Bioisosteric synthesis of nitrogen containing derivatives of salicyl alcohol, their in vivo pharmacological studies with molecular modeling

Article abstract of DOI:10.1007/s00044-013-0473-z

Starting with salicylaldehyde, compounds (I) [1-(2-hydroxybenzyl) piperidinium chloride] and (II) [4-carbamoyl-1-(2-hydroxybenzyl)piperidinium chloride] were prepared via multi step synthesis. The synthesized compounds were evaluated in vivo for their anti-inflammatory, analgesic, and anti-pyretic activities. Both compounds showed significant pharmacological profile when compared with reference standard, aspirin. In an attempt to understand the ligand-protein interaction in terms of the binding affinity, the synthetic molecule II was subjected to docking analysis using AutoDock which showed better binding modes with the active sites of COX's enzymes.

Full text of DOI:10.1007/s00044-013-0473-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4677–4684
DOI 10.1007/s00044-013-0473-z
ORIGINAL RESEARCH
Bioisosteric synthesis of nitrogen containing derivatives of salicyl
alcohol, their in vivo pharmacological studies with molecular
modeling
•
Nasir Ullah Nazar Ul Islam Gowhar Ali Fazal Subhan
•
•
•
•
Faridoon Ikhtiar Khan
Received: 13 August 2012 / Accepted: 6 January 2013 / Published online: 18 January 2013
Ó Springer Science+Business Media New York 2013
Abstract Starting with salicylaldehyde, compounds (I)
[1-(2-hydroxybenzyl)piperidinium chloride] and (II) [4-car-
bamoyl-1-(2-hydroxybenzyl)piperidinium chloride] were
prepared via multi step synthesis. The synthesized com-
pounds were evaluated in vivo for their anti-inflammatory,
analgesic, and anti-pyretic activities. Both compounds
showed significant pharmacological profile when compared
with reference standard, aspirin. In an attempt to understand
the ligand–protein interaction in terms of the binding affin-
ity, the synthetic molecule II was subjected to docking
analysis using AutoDock which showed better binding
modes with the active sites of COX’s enzymes.
work through complex mechanistic pathways which are
controlled by many factors. It is mainly the chemical
structure of a drug which determines its ultimate pharma-
cological responses. Some pharmacological activities are
clinically desirable to treat a particular disease while others
may be undesirable and may cause toxicity; so structural
changes are required to minimize toxic effects and maxi-
mize health benefits. Salicin (Fig. 1), first reported by
Machagan was used in the treatment of acute rheumatism
and was obtained from willow bark (Salix alba) (Macha-
gan, 1876). Salicin is a glycoside of saligenin (2-hydroxy
methyl phenol; salicyl alcohol; Fig. 2), and is chemically
related to aspirin and possesses almost comparable phar-
macological activities. Salicin on hydrolysis results in
liberation of saligenin. Phenolic hydroxyl group of sali-
genin is making a b-glucosidic bond with D-glucopyranose
in salicin structure. We were interested in the replacement
of methylene hydroxyl group with nitrogen to see desirable
pharmacological activities. In general, it has been argued
that exchanging one bioisostere for another enhances the
biological and/or physical properties of a compound,
without making significant changes in a chemical structure
(Joseph et al., 1999). Recently, it has been reported that
salicin acts as anti-pyretic pro-drug with no propensity
for gastric injury (Akao et al., 2002). Salicyl alcohol which
is a part of salicin structure has also been reported to have
local anesthetic properties (Harischfelder et al., 1920;
Harischfelder and Wynne, 1920). Moreover, Willson and
his co-workers have found anti-pyretic and anesthetic
activities of saligenin (Charles and Tony, 1956). Lately,
discovery of long acting saligenin adrenergic receptor
agonists incorporating uracil ring and urea has been
reported (Procopiou et al., 2011a, 2011b). It has also been
reported that certain 4-hydroxypiperidine derivatives pos-
sess analgesic activities (Saeed et al., 1997). The great
Keywords 1-(2-Hydroxybenzyl)piperidinium chloride ꢀ
4-Carbamoyl-1-(2-hydroxybenzyl)piperidinium chloride ꢀ
Anti-inflammatory ꢀ Anti-pyretic ꢀ Analgesic ꢀ
Molecular docking
Introduction
Pharmacological activities of drugs depend on their
reception in the living system. In majority of cases, drugs
N. Ullah ꢀ N. Ul Islam (&) ꢀ Faridoon ꢀ I. Khan
Institute of Chemical Sciences, University of Peshawar,
Peshawar 25120, Pakistan
e-mail: islanaz@yahoo.com
G. Ali ꢀ F. Subhan
Department of Pharmacy, University of Peshawar,
Peshawar 25120, Pakistan
N. Ul Islam
Sarhad University of Sciences and Information Technology,
Peshawar, Pakistan
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Med Chem Res (2013) 22:4677–4684
Fig. 2 Salicyl alcohol
importance of saligenin as a drug or pro-drug and piperi-
dine derivatives possessing analgesic activities encouraged
us to combine these together as bioisosters and evaluate
their activities. Piperidinium and piperidinium-4-carbox-
amide derivatives were prepared for evaluation.
OH
OH
Non-steroidal anti-inflammatory drugs (NSAIDs) are
used worldwide for the management of pain, inflammation,
and hyperpyrexia while opiates are prescribed for severe
pain that cannot be controlled by classical NSAIDs.
However, across the globe, it is still a major challenge to
the medical world that on chronic administration, NSAIDs
exhibit several side effects like ulceration and subsequent
bleeding of gastrointestinal tract, cardiovascular disorders,
and renal damage while opiates cause dependence and drug
tolerance, which limits their therapeutic spectrum value
reported as parts per million (d ppm) using TMS as an
internal standard. Mass spectra were made on JEOL
MSRoute spectrometer. Digital Plethysmometer (Model LE
7500 Plan lab S.L.) was used to measure the paw volume
and digital thermometer (Model CA92121, ACON Labora-
tories, USA) was used to measure the rectal temperature.
Glacial acetic acid (Panreac, Spain), acetylsalicylic acid
(Sigma, USA), Lambda Carrageenan (Sigma, USA), Brewer
yeast (Merck, Germany), morphine sulfate were obtained
through proper channel from Punjab Drug House, Lahore,
Pakistan. Salicylaldehyde was purchased from Sigma-Aldrich.
All the chemicals were used without further purification.
´
(Perez et al., 1996; Jones et al., 2008; Mayer et al., 1995).
Therefore, there is a definite need for an alternative to
opiates and NSAIDs which possess analgesic, anti-
inflammatory, and anti-pyretic activities yet devoid of such
adverse effects. The current work was a step forward in this
direction.
Synthesis
We synthesized salicyl alcohol derivatives by incorpo-
rating piperidine and piperdine-4-carboxamide moieties.
These were evaluated for their analgesic, anti-inflamma-
tory, and anti-pyretic pharmacological profiles. The inter-
action of the synthesized compounds with binding sites of
COX’s was examined using molecular modeling to ratio-
nalize their activities. The structures of the products were
confirmed by physical data and spectroscopic methods like
(IR, -1H and 13C NMR, and mass spectrometry). Fur-
thermore, due to their solubility in water as compared to
aspirin, these may be used for parental and oral liquid
dosage forms.
Starting from salicylaldehyde, compounds I and II were
synthesized by the following general procedure;
A mixture of salicylaldehyde (10 mmol), NaBH4
(10 mmol), and boric acid (10 mmol) were pulverized with
mortar and pestle until TLC showed complete disappear-
ance of the starting material. The reaction mixture was
quenched with 1 N HCl (10 mL) solution and extracted
with ethyl acetate. The ethyl acetate layer was separated
and dried over sodium sulfate. On evaporation of the sol-
vent, pure salicyl alcohol was obtained, which was used in
further reactions without purification.
To a solution of salicyl alcohol (1 mmol) in dichloro-
methane, thionyl chloride was slowly added at room tem-
perature. When the addition was complete, the reaction
mixture was refluxed for 2 h. It was cooled to 0 °C and
amine (1 mmol) was slowly added. The product precipi-
tated as white powder. It was filtered, washed with
dichloromethane, and kept under vacuum for 24 h (Fig. 3).
Methods and materials
Chemistry
General
1-(2-Hydroxybenzyl)piperidinium chloride (I) Yield, 65.5 %;
mp 160 °C; IR (neat): t cm-1 3381, 2947, 2731, 1591,
1456, 1136; 1H NMR (300 MHz, D2O): d 7.45–13 (m, 4H),
4.55 (s, 2H), 3.08 (t, 4H), 1.71 (m, 4H), 1.63 (m, 2H); 13C
NMR (75 MHz, D2O): d 158.5, 137.5, 134.9, 123.0, 121.6,
119.0, 58.7, 47.2 (2C), 24.8 (2C), 24.1; ESI–MS (m/z):
M?191
Melting points of the compounds were determined with
Gallenkamp Melting Point apparatus. Infrared spectra were
recorded on Nicolet 380 thermoscientific FTIR. NMR
spectra were scanned on BRUKER 300-MHz spectropho-
tometer using D2O as solvent. The chemical shifts were
Fig. 1 Salicin
H
O
H
H
H
O
O
4-Carbamoyl-1-(2-hydroxybenzyl)piperidinium chloride (II)
Yield, 58.7 %; mp 206 °C (decomposes); IR (neat): t cm-1
3387, 3203, 3001, 2937, 2817, 1667, 1619, 1429, 610; H
O
O
O
1
HO
NMR (300 MHz, D2O): d 7.39–7.01 (m, 4H), 4.12 (s, 2H),
123

Med Chem Res (2013) 22:4677–4684
4679
OH
O
OH
OH
I, II
Cl
H
OH
i) SOCl2, DCM
ii) HNR1R2
NaBH4, H3BO3
NHR1R2
(solvent free
condition)
Where;
HN
NHR1R2=
I)
NH2
O
II)
NHR1R2= HN
Fig. 3 Synthesis of compounds I and II
3.05 (m, 4H), 2.66 (m, 1H), 1.87 (m, 4H); 13C NMR
(75 MHz, D2O): 181.8, 158.2, 135.6, 134.7, 130.7, 123.2,
118.5, 58.5, 45.8 (2C), 41.8, 27.6 (2C); ESI–MS (m/z):
M?234
Anti-pyretic study
Hyperpyrexia was induced by subcutaneous injection
of 20 % solution of Brewer’s yeast (Al-Ghamdi, 2001;
Al-Harbi et al., 1994). Changes in rectal temperature were
noted after 24 h of Brewer’s yeast injection at 0.5, 1.0, and
1.5 h. Before insertion, the rectal probe of digital ther-
mometer was lubricated with olive oil and maintained for
30-s insertion time for recording temperature.
Pharmacology
Animals
Analgesic activity
For pharmacological study, Albino mice (Balb-C), weigh-
ing 25–30 g of either sex, were used. For each pharma-
cological assay, animals were randomly divided into four
groups and each group was composed of eight animals.
Acetic acid (AA)-induced writhing test in mice Writhing
behavior was induced by intraperitoneal administration of
1 % AA (10 mL kg-1). The number of writhes (abdominal
constrictions) occurring over a period of 20 min were
counted (starting 5 min after the administration of 1 %
AA) (Gray et al., 1999, 1998).
Anti-inflammatory activity
Anti-inflammatory activity was evaluated by carrageenan-
induced paw edema test (Winter et al., 1962). Aspirin was
administered as a standard drug for comparison. The test
compounds were administered at three dose levels (50,
100, and 150 mg kg-1). The paw volumes were measured
using a digital Plethysmometer immediately before and 1,
2, 3, 4, and 5 h after carrageenan injection. The percentage
inhibition of paw edema was calculated using the following
formula:
% Protection ¼ ð1 ꢁ mean number of writhes of treated
drug=mean number of writhes of controlÞ ꢃ 100:
Hot plate test in mice Prior to the start of experimental
procedure, mice were acclimatized to laboratory environ-
ment at least for 2 h. A transparent glass cylinder was used
to restrict the animals to the surface of hot plate of anal-
gesiometer (Harvard apparatus, USA) and the temperature
maintained at 54.0 0.10 °C. Hot plate reaction time
(latency to response in seconds) was observed by noting
licking, flicking of hind limb, or jumping from cylinder
(Brochet et al., 1986; Grillet et al., 2005). A cut-off time of
30 s was fixed so that if the animal did not respond within
the prescribed time, then they could be immediately
removed from the hot plate surface to avoid tissue damage.
30 min after the pretest, control, standard, and test samples
were distributed into their respective groups. The animals
were tested again after 30 min and response recorded at 30
% Inhibition ¼ 100 ½1 ꢁ ða ꢁ xÞ=ðb ꢁ yÞꢂ;
where x is the mean paw volume of mice before the
administration of carrageenan and test compounds or ref-
erence compound (test group), a is the mean paw volume
of mice after the administration of carrageenan in the test
group (drug treated), b is the mean paw volume of mice
after the administration of carrageenan in the control
group, and y is the mean paw volume of mice before the
administration of carrageenan in the control group.
123

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Med Chem Res (2013) 22:4677–4684
(a) 0.10
Saline
Aspirin 50 mg/kg
Aspirin100 mg/kg
Aspirin 150 mg/kg
0.08
0.06
0.04
0.02
0.00
*
*
*
*
1
2
3
4
5
Fig. 5 Binding mode of compound II in active site of COX-1 (PDB
Code: 1EQG). Colors of atoms are as follow: yellow carbon, blue
nitrogen, and red oxygen. The native co-crystallized ibuprofen is
shown as stick (cyan) and hydrogen bonds are shown as dashed lines
Hours
0.10
0.08
0.06
0.04
0.02
0.00
(b)
Saline
Compound I 50 mg/kg
Compound I 100 mg/kg
Compound I 150 mg/kg
*
*
*
*
1
2
3
4
5
Hours
Saline
(c)
Fig. 6 Binding mode of compound II in active site of COX-2 (PDB
Code: 1CX2). Colors of atoms are as follow: yellow carbon, blue
nitrogen, and red oxygen. The native co-crystallized S58 is shown as
stick (cyan) and hydrogen bonds are shown as dashed lines
0.10
0.08
0.06
0.04
0.02
0.00
Compound II 50 mg/kg
Compound II 100 mg/kg
Compound II 150 mg/kg
and 60 min on the hot plate of analgesia meter. Analgesic
activity was calculated using the following formula:
*
*
*
*
*
*
*
*
*
*
*
*
% Analgesic activity ¼ ðTest latency ꢁ control latencyÞ
= ðCut - off time ꢁ control latencyÞ ꢃ 100
*
*
*
*
*
*
*
*
*
Statistical analysis
1
2
3
4
5
Statistical analysis of the biological activity of the syn-
thesized compounds on animals was evaluated using a
one-way analysis of variance (ANOVA). In all cases, post
hoc comparisons of the mean of individual groups were
performed using Dunnett’s test. A significance level of
Hours
Fig. 4 a Anti-inflammatory activity of aspirin in Carrageenan-induced
Paw edema model. b Anti-inflammatory activity of compound I in
Carrageenan-induced Paw edema model. c Anti-inflammatory activity
of compound II in Carrageenan-induced Paw edema model
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Med Chem Res (2013) 22:4677–4684
4681
(a) 40.0
(a)100
Saline (Pre treatment temperature)
Aspirin (Post treatment temperature) (0.5 hour)
Aspirin (Post treatment temperature) (1.0 hour)
Aspirin (Post treatment temperature) (1.5 hour)
39.5
39.0
38.5
38.0
37.5
37.0
36.5
36.0
80
60
40
20
0
Saline
Aspirin 15 mg/kg
Aspirin 30 mg/kg
Aspirin 45 mg/kg
0
15
30
45
Dose (mg/kg)
80
(b)
0
50
100
150
Saline
Dose (mg/kg)
Compound I 15 mg/kg
Compound I 30 mg/kg
Compound I 45 mg/kg
*
60
40
20
0
Saline (Pre treatment temperature)
(b)
Compound I (Post treatment temperature) (0.5 hour)
Compound I (Post treatment temperature) (1.0 hour)
Compound I (Post treatment temperature) (1.5 hour)
40.0
39.5
39.0
38.5
38.0
37.5
37.0
36.5
36.0
0
15
30
45
Dose (mg/kg)
80
(c)
Saline
60
40
20
0
Compound II 15 mg/kg
Compound II 30 mg/kg
Compound II 45 mg/kg
0
50
100
150
Dose (mg/kg)
(c)
Saline (Pre treatment temperature)
40
39
38
37
36
Compound II (Post treatment temperature) (0.5 hour)
Compound II (Post treatment temperature) (1.0 hour)
Compound II (Post treatment temperature) (1.5 hour)
*
*
*
*
*
*
*
*
*
0
15
30
45
*
*
*
*
*
*
*
*
*
*
Dose (mg/kg)
*
Fig. 8 a Anti-nociceptive activity of aspirin in writhing test. b Anti-
nociceptive activity of compound I in writhing test. c Anti-nocicep-
tive activity of compound II in writhing test
0
50
100
150
Molecular docking
Dose (mg/kg)
The COX-1 (PDB Code: 1EQG) and COX-2 (PDB Code:
1CX2) crystal structures were used for docking. AutoDock
tools were used to remove water molecules from the crystal
structures of COXs. The polar hydrogens were added and
charges were assigned with the Gasteiger method. Then,
the active sites were defined by fixing the grid box having
Fig. 7 a Anti-pyretic activity of aspirin in Brewer’s yeast-induced
pyrexia test. b Anti-pyretic activity of compound I in Brewer’s yeast-
induced pyrexia test. c Anti-pyretic activity of compound II in
Brewer’s yeast-induced pyrexia test
p \ 0.05 denoted significance in all cases. All values are
expressed as mean SD (standard deviations). For statis-
tical analysis we have used Graph Pad Prism 5.0 version.
˚
dimensions 40 9 40 9 40 A with grid spacing of 0.375 A
˚
123

4682
Med Chem Res (2013) 22:4677–4684
Fig. 9 a Anti-nociceptive
activity of compound I in hot
plate mode. b Anti-nociceptive
activity of compound II in hot
plate model
(a)
30 min.
60 min.
100
80
60
40
20
0
Saline
Morphine 5 mg/kg
Compound I 15 mg/kg
Compound I 30 mg/kg
Compound I 45 mg/kg
0
5
15
30
45
0
5
15
30
45
Dose (mg/kg)
(b)
30 min.
60 min.
100
50
0
Saline
Morphine 5mg/kg
Compound II 15 mg/kg
Compound II 30 mg/kg
Compound II 45 mg/kg
0
15
15
30
45
0
5
15
30
45
Dose (mg/kg)
-50
centered on the active site of the protein, and the structures
of the enzymes as receptors into the required pdbqt formats
were saved. To gain insight into the possible binding
modes, compound II in the active site of the COX’s
enzymes was examined using AutoDock Vina (Trott and
Olson, 2010).
peak level at 5 h. Compound II [4-carbamoyl-1-(2-hydroxy-
benzyl)piperidinium chloride] exhibited the most potent anti-
inflammatory activity and it is moderately more potent when
compared with the reference standard aspirin.
The interaction of compound II with binding sites of
COXs was examined using molecular modeling to ratio-
nalize their activities. The lowest energy binding orientation
of compound II in the active site of COX-1 shown in Fig. 5
indicates that the hydroxyl group of inhibitor (compound II)
is involved in the polar interactions, which include the
hydrogen bonds between the inhibitor and amino group of
Results and discussion
Anti-inflammatory activity was evaluated by the carrageenan-
induced paw edema test in mice. The anti-inflammatory
activity data (Fig. 4a–c) indicated that compounds I and II
protected mice from carrageenan-induced inflammation
moderately at 1-h reaction time, with activity increasing to a
˚
˚
Arg120 (3.0 A) and phenolic hydroxyl of Tyr355 (3.0 A).
Besides these polar interactions, the oxygen atom of the
amide moiety of the inhibitor makes hydrogen bonds with
˚
amino group of Tyr355 (3.1 A) and hydroxyl of Ser353
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Med Chem Res (2013) 22:4677–4684
4683
˚
(3.1 A), while the nitrogen atom of amide moiety interacts
compared with the reference standard aspirin. Hence, this
series could be developed as a novel class of analgesic, anti-
pyretic, and anti-inflammatory agents. However, further
structural modifications are needed to increase the analgesic,
anti-pyretic, and anti-inflammatory activities with decreased
ulcerogenicity.
with Leu352, which firmly locks the inhibitor in the active
site of COX-1.
The molecular modeling of compound II in the active
site of COX-2 enzyme (Fig. 6) shows that compound II
almost superimposed on the native ligand (S58) and
exhibits one strong hydrogen bond between C–NH2 of
˚
inhibitor and p-OH of Tyr355 (1.4 A), while C=O moiety
Acknowledgments The authors gratefully acknowledge the Higher
Education Commission of Pakistan for financial support for research. The
authors sincerely thank and acknowledge PCSIR laboratories, Peshawar,
Pakistan and Punjab Drug House (PDH), Lahore for providing some
reagents.
of the inhibitor II has two hydrogen bonds with Arg513
˚
(3.1 A and 3.2 A). The hydroxyl group of the inhibitor
˚
˚
˚
bounds to Ser119 (3.1 A) and Arg120 (3.1 A) amino acids
of the COX-2 enzyme.
The synthesized compounds I and II were screened for
anti-pyretic activity using the Brewer’s yeast-induced
hyperpyrexia method. The graphical results (Fig. 7a–c)
show that compounds I and II significantly decreased the
temperature of pyretic mice at 0.5, 1.0, and 1.5 h after
intraperitoneal (i.p) administration of the compounds. The
maximum mean rectal temperatures produced by Brewer’s
yeast in the presence of compounds I and II were found to
be 37.7 and 37.2 °C, respectively, after 3 h, compared to
the control group 38.7 °C.
The analgesic activities of the compounds were studied
by AA-induced writhing test in mice. The analgesic activity
was evaluated at doses equivalent to 15, 30, and 45 mg kg-1
(aspirin).These compounds presented an important analgesic
profile measured by the classical AA-induced writhing
model. From the results of AA-induced writhing test, it
was noticed that compounds I and II possess significant
analgesic activity (Fig. 8a–c). The analgesic effects of I and
II (67.62 and 67.34 %, respectively) were found to be
comparable to that of the reference standard aspirin
(78.38 %).
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