Analgesic, Antipyretic and pass prediction activities of 1,3-bis (2-hydroxybenzylidene) thiourea
Valli
G.*, Ramu K., Mareeswari
P.
Department
of Chemistry, SFR College for Women, Sivakasi.
ABSTRACT:
The
Schiff base 1,3-bis(2-hydroxybenzylidene)thiourea was prepared from salicylaldehyde
and thiourea by condensation method using standard
procedure. Analgesic and antipyretic activities 1,3-bis(2-hydroxybenzylidene)thiourea Schiff base
were studied using albino rats of both
the sexes. Animals were divided into three groups, each consisting of four
animals. Group 1 served as control and group 2 received standard drug. Group 3
received 250 mg/kg of 1,3-bis(2-hydroxybenzylidene)thiourea . For the determination of antipyretic
activity, pyrexia was induced by 20% yeast suspension. The analgesic activity
was determined by tail immersion method. The results obtained showed that the
Schiff base was found to exhibit analgesic, antipyretic activities. The
analgesic activity of the Schiff base compared to the standard drug pentazocine was found to be higher in the first hour and
then the activity decreases slowly. The reduction in the rectal temperature for
this compound was observed to be less than the standard drug paracetamol. PASS prediction of 1,3-bis(2-hydroxybenzylidene)thiourea schiff base was found to
exhibit Laccase inhibitor and Monophenol monooxygenase inhibitor activities greater than 90%
and can also possessed other activities like Corticosteroid side-chain-isomerase inhibitor, 3-Hydroxybenzoate 4-monooxygenase
inhibitor greater than 80%
KEYWORDS: Salicylaldehyde, Thiourea, analgesic, antipyretic and PASS
INTRODUCTION:
Schiff bases are capable of forming coordinate bonds with
many of metal ions through both azomethine group and phenolic group or via its azomethine
or phenolic groups 1-5.The Schiff bases
find use in analytical chemistry, agriculture, dyes and polymer industries
besides their utility as model systems in the field of bio-inorganic chemistry
and also serve as useful gravimetric, colorimetric agents regulant
and as anti-coagulant. The oxygen carrying property and electron transfer
reactions of various schiff bases have been reported.
Schiff bases exhibit good antimicrobial activity and finds
its applications in pharmacology 6. These compounds showed good
fungicidal activity and anti-inflammatory activities. Number of formazans have been claimed to possess promising
antifertility7 and antiviral activities particularly against ranikhet disease virus and plant virus. Recently, Jolly et.
al. have synthesized new formazans for assessing
their antiviral, anticancer and anti HIV activities8. Schiff bases
are frequently studied due to optical, catalytic, chromophoric,
thermo chromic and photo chromic
properties.
In view of these above biological importance of schiff bases, we plan to synthesis
1,3-bis(2-hydroxybenzylidene)thiourea Schiff base by standard procedure9.
MATERIALS AND METHODS:
Materials used:
The chemicals such as salicylaldehyde, thiourea of E.merck grade and distilled ethanol were used. The melting point was determined
using melting point apparatus and IR spectra was recorded in FT IR Shmadzu 8400.
Drugs:
Pentazocine
(standard for analgesic) and paracetamol (standard
for antipyretic) were chosen for our work.
Animals used
For the analgesic, anti-pyretic activity studies twelve albino rats of both sexes of weight
100-165g for each studies were used. The animals were kept in poly propylene
cages in a dark/light cycle, 12hrs/12hrs and animals were fed with pelleted diet and drinking water ad libitum.
All the experimental protocols were approved by the committee for the purpose
of control and supervision on experiments on animals (CPCSEA), animal ethics
committee vide number SBCP/ 2011-2012/ IAEC/ CPCSEA/6.
Methods used Preparation of Schiff bases:
The salicylaldehyde (0.02mol)
and thiourea
(0.01mol) were taken and refluxed with ethanol for 2hours. After refluxing, the
product obtained was filtered, dried and recrystallized
using ethanol. The synthesized compound was used to study the analgesic, antipyretic and CNS activities.
The structure of the compound was proved by melting point determination
and IR spectral studies.
The melting point was recorded using melting point apparatus.
IR spectral studies reveals the presence of OH, C-N, C=N and C-O
functionalities and showed the following stretching frequencies. O-H Stretching
at u3370cm-1
and C-N Stretching at u1100cm-1,
C=O stretching at u1680cm-1,
C=N stretching at u1610cm-1.
Determination of analgesic activity10
The tail immersion test was carried out as described by
standard procedure. The albino rats were selected and last 3.5 cm of their tail
was immersed in hot water thermo-statistically maintained at 55°C, a procedure that
caused them to rapidly withdraw their tail. Three groups of animals were held in position in a
suitable restrainer with the tail extending out. The latency to withdraw the
tail was recorded with a stopwatch, and a cut-off maximum latency of 15 sec was
established in order to prevent tissue damage. Group I served as control, which
received only vehicle (5 mg/kg, i.p). Other groups of
animals received one of the following in a similar manner: Pentazocine
(4 mg/kg,i.p) and 1,3-bis(2-hydroxybenzylidene)thiourea schiff base (250mg/kg,p.o). The
initial reading was taken immediately before administration of test samples and
then at 1, 2, 3 and 4 hours after the administration and the recorded data were
listed in Table-1.
Antipyretic activity determination11,12:
Three groups of four animals of albino rats of both sexes
of weight 100-165g were used for the study.
The animals were kept in polypropylene cages in a room maintained under
controlled atmospheric conditions. The animals were fed with standard diet
(Hindustan liver, Mumbai, India) and had free access to clean drinking water.
Antipyretic activity was measured by Brewer’s induced pyrexia model in rats.
Rats were fasted overnight with water ad lib before the experiments. Pyrexia
was induced by subcutaneously injecting 20% w/v brewer's yeast suspension (10
ml/kg) into the animals' dorsum region. Eighteen hours after the injection, the
rectal temperature of each rat was measured using a digital thermometer (Sato Keiryoki Mfg. Co., Ltd., Japan). Only rats that showed an
increase in temperature of at least 0.7°C were used for the experiments.
Animals were divided in to 3 groups, each containing four animals. Group I
served as control (received distilled water), Group II received the standard
drug (received paracetamol 33mg/kg, p.o) .Group III received1,3-bis(2-hydroxybenzylidene)thiourea schiff base (250mg/kg, p.o). The temperature was measured at 1, 2, 3 and 4hr after
drug administration. The temperature was measured at 1, 2, 3 and 4hr after drug
administration. The recorded values were listed in Table-2.
Chem
Draw Ultra 11.0 software
The structure of 1,3-bis(2-hydroxybenzylidene)thiourea
schiff base was drawn in chemultra11.0 appear
as given in Fig.1. and their structure was saved as molfiles (*.mol).
Fig 1: Structure of
1,3-bis(2-hydroxybenzylidene)thiourea Schif base
Docking
The possible bioactivities were predicted with PASS
software (V. Poroikov
et al, version 1.917) as given in Fig.2 and the result was given
as Table-3.
Fig.2. PASS Prediction window
RESULT AND DISCUSSION:
Analgesic activity
The increase in the basal reaction times from 2.25 to 8 seconds for 4mg/kg of pentazocine and from 2 to 3.5 seconds for 250mg/kg
of1,3-bis(2-hydroxybenzylidene) thiourea were observed.The schiff base
1,3-bis(2-hydroxybenzylidene)thiourea was found to possessed higher
activity at the first hour
and lesser activity at the second hour than the standard with a probability <0.01.
Antipyretic activity
The reduction in temperature from 37.75 to 36.5 for
33mg/kg for paracetamol
and 36.9 to36.3 for 250mg/kg of
1,3-bis(2-hydroxybenzylidene)thiourea schiff base were
observed. The reduction in temperature of 1,3-bis(2-hydroxybenzylidene)thiourea schiff base (0.7%)
was found to possess slightly lower antipyretic activity than that of the
standard (1.2%) with probability<0.1.
PASS Prediction activity
The PASS prediction of 4-(4-hydroxy benzylidene
amino)phenol Schiff base showed Laccase inhibitor
activity as (Pa=0.929), Corticosteroid side-chain-isomerase
inhibitor as (Pa=0.891), 3-Hydroxybenzoate 4-monooxygenase inhibitor was
observed as (Pa=0.886), (Pa=0.873) for Arylacetonitrilase
inhibitor, Alkane 1-monooxygenase inhibitor activity
as (Pa=0.862), Glutathione thiolesterase inhibitor
was observed (Pa=0.860), Cysteamine dioxygenase inhibitor activity as (Pa=0.855) ,
Hydroxylamine reductase (NADH) inhibitor was possess
(Pa= 0.851), Spermicide activity observed with
(Pa=0.845), Glucan endo-1,6-beta-glucosidase
inhibitor was found to exhibit
(Pa=0.837), Catechol oxidase
inhibitor at (Pa=0.835), (Pa=0.822) for Anthranilate
3-monooxygenase (deaminating) inhibitor, Antiseborrheic, activity observed as (Pa=0.813), Feruloyl esterase
inhibitor activity as (Pa=0.803).
Table -1 Effect
of 1,3-bis(2-hydroxybenzylidene)thiourea Schiff base
on reaction time (in sec) in albino rats
|
Drug
treatment |
Dose
(mg/kg) |
Mean
time (in seconds) ±SEM |
|||
|
1hr |
2hr |
3hr |
4hr |
||
|
Control |
5 |
1.25±0.2886 |
1.25±0.2886 |
1.25±0.2886 |
1.5±0.3333 |
|
Pentazocine |
4 |
2.25±0.5527
(44.44%) |
6.75±0.7264
(81.48%) |
7±1.9437(82.14%) |
8±0.4713(81.25%) |
|
1,3-bis (2hydroxybenzylidene)thiourea |
250 |
2.5±0.3333 (50%) |
4.25±0.2880 (70.58%) |
5.25±0.5527 (76.19%) |
5.5±0.7453 (72.72%) |
|
One
way ANOVA |
||||
|
F |
3.5 |
43.68 |
8.34 |
48.375 |
|
df |
(2,9) |
(2,9) |
(2,9) |
(2,9) |
|
P |
- |
<0.01 |
<0.5 |
<0.02 |
Table -2Effect of
1,3-bis(2-hydroxybenzylidene)thiourea Schiff base on rectal temperature(0C)
in albino rats
|
Drug
treatment |
Dose
(mg/kg) |
Rectal
temperature after yeast administration(oC) |
Rectal
temperature after administration of drug(oC) |
Reduction
in temperature(oC) |
||||
|
Normal
|
18
hr |
1
hr |
2
hr |
3
hr |
4
hr |
|||
|
Control
saline |
1ml |
36.6± 0.2827 |
37.57± 0.2994 |
37.57± 0.2994 |
37.57± 0.6504 |
37.47± 0.2994 |
37.35± 0.2994 |
|
|
Standard
Paracetamol |
33 |
36.5± 0.2 |
37.75± 0.2185 |
37.45± 0.1971 |
37.05± 0.1971 |
36.75± 0.2380 |
36.5± 0.2000 |
1.25 |
|
1,3-bis(2-hydroxybenzylidene)thiourea |
250 |
36.85± 0.05773 |
37.8± 0.2108 |
37.65± 0.1795 |
37.47± 0.1589 |
37.27± 0.1280 |
37.1± 0.1154 |
0.7 |
|
One
way ANOVA |
||||
|
F |
0.2538 |
2.0198 |
3.4453 |
5.5980 |
|
df |
(2,9) |
(2,9) |
(2,9) |
(2,9) |
|
P |
- |
<0.5 |
<0.5 |
<0.1 |
Table-3PASS
Prediction activity of
1,3-bis(2-hydroxybenzylidene)thiourea
|
S.NO |
Activity |
Pa |
Pi |
|
1. |
Laccase inhibitor |
0.929 |
0.003 |
|
2. |
Laccase inhibitor |
0.927 |
0.003 |
|
3. |
Corticosteroid
side-chain-isomerase inhibitor |
0.891 |
0.003 |
|
4. |
3-Hydroxybenzoate
4-monooxygenase inhibitor |
0.886 |
0.003 |
|
5. |
Arylacetonitrilase
inhibitor |
0.873 |
0.014 |
|
6. |
Alkane 1-monooxygenase inhibitor |
0.862 |
0.006 |
|
7. |
Glutathione
thiolesterase inhibitor |
0.860 |
0.007 |
|
8. |
Cysteamine dioxygenase inhibitor |
0.855 |
0.002 |
|
9. |
Hydroxylamine
reductase (NADH) inhibitor |
0.851 |
0.004 |
|
10. |
Spermicide |
0.845 |
0.004 |
|
11. |
Glucan endo-1,6-beta-glucosidase inhibitor |
0.837 |
0.011 |
|
12. |
Catechol oxidase
inhibitor |
0.835 |
0.004 |
|
13. |
Anthranilate
3-monooxygenase (deaminating) inhibitor |
0.822 |
0.003 |
|
14. |
Antiseborrheic |
0.813 |
0.046 |
|
15. |
Feruloyl esterase inhibitor |
0.803 |
0.029 |
CONCLUSION:
The Schiff bases can be derived from salicylaldehyde
and thiourea by condensation method using standard
procedure. The analgesic activity of
the Schiff base compared to the standard drug pentazocine
was found to be higher in the third
hour and then the activity decreases slowly. The reduction in the rectal
temperature for this compound was observed to be less than the standard drug paracetamol. The PASS prediction of bioactivity have shown that the above schiff base was found to
possess Laccase inhibitor, Monophenol monooxygenase inhibitor greater than 90% and can also
exhibit other inhibitor
activities like Corticosteroid side-chain-isomerase
inhibitor, 3-Hydroxybenzoate 4-monooxygenase inhibitor having greater than 80%.
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Received on 30.03.2012
Modified on 04.04.2012
Accepted on 06.04.2012
© A&V Publication all right
reserved
Research J. Pharmacology and
Pharmacodynamics. 4(3): May-June, 2012, 172-175