.38 x 0.28 x 0.08 mm
Multiconfermer library FRED 2.1 used for the docking of OMEGA pre-
generated multi-conformer, exhaustive docking / scoring of all orientations and
position of ligand in the binding site. For exhaustive search, rigid rotations
and translations of each conformer within the binding site make the grounds.
Filtered by FRED and caused ensemble by rejecting those that have clashes
with the protein (LOX) or having no connection with protein. The smooth
shape-based Gaussian scoring function (shapegauss) was used for evaluating
the complementary shape of ligand and binding pocket to score or rescore the
final poses. Default FRED protocol was used for defining the binding sites
except the size of the box. To optimize the docking-scoring performance for
exhaustive docking, the optimization mode of shapeguass was used, which
involved the optimization of a solid body systematically of the top ranked
poses. For this, three different solid bodies or boxes LOX (PDB ID: 1JNQ)
were used. The method adopted, involved three different simulations around
the reference ligand with an additional value of 8 Å [19].
Figure 7: Favorable electrostatic and steric interaction of 5 inside active
site of LOX with Fe (yellowish round object). Color encoding (white area:
hydrophobic region, red area: area with aggregated negative electrostatic
potential and blue area: area with aggregated positive electrostatic potential).
The inside active site of LOX consists of His 523, Ile 857, His 518 and
iron which catalyze the polyunsaturated fatty acids to leukotrienes. The active
LOX inhibitors establish the strong molecular interactions at these residues
1
870

J. Chil. Chem. Soc., 58, Nº 3 (2013)
UREASE INHIBITION ACTIVITY
Both the target compounds 4-5 were studied against urease enzyme and
they showed non-significant activity (Table 2).
7.- M. B. C. Moncrief, L. G. Hom, E. Y. Jabri, P. A. Karplus, R. P. Hausinger,
Protein Sci. 4, 2234 (1995).
8.- M. Yildiz, A. Kiraz, B. Dülger, J. Serb. Chem. Soc. 72, 215 (2007).
9
.- R. Gudipati, R. N. R. Anreddy, S. Manda, Saudi Pharm. J. 19, 153 (2011).
10.- (a) M. Verma, S. N. Pandeya, K. N. Singh, J. P. Stables, Acta Pharm. 54,
9 (2004); (b) C. R. Prakash, S. Raja, G. Saravanan, Int. J. Pharm. Pharm.
CONCLUSION
4
The Schiff bases 4 and 5 were derived from 2-aminophenol (1) and
Sci. 2, 177 (2010).
2
-hydroxybenzaldehyde (2) or 4-N,N-dimethylaminocinnamaldehyde (3),
11.- S. Ghosh, S. Malik, B. Jain, S. A. Iqbal, J. Saudi Chem. Soc. 16, 137
respectively. Both target compounds are good antioxidant agent whereas 4
is potent antioxidant as expecting due to presence of hydroxyl group. They
are good lipoxygenase inhibitors and have good antibacterial activities against
all mentioned bacteria except P. aeruginosa while compounds 5 and 4 are
excellent active against B. subtilis and S. typhi, respectively.
(2012).
12.- W. Meiyi, L. Zhengming, L. Yonghong, Chin. J. Org. Chem. 30, 877
(2010).
13.- A. Pandey, R. Rajavel, S. Chandraker, D. Dash, E-J. Chem. 9, 2524
(2012).
1
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ACKNOWLEDGMENTS
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Dr. Nighat Afza and Muhammad Aslam express their compliments to
Pharmaceutical Research Centre, Pakistan Council of Scientific and Industrial
Research Laboratories Complex, Karachi for providing financial support and
Dr. Itrat Anis expresses her thanks to Department of Chemistry, University of
Karachi for providing research facilities.
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