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Goswami et al. World Journal of Pharmacy and Pharmaceutical Sciences
SYNTHESIS AND ANTI-INFLAMMATORY ACTIVITIES-
PREDICTION AND EXPERIMENTAL VALIDATION FOR SOME
PYRIDINE CONTAINING HYDROXYTRIAZENES
Ashok Kumar Patidar1, Ajay Kumar Goswami*
1, Sharad Sharma
1, Anita Mehta
1,
Amit Bhargava2
1Synthetic Organic Chemistry Laboratory, M. L. Sukhadia University, Udaipur, Rajasthan
,INDIA 313001.
2B N Institute of Pharmacy, Udaipur, Rajasthan, India 313001.
ABSTRACT
In-silico prediction of newly synthesized compounds and their
experimental validation has recently attracted attention of researchers.
PASS (Prediction of Activity Spectra for Substances) is a very
simple tool for prediction of probable activity theoretically on the basis
of molecular structure. In the present study, a series of
hydroxytriazenes (4a-h) have been synthesized and characterized
through their spectral and physical analysis. All synthesized
compounds have been screened for probable activities using PASS
(http://pharmaexpert.ru/passonline/) and have Pa value in the range of
95.2% to 80.9% indicating their excellent probability to have anti-
inflammatory activity. In view of this synthesized compounds have
been used to validate anti-inflammatory activities as predicted by PASS. It is first such
attempt to use In-silico prediction before synthesis and test validity of PASS for designing
drugs with respect to hydroxytriazenes.
KEYWORD: Hydroxytriazenes, Pyridine, PASS and Activity prediction, anti-inflammatory
activity.
INTRODUCTION
Hydroxytriazenes are an important class of compounds which contain three linear nitrogen,
have been studied for their biological and pharmacological activities. They have been shown
WWOORRLLDD JJOOUURRNNAALL OOFF PPHHAARRMMAACCYY AANNDD PPHHAARRMMAACCEEUUTTIICCAALL SSCCIIEENNCCEESS
SSJJIIFF IImmppaacctt FFaaccttoorr 22..778866
VVoolluummee 44,, IIssssuuee 0044,, 11001100--11002211.. RReesseeaarrcchh AArrttiiccllee IISSSSNN 2278 – 4357
Article Received on
07 Jan 2015,
Revised on 01 Feb 2015,
Accepted on 24 Feb 2015
*Correspondence for
Author
Ajay Kumar Goswami
Synthetic Organic
Chemistry Laboratory, M.
L. sukhadia University,
Udaipur, Rajasthan,
INDIA, 313001.
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Goswami et al. World Journal of Pharmacy and Pharmaceutical Sciences
to exhibit a broad range of activities including antibacterial, antifungal, insecticidal,
analgesic, wound healing and anti-inflammatory properties.[1-5]
They are also used as a
helating ligand for spectrophotometric and complexometric determination of metal.[6-10]
N N
OH
N
(i)
123
A large number of heterocyclic compounds containing pyridine ring are associated with
diverse pharmacological properties such as anti-inflammatory[11,12]
, anticancer[13]
,
anticonvulsant [14]
, antiviral[15]
, anti-HlV [16]
and antimycobacterial[17]
activities. Addition of
pyridine moiety to hydroxytriazene chain may lead to good biologically active compounds.
In-silico prediction of biological activities of compounds on the basis of compounds structure
is commonly used technique in drug designing and synthesis. It is possible with computer
program PASS (Prediction of Activity Spectra for Substances
http://pharmaexpert.ru/passonline/), provides simultaneously large number of biological
activities (pharmacological main and side effects, mechanisms of action, mutagenicity,
carcinogenicity, teratogenicity and embryo toxicity) spectrum for a compound on the basis of
structural formulae of drug like substance with average accuracy 95% according to leave-
one-out cross validation (LOO CV) estimation. Algorithm of activity spectrum estimation is
based on Bayesian approach that estimates the probabilities of a compound belonging to the
classes of active and inactive compounds, respectively. PASS predictions are based on the
analysis of structure-activity relationships (SAR) for the training set consisting of about
46,000 biologically active compounds. Despite the incompleteness of the training set, PASS
algorithm is robust enough to obtain the reliable SAR (Structure Activity Relationship)[18]
or
even to predict such “raw” characteristics of compound as “drug-likeness”.[19]
Therefore, it
can be effectively applied for drug designing.
In the present investigation hydroxytriazenes containing pyridine moiety have been
synthesized and screened for their probable activity on the basis of PASS (prediction of
biological activity spectra for substances). Among the predicted activities anti-inflammatory
activity has been experimentally validated and results have excellent agreement with
prediction.
MATERIALS AND METHOD
Melting points of all synthesized compounds were taken in open capillaries and are
uncorrected. IR spectra (KBr) were recorded on a Perkin-Elmer FT IR spectrometer and 1H
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Goswami et al. World Journal of Pharmacy and Pharmaceutical Sciences
NMR and 13
C NMR were determined on a Bruker WM-500 (500 MHz FT NMR)
spectrometer using TMS as internal standard. TLC using silica gel-G as adsorbent checked
purity of compounds and visualization was accomplished with iodine. All the compounds
were synthesized according to the Reaction scheme (Figure 1)
2.1. Preparation of alkylhydroxylamine (1)
In a one litre beaker 0.05 moles of nitro alkyl compound was reduced with Zn dust (9 g) in
the presence of NH4Cl (2.7 g) in aqueous medium using mechanical stirrer at 0-10oC to
obtain corresponding alkylhydroxylamine. The resulting mixture was stirred for 1 hr. at
maintained temperature. After completion of reduction, product was filtered and used in
coupling process.
2.2. Synthesis of N'-[1-(4-aminophenyl)ethylidene]pyridine-4-carbohydrazide. (2a,b)
A mixture of pyridinecarbohydrazide (0.01 mol) and p-aminoacetophenone (0.01 mol) in
methanol (50 mL) was refluxed for 6 hrs. The reaction mixture was concentrated under
reduced pressure, cooled and the obtained solid product was filtered, washed with water. The
crude product was purified by crystallization from ethanol.
2.3. Diazotisation of N'-[1-(4-aminophenyl)ethylidene]pyridine-4-carbohydrazide (3a,b)
N'-[1-(4-aminophenyl)ethylidene]pyridine-4-carbohydrazide (0.05) were dissolved in mixture
containing 12 ml of HCl and 25 ml of water. In other beaker 0.05 moles of sodium nitrite was
dissolved in minimum quantity of water. The temperature of the reaction mixture was
maintained between 0-5o C. To this solution, sodium nitrite solution was added drop by drop
with stirring. The diazotised product so obtained was directly used for coupling.
2.4. Coupling of diazonium salt and alkyl hydroxylamine (4a-h)
The temperature of alkyl hydroxylamine and diazonium was maintained between 0-5oC,
diazonium salt solution was added drop-by-drop to the solution of alkyl hydroxylamine and
pH of solution was maintained between 5 to 6 using sodium acetate solution. The resultant
product (4a-h) was filtered, washed with cold water and recrystallized from ethanol.
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REACTION SCHEME
4a. 3-hydroxy-3-n-propyl-1-[N'-(1-phenylethylidene)pyridine-3-carbohydrazide]triazene.
Yeild- 67% FTIR (KBr) cm-1
: 3451 broad(ν O-H), 3296(ν N-H), 1634(C=O), 1425 (N=N),
1325(C-N). 1H NMR (CDCl3) δ: 10.58 (s, 1H, N-OH), 9.20 (s, 1H, N-H) 7.10-8.89 (m, 8,
Ar-H), 3.91 (t, 2H, N-CH2-), 2.48 (s, 3H, -CH3), 1.71 (sextet, 2H, -CH2-), 1.20 (t, 3H, -CH3).
13C NMR (CDCl3) δ : 161.27 (1C, C=O), 148.7 (1C), 155.2 (1C. C=N), 148.1 (1C), 150
(1C), 135 (1C), 130.7 (1C), 129.25 (2C), 125.1 (1C), 113 (2C), 43.23 (1C, N-CH2-), 22.64
(1C,-CH2-), 26.45 (1C, -CH3), 11.56 (1C, -CH3). Mass: (m/z) M+ 340.37.
4b. 3-hydroxy-3-isopropyl-1-[N'-(1-phenylethylidene)pyridine-3-carbohydrazide]triazene.
Yeild- 70% FTIR (KBr) cm-1
: 3455 broad(ν O-H), 3289 (ν N-H), 1632(C=O), 1419 (N=N),
1323 (C-N). 1H NMR (CDCl3) δ: 10.52 (s, 1H, N-OH), 9.22 (s, 1H, N-H) 7.13-8.60 (m, 8,
Ar-H), 3.98 (hep, 1H, N-CH<), 2.47 (s, 3H, -CH3), 1.36 (d, 6H, -CH3). 13
C NMR (CDCl3) δ :
161.21 (1C, C=O), 148.61 (1C), 155.21 (1C. C=N), 148.15 (1C), 147.12 (1C), 135 (1C),
130.7 (1C), 129.28 (2C), 125.11 (1C), 113 (2C), 49.30 (1C, N-CH<), 19.70 (2C,-CH2-),
26.45 (1C, -CH3). Mass: (m/z) M+ 340.37.
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4c. 3-hydroxy-3-ethyl-1-[N'-(1-phenylethylidene)pyridine-3-carbohydrazide]triazene.
Yeild- 59%FTIR (KBr) cm-1
: 3449 broad (ν O-H), 3311 (ν N-H), 1660 (C=O), 1427 (N=N),
1327 (C-N). 1H NMR (CDCl3) δ: 10.51 (s, 1H, N-OH), 9.26 (s, 1H, N-H) 7.01-9.85 (m, 8,
Ar-H), 3.97 (q, 2H, N-CH2-), 2.46 (s, 3H, -CH3), 1.69 (t, 3H, -CH3). 13
C NMR (CDCl3) δ :
161.22 (1C, C=O), 148.60 (1C), 155.05 (1C. C=N), 148 (1C), 147.21 (1C), 135 (1C), 130.71
(1C), 125.25 (2C), 129.12 (1C), 113 (2C), 45.60 (1C, N-CH2-), 14.50 (1C,-CH3), 26.42 (1C, -
CH3). Mass: (m/z) M+ 326.35.
4d. 3-hydroxy-3-methyl-1-[N'-(1-phenylethylidene)pyridine-3-carbohydrazide]triazene.
Yeild- 62% FTIR (KBr) cm-1
3455 broad (ν O-H), 3260 (ν N-H), 1648 (C=O), 1422 (N=N),
1320 (C-N).). 1H NMR (CDCl3) δ: 10.56 (s, 1H, N-OH), 9.25 (s, 1H, N-H) 7.05-8.88 (m, 8,
Ar-H), 3.97 (s, 3H, N-CH3), 2.46 (s, 3H, -CH3). 13
C NMR (CDCl3) δ : 161.26 (1C, C=O),
148.50 (1C), 155.22 (1C. C=N), 148.15 (1C), 147.32 (1C), 135.20 (1C), 130.51 (1C), 129.16
(2C), 125 (1C), 113.5 (2C), 41.3 (1C, N-CH3), 26.25 (1C, -CH3). Mass: (m/z) M+ 312.32.
4e.3-hydroxy-3-n-propyl-1-[N'-(1-phenylethylidene)pyridine-4-carbohydrazide]triazene.
Yeild- 65% FTIR (KBr) cm-1
: 3455 (ν O-H), 3298(ν N-H), 1648 (C=O), 1427 (N=N), 1326
(C-N).1H NMR (CDCl3) δ: 10.35 (s, 1H, N-OH), 9.19 (s, 1H, N-H) 7.10-8.89 (m, 8, Ar-H),
3.94 (t, 2H, N-CH2-), 2.48 (s, 3H, -CH3), 1.65 (sex, 2H, -CH2-), 1.15 (t, 3H, -CH3). 13
C NMR
(CDCl3) δ : 163.54 (1C, C=O), 150.27 (2C), 154 (1C. C=N), 151 (1C), 130.2 (2C), 121 (2C),
114.7 (2C), 44.58 (1C, N-CH2-), 23.19 (1C,-CH2-), 27.31 (1C, -CH3), 12.86 (1C, -CH3).
Mass: (m/z) M+ 340.37.
4f. 3-hydroxy-3-isopropyl-1-[N'-(1-phenylethylidene)pyridine-4-carbohydrazide]triazene.
Yeild- 69% FTIR (KBr) cm-1
: 3448 broad (ν O-H), 3302 (ν N-H), 1645 (C=O), 1425 (N=N),
1329 (C-N). 1H NMR (CDCl3) δ: 10.41 (s, 1H, N-OH), 9.15 (s, 1H, N-H) 7.09-8.78 (m, 8,
Ar-H), 23.99 (hep, 1H, N-CH<), 2.47 (s, 3H, -CH3) 1.38 (d, 6H, -CH3). 13
C NMR (CDCl3) δ
: 163.54 (1C, C=O), 150.27 (2C), 154 (1C. C=N), 151 (1C), 130.2 (2C), 121 (2C), 114.7
(2C), 54.58 (1C, N-CH<), 27.31 (1C, -CH3), 22.75 (2C, -CH3). Mass: (m/z) M+ 340.37.
4g. 3-hydroxy-3-ethyl-1-[N'-(1-phenylethylidene)pyridine-4-carbohydrazide]triazene.
Yeild- 61%FTIR (KBr) cm-1
: 3472 broad (ν O-H), 3320 (ν N-H), 1651 (C=O), 1420 (N=N),
1326 (C-N). 1H NMR (CDCl3) δ: 10.40 (s, 1H, N-OH), 9.22 (s, 1H, N-H) 7.14-9.05 (m, 8,
Ar-H), 3.96 (q, 2H, N-CH2-), 2.48 (s, 3H, -CH3) 1.66 (t, 3H, -CH3). 13
C NMR (CDCl3) δ :
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Goswami et al. World Journal of Pharmacy and Pharmaceutical Sciences
163.52 (1C, C=O), 150.29 (2C), 154.61 (1C. C=N), 151 (1C), 130.22 (2C), 121 (2C), 114.72
(2C), 46.32 (1C, N-CH2-), 27.0 (1C, -CH3), 13.1 (1C, -CH3). Mass: (m/z) M+ 326.35.
4h. 3-hydroxy-3-methyl-1-[N'-(1-phenylethylidene)pyridine-4-carbohydrazide]triazene.
Yeild- 60% FTIR (KBr) cm-1: 3448 broad (ν O-H), 3308 (ν N-H), 1645 (C=O), 1429 (N=N),
1329 (C-N). 1H NMR (CDCl3) δ: 10.39 (s, 1H, N-OH), 9.21 (s, 1H, N-H) 7.14-9.01 (m, 8,
Ar-H), 3.93 (s, 3H, N-CH3), 2.49 (s, 3H, -CH3). 13
C NMR (CDCl3) δ: 163.53 (1C, C=O),
150.26 (2C), 154.25 (1C. C=N), 151.35 (1C), 130.23 (2C), 121 (2C), 114.70 (2C), 41.42 (1C,
N-CH3), 27.18 (1C, -CH3). Mass: (m/z) M+ 312.32.
Thus it is evident that all the compounds synthesized were in pure state and were fit to be
screened for the predicted activity.
2.5. Biological activity predicted by PASS
The biological activity spectra of the 3-hydroxy-3-alkyl-1-[N'-(1-phenylethylidene)pyridine-
carbohydrazide]triazene 4a-h were obtained by PASS software. The predictions were carried
out based on analysis of training set containing about 46,000 drugs and biologically active
compounds. This set consider as reference compounds for known chemical compounds as
well as different biological activities. Percent activity (pa) and inactivity (pi) of compounds
4a-h represented in (Table 2).
2.6. Anti-inflammatory activity
Male or female Wister albino rats with a body weight between 175 to 225 gm were used. The
rats were divided into ten groups (n=6) and the first group served as control (given only
carrageen), second group was given Diclofenac sodium orally (100 mg/kg) as a standard
drug. Groups 3-10 were administered synthesized hydroxytriazenes compounds (4a, 4b, 4c,
4d, 4e, 4f, 4g, and 4h) dissolved in DMSO at dose (100 mg/kg) orally. Edema was produced
according to the method described by Winter et al (1962)[22]
by sub planter injection 0.1 ml of
1% freshly prepared suspension of carrageenan (Sigma chemical co.). The paw volume was
measured plethysmographically at various intervals (1, 2, 3 and 4 hr.). Mean increase in paw
volume was measured and % inhibition was calculated (Table 3).
Percent edema inhibition = (vc – vt/ vc)× 100, where vt represents the mean increase in paw
volume in rats treated with tested compounds and vc represents the mean increase in paw
volume in the control group of rats.
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2.7. Statistical analysis
The data are reported as mean ± standard error of the mean (SEM) and were compared using
one way analysis of variance (ANOVA), followed by the Dunnett’s multiple comparison test,
and p- values < 0.01 was considered significant.
RESULTS
3.1. Chemistry
p-amino acetophenone were allowed to react with equal mole of isoniazid and nicotinic
hydrazide in methanol to form compounds 2a and 2b. Treatment of compounds 2a and 2b
with HCl and NaNO2 gave intermediates 3a and 3b. Coupling of intermidiates 3a and 3b
with various alkylhydroxylamine afforded corresponding compounds 4(a-h) which were
confirmed by 3405 ± 5 cm-1
of OH bond stretching band and intense peak at 10.26 ± 0. 13
ppm in 1H NMR spectra. Physical data of synthesized compounds are given in table 1.
Table 1: Physical data of synthesized compounds.
COMPOUNDS N
O
NH
NH2
R
MOLECULAR
FORMULA
MOLECULAR
WEIGHT
MELTING
POINT
(oC)
ELEMENTAL
ANALYSIS
C % H % N%
4a N
O
NH
NH2
n-
C3H7 C17H22N6O2 340.37 107 59.58 5.86 24.31
4b N
O
NH
NH2
Iso-
C3H7 C17H22N6O2 340.37 104 59.55 5.90 24.52
4c N
O
NH
NH2
-
C2H5 C16H20N6O2 326.35 110 58.90 5.51 25.62
4d N
O
NH
NH2
-CH3 C15H18N6O2 312.32 125 57.12 5.19 27.00
4e N
O
NH
NH2
n-
C3H7 C17H22N6O2 340.37 98 59.88 5.92 24.62
4f N
O
NH
NH2
Iso-
C3H7 C17H22N6O2 340.37 92 60.00 5.89 24.59
4g N
O
NH
NH2
-
C2H5 C16H20N6O2 326.35 102 58.76 5.55 25.69
4h N
O
NH
NH2
-CH3 C15H18N6O2 312.32 114 57.50 5.15 26.89
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3.2. Biological activity
3.2.1. Activity Predicted by PASS
At first, the substances were screened for probable activities on the basis of structure of
compounds by PASS computer programme. All compounds shows good anti-inflammatory
activity more than 80% and good to moderate antiviral, antituberculosis, antineoplastic and
antimycobacterial activities. PASS activity results of all synthesized compounds are
summarized in table 2.
Table 2: Predicted activity of synthesized compounds.
3.2.2. Anti-inflammatory activity
The anti-inflammatory activity results are given in table 3. All the synthesized compounds
exhibited good anti-inflammatory activity with 73.58 – 84.90% inhibition of carrageenan
induced paw edema. The compound with n-propyl and 3-substituted pyridine ring (4a,
84.90%) has shown highest activity in the series close to standard Diclofenac (88.02%). On
the other hand compound having methyl group and 4-substituted pyridine ring (4h 73.58%)
shows lowest activity. It can be seen from the result of anti-inflammatory activities of
compounds the length of alkyl group increase, anti-inflammatory activity increase. The
compounds having 3-substituted pyridine moiety shows more prevention toward
inflammation rather than compounds having 4-substituted pyridine moiety. It is also seen
from the results of anti-inflammatory activity that as the branches of alkyl group increase, it
slightly decreases in anti-inflammatory activity.
Compou
nds
Anti-
inflammatory Antiviral Antineoplastic Antituberculosis antimycobacterial
Pa Pi Pa Pi Pa Pi Pa Pi Pa Pi
4a .869 .005 .404 .106 .446 .006 .407 .029 .357 .053
4b .834 .005 .524 .041 .484 .005 .476 .015 .431 .032
4c .809 .006 .405 .105 .475 .005 .442 .021 .390 .042
4d .950 .004 .395 .113 .462 .005 .376 .039 .318 .070
4e .873 .005 .531 .038 .452 .005 .490 .013 .450 .028
4f .838 .005 .635 .013 .491 .005 .564 .007 .516 .017
4g .814 .006 .532 .038 .482 .005 .529 .010 .480 .022
4h .952 .004 .523 .041 .468 .005 .457 .018 .407 .037
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Table 3: Anti-inflammatory activity of compounds.
GROUP
DOSE
(mg/kg) 0 HOUR 1 HOUR 2 HOUR 3 HOUR 4 HOUR
%
INHIBITION
OF EDEMA
VOLUME
CONTROL 3.22±0.07 4.13±0.07 4.89±0.06 5.21±0.05 5.34±0.04
2.12
DICLOFENAC
SODIUM 100 3.21±0.05 3.51±0.08 3.56±0.07 3.51±0.06
3.46±0.05
0.25 88.02
NO
NH
N
CH3
N
N N
OH
CH3
( 4a )
100 3.24±0.04 3.56±0.06 3.84±0.08 3.65±0.04 3.56±0.06
0.32 84.90
N O
NH
N
CH3
N
N N
OH
CH3
CH3
( 4b )
100 3.22±0.06 3.62±0.06 3.88±0.05 3.63±0.06 3.60±0.06
0.38 82.07
N O
NH
N
CH3
N
N N
OH
CH3
( 4c )
100 3.20±0.05 3.53±0.13 3.75±0.045 3.85±0.05 3.67±0.04
0.47 77.83
N O
NH
N
CH3
N
N N
OH
CH3
( 4d )
100 3.23±0.06 3.66±0.02 4.09±0.06 3.86±0.07 3.74±0.05
0.51 75.64
N
O
NH
N
CH3
N
N N
OH
CH3
( 4e )
100 3.22±0.08 3.61±0.07 3.8±0.05 3.79±0.07 3.63±0.06
0.40 81.13
N
O
NH
N
CH3
N
N N
OH
CH3
CH3
( 4f )
100 3.21±0.07 3.63±0.07 3.84±0.04 3.81±0.025 3.65±0.07
0.44 79.24
N
O
NH
N
CH3
N
N N
OH
CH3
( 4g )
100 3.20±0.04 3.69±0.04 4.05±0.08 3.9±0.061 3.66±0.06
0.46 78.30
N
O
NH
N
CH3
N
N N
OH
CH3
( 4h )
100 3.23±0.06 3.79±0.26 4.23±0.031 4.7±0.05 3.79±0.05
0.56 73.58
All value are represented as mean ± SEM ( n=6 ), p- values < 0.01
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DISCUSSION
Probable mechanism of action of hydroxytriazenes as a anti-inflammatory compounds –
The already available probable mechanism of action of carrageenan induced edema has been
describe to be a biphasic mechanism. The release of histamine 5 HT kinin is in the first phase
that is in the first hour while the second phase is attributed to release of prostaglandins like
substances within two to three hours.[20]
In the present study two observation are clear and
evident- 1. There is no anti-inflammatory activity of DMSO. 2. The parent compound 1,3-
diphenylhydroxytriazene has been reported to have anti-inflammatory activity for a shorter
period of time.
Effect of hydroxytriazenes as anti-inflammatory agent as reported earlier is structure
depended and significant activity has been exhibited.[21]
This is first report present on
experimental validation of predicted anti-inflammatory activities of hydroxytriazenes using
PASS the activities predicted on the basis of Pa has shown a trend as 4a = .869, 4b = .834, 4c
= .809 , 4d = .950, 4e = .873, 4f = .838, 4g = .814, 4h = .952. However on the basis of
experimental observation although all of the hydroxytriazenes screen show significant
activities varying from 73.58 to 84.90 which is even close to standard drug Diclofenac
sodium i.e. 88.02. It’s quite evident that lengthening of alkyl chain on 3 sides shows definite
enhancement in the ant-inflammatory activities. Further except compound number 4d and 4h
in general the trend of anti-inflammatory activities is exactly in accordance with the predicted
activity via PASS. Summarily it can be said that PASS can be an excellent tool for designing
drug as has been shown in the present study.
ACKNOWLEDGEMENTS
Authors are thankful to Head Department of Chemistry, MLS University and Dr. C. S.
Chauhan, Principal B. N. Institute of Pharmacy, Udaipur, for providing necessary facilities to
carry out this work
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2. John LM. 3-aryl-triazene-1-oxide for treating inflammatory diseases U.S. Patent US,
3962434, 1976.
3. Ombaka O. Gichumbi JM. Synthesis and insecticidal activities of some selected
hydroxytriazenes. J. Environ. Chem. Ecotoxic., 2011; 3(11): 286-289.
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4. Chauhan LS. Jain CP. Chauhan RS. Goswami AK. Wound-healing activity of
hydroxytriazenes - a new class of bioactive compounds. J. Chem. and Pharm. Res., 2010;
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