SYNTHESIS AND ANTI-INFLAMMATORY …...Goswami et al. World Journal of Pharmacy and Pharmaceutical Sciences to exhibit a broad range of activities including antibacterial, antifungal,

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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

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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.

http://www.wjpps.com/

http://pharmaexpert.ru/passonline/


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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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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.


: 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),


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.


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.


: 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.




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



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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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),


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



1019


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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SYNTHESIS AND ANTI-INFLAMMATORY …...Goswami et al. World Journal of Pharmacy and Pharmaceutical Sciences to exhibit a broad range of activities including antibacterial, antifungal,