PART-II STUDIES ON SCHIFF BASES -...

PART-II

STUDIES ON

SCHIFF BASES

Studies on Some Heterocyclic Entities......

31

INTRODUCTION

There is always need for the safer antibacterial agents and research efforts are

going on for developing safer antibacterial agents. Schiff base approach is one of the most

promising amongst these[1]. In recent years, there has been an increasing interest in the

design and development of Schiff base derivatives Schiff base are associated with

antibacterial, antifungal and antitubercular activities and have diverse biological

activities[2].

General account of the summary of reaction of aldehydes with amine (aromatic or

aliphatic) has been reviewed by Murray[3]. Some Schiff bases from 2-hydroxy

benzaldehyde and 3-hydroxy-4-pyridine-carboxaldehyde with various amines were also

synthesized and the effect of substituent on Ketoenol equilibria[4] and hydrogen bonds[5]

have also been reported. Some other Schiff bases have also been synthesized from

salicyaldehydes with aromatic amines and aliphatic amines and their characterizations

were done by using IR, NMR and mass spectra[6-9]. Dayagi and Degani[10] have reported

some methods for the synthesis of Schiff bases. Sampat et al.[11] gave the detail study

report on heterocyclic Schiff bases ligands by condensing pyrrole 2-carboxaldehyde and

pyridine 2-carboxaldehyde with aromatic amines. Singh et al.[12] had synthesized Schiff

bases derived from 4-amino antipyrine and studied their IR and thermal properties. A

series of new thorium (IV) complexes with a Schiff bases derived from fluoroaniline and

p-(N, N’-dicyanoethyl) amino benzaldehyde have been synthesized by Goyal et al.[13]

Chang and Pan reported some Schiff bases derived from amino phenols and aromatic

aldehydes[14]. A new one pot procedure for the generation of azomethine via

chlorominium salt has been investigated by

Anderson and co-workers[15]. Amanda J. Gallant et al.[16] have preparedSchiff base by

condensation of equimolar quantity of 3,6 diformyl catechol and substituted o-

phenylenediamine. Pierre L. Beaulieu et al.[17] have synthesized (E)-N-phenyl

methyleneglycineethyl ester by the cyclocondensation of glycine ethyl ester

hydrochloride, t-butylmethyl ether (TBME), benzaldehyde was added followed by

anhydrous Na2SO4 and triethylamine.

Schiff bases are known to be useful in perfumery [18,19] as corrosion inhibitor[20,21]

as complexing agents[22-24] and as intermediate in many reactions[25-29]. They are used in

optical and electrochemical sensors, as well as in various chromatographic methods, to

enable detection of enhance selectivity and sensitivity[30-32]. In literature, some other

Schiff Bases…


32

applications of Schiff bases have also been reported in various fields [33-37]. Some of these

compounds and their metal complexes have also been used in the preparation of various

medicines[38-42]. Further, many workers[43-50] reported a wide range of biological activities

of various Schiff bases. Besides, several Schiff bases have been reported to possess

remarkable antibacterial[51-55], antifungal[56-61], anticancer[62-66], anti HIV[67-69], anti-

inflammatory[70-73], antiparasitic[74,75] and diuretic[76] activities.

SYNTHETIC ASPECT

1. General account of the summary of reaction of aldehydes with amine (aromatic or

aliphatic) has been reviewed by Murray[77]

R CHO + R' NH2R C

HN R' + H2O

2. Amanda J. Gallant et al.[78] have prepared schiff bases by the condensation of

equimolar quantity of 3, 6 diformyl catechol and substituted o-phenylenediamine.

OH

OH

O

O

H2N

NH2

OR

OR

OH

OH

O

NH2

OR

OR

N+

3. Oddo and Tognacchini[79] have introduced the comparative rates of formation of

Schiff’s base from aniline, substituted aniline and aromatic aldehydes using a

cryscopic method follow the course of reaction.

Schiff Bases…


33

MECHANISM

The condensation takes place in two steps. The first is marked by the formation of

an addition compound (an amino-alcohol). In second step one molecule of water from the

addition product splits off. The mechanism is given bellow.

N NH

N

NH2

..

+ R C

H

O

N NH

N

+H2N CH

O-

R

N NH

N

N CH

OH

R

H

H2O-

N NH

N

NHC

R

THERAPEUTIC IMPORTANCE

Schiff bases exhibit a wide range of pharmacological activities like antifungual,

antibacterial, antiviral, antiinflammatory etc. Pandey Taruna et al..[80] prepared

azomethines and their boron complexes and screened for their antifungal and antibacterial

properties. It is evident that azomethines alone were quite toxic but their activity

increased after complexation. Omar et al.[81] have determined cyclocondensation of

azomethines having good antischistosomal activity. Praveen M. and co-workers[82] have

synthesized a novel class of acetyl ferrocene derived from Schiff bases having

antimicrobial activity.

Ram Tilak et al.[83] have synthesized some Schiff’s bases, thiazolidinones 4-

triazolines, and formazones of 2-chloro phenothiazines and screened against

Schiff Bases…


34

carrageenininduced edema in albino rats. The thiazolidinones showed promising anti-

inflammatory activity.

Ravindra V. Chambhare et al.[84] have prepared some azomethines and tested for

their antimicrobial activity. B. Shivarama Holla et. al.[85] have synthesized azomethines of

(I) having antibacterial and anti-inflammatory activity.

Cl

Cl

Cl

S

NHN

N O R

(I)

R = 2-NO2, 4-NO2,4-Br etc.

Pawar R. P. et al[86] have synthesized azomethines by the condensation of

iodovanillin with different substituted aromatic amines and tested for antibacterial

activity. Ergenc and co-workers[87] have synthesised azomethine derivatives having

antifungal activity. Yadav Bodke[88] have synthesized some azomethines and tested for

their biological activity. B. Shivarama Holla et al.[89] have prepared and reported

anticancer activity of some new Schiff bases.

Mehta R. H. et al.[90] have synthesized coummarin schiff’s base derivatives of (II)

and examined for their antibacterial activity. Khalafallah A. K. and Hassan M. E.[91] have

prepared some styryl Schiff’s bases spiro derivatives as potential antibacterial and

antifungal activity. Sharaf El-Din, and Nabaweyal[92] have synthesized some azomethine

derivatives (III) having good antibacterial activity.

ON

O N

OH

MeR

(II)(III)

R=Ph, 4-Br-C6H4,4-NO2-C6H4 2-Cl-C6H4CONH

R=3,4-OH, 3,4-NO2 3,4-(OMe)2

R

Schiff Bases…


35

Cascaval Alexandru et al.[93] have synthesized azomethines, which have good

analgesic and antipyretic properties. Pandeya S. N. et al.[94] have synthesized Schiff bases

showed good activity against Vibrio cholerae non-o., Shigella boydii, Enterococcus

faecalis and Edwaredsiella torla with MIC in the rang of 10-25 μg/ml. Some compounds

were found to be active against Salmonellal typhi and Vibro cholerae-0, MIC 25-150

μg/ml).

Ali Yousif et al.[95] have synthesized some Schiff’s base derivatives of glucose

containing acetylenic bond and tested for their bactericidal activity against E. coli and

Staphylococcus aureus.

S. J. Wadher et al.[96] have synthesized some schiff’s base derivatives of Para

amino salicylic acid tested for their antibacterial activity against the E. coli, S. aureus,

and ntifungal activity of compounds was studied against C. albicans and A. niger

according to cup-plate method. The synthesised compound found to have better

antimicrobial activity than the parent compound.

NH2

HO

O

HO

R

O

H N

HO

O

HO

R

+

Iana Vazzana et. al.[97] described sets of Schiff bases (IV) and (V) (diaryl- and

arylheteroaryl azomethines) endowed with strong and long lasting antiinflammatory

activity against the rat hind paw edema induced by carrageenan.

N

CH

N

CF3

CH

NS

O

O

H2N F

(IV) (V)

Vijay Kumar.M.M.J.et. al.[98]have synthesized some new Schiff bases (VI)

containing different functional groups and check antimicrobial activity against gram-

positive and gram-negative bacteria.

Schiff Bases…


36

N

C

O

HN

N

NH

Cl

F

HC

OCH3

HO

(VI)

Gundibasappa K. Nagaraja et. al.[99] have been synthesized some Schiff bases

(VII) and screened for their antibacterial and antifungal activities.

O

HN

O

N N

Cl

R3 R2

R1

R

(VII)

Looking to the interesting properties of azomethines, we have synthesized some

new azomethines, which have been described as under.

SECTION I: SYNTHESIS AND BIOLOGICAL EVALUATION OF N-((Z)

BENZYLIDINE)-1H-PYRAZOLO[3,4-b]PYRIDINE-3-AMINE

SECTION II: SYNTHESIS AND BIOLOGICAL EVALUATION OF (Z)-N-(1-((Z)

PHENYL)ETHYLIDENE)-1H-PYRAZOLO[3,4-b]PYRIDIN-3-

AMINE

Schiff Bases…


37

SECTION I

SYNTHESIS AND BIOLOGICAL EVALUATION OF N-((Z)BENZYLIDINE)-1H-

PYRAZOLO[3,4-b]PYRIDINE-3-AMINE

Looking to the interesting properties of azomethines, with an intension to

synthesizing better therapeutic agents, azomethine derivatives of Type (II) have been

synthesized by the condensation of 1H-Pyrazolo[3,4-b]Pyridine-3-amine with different

aromatic aldehydes in order to study their biodynamic behavior.

The constitution of the synthesized products have been characterized by using

elemental analysis, infrared and 1H-nuclear magnetic resonance spectroscopy and further

supported by mass spectroscopy.

All the compounds have been evaluated for their in vitro biological assay like

antibacterial activity towards Gram positive and Gram negative bacterial strains and

antifungal activity towards A. niger, C. Albicans and A. Clavatus at a different

concentration. The biological activities of synthesized compounds were compared with

standard drugs.

Schiff Bases…


38

REACTION SCHEME

N

N

NH

NH2

OHC

N

N

NH

N

R

R

8.0 Hrs., Reflux

Ethanol

+

(Type II)

gl. CH3COOH

Type (I)

R = OH, Cl, NO2, N(CH3)2,OCH3 etc.





standard drugs.

Schiff Bases…


39

IR SPECTRAL STUDIES OF 2-[(1H-PYRAZOLO[3,4-b]PYRIDIN-3-YL-

IMINO)METHYL]PHENOL

N NH

N

N CH

HO

Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400 cm-1 (KBr disc.)

Frequency cm-1

Type Vibration

Mode Observed Reported Ref.

Alkane

C-H str. (asym.)

C-H str. (sym.)

C-H def. (asym.)

C-H def. (sym.)

2918

2850

1429

1348

2975-2920

2880-2860

1470-1435

1395-1370

100

”

”

”

Aromatic

C-H str.

C=C

C-H i.p. def.

C-H o.o.p. def.

3012

1537

1099

821

3100-3000

1585-1480

1125-1090

860-810

”

”

”

”

Azomethine N=C str.

C-N str.

1589

1259

1650-1580

1350-1200

”

”

Hydroxy O-H str.

O-H def.

3219

1309

3650-2590

1410-1310

”

”

Schiff Bases…


40

1HNMR SPECTRAL STUDIES OF 2-[(1H-PYRAZOLO[3,4-b]PYRIDIN-3-YL-

IMINO)METHYL]PHENOL

Internal Standard: TMS; Solvent: CDCl3 Instrument: BRUKER Spectrometer

(300MHz)

Signal

No.

Signal Position

δppm

Relative No.

of Protons Multiplicity Inference

1

2

3

4

5

6.94-7.02

7.35-7.48

8.71

11.39

13.01

4H

3H

1H

1H

1H

multiplet

multiplet

singlet

singlet

singlet

Ar-H(b,e,f,g)

Ar-H(a,c,d)

-CH(h)

Ar-OH

-NH

Schiff Bases…


41

EXPANDED AROMATIC REGION

Schiff Bases…


42

MA

SS S

PEC

TR

UM

OF

2-[(

1H-P

YR

AZ

OL

O[3

,4-b

]PY

RID

IN-3

-YL

- IM

INO

)ME

TH

YL

]PH

EN

OL

Schiff Bases…


43

EXPERIMENTAL

SYNTHESIS AND BIOLOGICAL EVALUATION OF N-((Z)BENZYLIDINE)-1H-


[A] SYNTHESIS OF 1H-PYRAZOLO[3,4-b]PYRIDINE-3-AMINE

See, Part-I, Experimental [A].

[B] SYNTHESIS OF 2-[(1H-PYRAZOLO[3,4-B]PYRIDIN-3-YL-IMINO)

METHYL]PHENOL

A mixture of 1H-Pyrazolo[3,4-b]pyridine-3-amine (0.01 mol, 1.34 gm) and 2-

hydroxy benzaldehydes (0.01 mol, 1.22 gm) was taken in ethanol (25.0 ml) using

catalytic amount of gla. acetic acid. The reaction mixture was refluxed for 8.0-10 hrs on

waterbath. The product was isolated and crystallized from absolute ethanol. Yield 90%;

m.p.1920C.

Similarly other Synthesis of N-((Z)benzylidine)-1H-pyrazolo[3,4-b]pyridine-3-

amine were obtained. Various physical constants for all the synthesized compounds are

given in Table 1.

[C] BIOLOGICAL EVALUATION OF N-((Z)BENZYLIDINE)-1H-


DETERMINATION OF MINIMAL INHIBITION CONCENTRATIONS BY

BROTH DILUTION METHOD

MATERIALS AND METHOD

1. All the Synthesized Drugs Were Used For Antibacterial Test Procedures

2. All Necessary Controls Like:

Drug Control

Vehicle Control

Agar Control

Organism Control

Known Antibacterial Drugs Control

Schiff Bases…


44

All MTCC Cultures Were Tested Against Above Mentioned Known and

Unknown Drugs.

Mueller Hinton Broth Was Used as Nutrient Medium to Grow and Dilute the

Drug Suspension for the Test bacteria.

Inoculum Size for Test Strain Was Adjust to 108 Cfu [Colony Forming Unit] per

milliliter by comparing the turbidity.

Following common standard strains were used for screening of antibacterial and

antifungal activities: The strains were procured from Institute of Microbial

Technology, Chandigarh.

E.COLI KL.PNEUMONIAE S.AUREUS S.PYOGENUS MTCC 442 MTCC 4030 MTCC 96 MTCC 443

DMSO was used as diluents / vehicle to get desired concentration of drugs to test

upon standard bacterial strains.

MINIMAL INHIBITION CONCENTRATION [MIC]:

The main advantage of the ‘Broth Dilution Method’ for MIC determination lies

in the fact that it can readily be converted to determine the MIC as well.

1. Serial dilutions were prepared in primary and secondary screening.

2. The control tube containing no antibiotic is immediately sub cultured [before

inoculation] by spreading a loopful evenly over a quarter of p[late of medium

suitable for the growth of the test organism and put for incubation at 370C

overnight. The tubes are then incubated overnight.

3. The MIC of the control organism is read to check the accuracy of the drug

concentrations.

4. The lowest concentration inhibiting growth of the organism is recorded as the

MIC.

5. The amount of growth from the control tube before incubation [which represents

the original inoculum] is compared.

METHODS USED FOR PRIMARY AND SECONDARY SCREENING:

Each synthesized drug was diluted obtaining 2000 microgram /ml concentration,

as a stock solution.

Schiff Bases…


45

PRIMARY SCREEN:

In primary screening 1000 micro/ml, 500 micro/ml, and 250 micro/ml

concentrations of the synthesized drugs were taken. The active synthesized drugs found in

this primary screening were further tested in a second set of dilution against all

microorganisms.

SECONDARY SCREEN:

The drugs found active in primary screening were similarly diluted to obtain 200

micro/ml 100 micro/ml, 50 micro/ml, 25 micro/ml, 12.5 micro/ml, 6.250 micro/ml, and

concentrations.

READING RESULT:

The highest dilution showing at least 99 % inhibition zone is taken as MIC. The

result of this is much affected by the size of the inoculum. The test mixture should

contain 108 organism/ml.

The antimicrobial activity was compared with standard drug viz Ampicillin,

Ciprofloxacin, Gentamycin, Chloramphenicol, Norfloxacin and antifungal activity was

compared with Nystatin Greseofulvin. Results of test solutions are recorded in Table 2.

Schiff Bases…


46

Sr

.

R

Mol

ecul

ar

Mol

ecul

ar

M

.P.

Y

ield

% o

f Nitr

ogen

Rf

Solv

ent

No.

Form

ula

W

eigh

t

0 C

%

C

alcd

.

Foun

d

V

alue

S

yste

m

1

2

3

4

5

6

7

8

9

10

1

a

2-h

ydro

xy

C

13H

10N

4O

2

38.2

4

19

2

90

2

3.52

2

3.50

0

.49

S 1

1

f

4-C

hlor

o

C

13H

9ClN

4

25

6.69

208

8

5

21

.83

21

.84

0

.47

S 1

1

g

4-N

itro

C

13H

9N5O

2

26

7.24

300

7

5

26

.21

26

.23

0

.53

S 1

1

h

H

C

13H

10N

4

222

.25

1

95

80

25.2

1

25.2

0

0.5

5

S 1

1

i

4-M

etho

xy

C14

H12

N4O

25

2.27

180

9

5

22

.21

22

.19

0

.53

S 1

1

j

2-C

hlor

o

C

13H

9ClN

4

2

56.6

9

150

9

2

21

.83

21

.84

0

.51

S 1

1

b

3-N

itro

C

13H

9N5O

2

26

7.24

205

7

0

26

.21

26

.20

0

.55

S 1

1

e

4-H

ydro

xy-3

-Met

hoxy

C

14H

12N

4O2

2

68.2

7

23

0

80

20.8

8

2

0.85

0.51

S

1

1

d

4-N

,N-D

imet

hyl

C15

H15

N5

265

.31

254

8

5

2

6.40

26.

41

0.

62

S1

1

c

4-H

ydro

xy

C13

H10

N4O

238

.24

288

70

23.

52

23.

54

0.4

8

S 1

1

k

4-Fl

uoro

C13

H9F

N4

24

0.24

178

71

23.

32

23.

35

0.

50

S1

TA

BL

E 1

: PH

YSI

CA

L C

ON

STA

NT

S O

F N

-((Z

)BE

NZ

YL

IDIN

E)-

1H-P

YR

AZ

OL

O[3

,4-b

]PY

RID

INE

-3-A

MIN

E

S 1- T

olue

ne :

Met

hano

l -9:

1

Schiff Bases…


47

TABLE 2: BIOLOGICAL EVALUATION OF N-((Z)BENZYLIDINE)-1H-

PYRAZOLO[3,4-b] PYRIDINE-3-AMINE

Antibacterial Activity Antifungal activity

Minimal bactericidal concentration μg/ml

Gram +ve Bacteria Gram –ve Bacteria

Minimal fungicidal concentration

μg/ml Sr. No. Code

S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus

1 1a 250 250 200 1000 500 1000 1000 2 1b 1000 500 250 250 500 1000 1000 3 1c 200 200 100 200 500 500 500 4 1d 100 100 1000 250 250 500 500 5 1e 200 200 250 500 1000 500 500 6 1f 250 250 62.5 100 200 500 500 7 1g 500 1000 100 200 500 >1000 >1000 8 1h 200 200 200 250 250 500 500 9 1i 100 100 1000 500 1000 250 250

10 1j 1000 250 500 1000 500 >1000 >1000 11 1k 100 250 100 250 500 250 1000

MINIMAL INHIBITION CONCENTRATION

E.coli P.aeruginosa S.aureus S.pyogenus

Standard Drugs (microgramme/ml)

Gentamycin 0.05 1 0.25 0.5 Ampicillin 100 100 250 100 Chloramphenicol 50 50 50 50 Ciprofloxacin 25 25 50 50 Norfloxacin 10 10 10 10

MINIMAL FUNGICIDAL CONCENTRATION

C.Albicans A.Niger A.Clavatus Standard Drugs

(microgramme/ml) Nystatin 100 100 100 Greseofulvin 500 100 100

Schiff Bases…


48

ANTIBACTERIAL ACTIVITY:

From screening results, substituted schiff base 1f (R = -4-Cl) possesses very good

activity against E. coli compared with ampicillin while 1d (R = -4-N,N(CH3)2) and 1i (R=

-4-OCH3) against S.aureus and S.pyogenus, 1c (R= -4-OH) and 1g (R= -4-NO2) against

E-coli, 1k (R= -4-F) against S.aureus and E-coli possesses moderate activity compared

with ampicillin. The remaining schiff bases possess poor to very poor activity against all

four bacterial species.

ANTIFUNGAL ACTIVITY:

Antifungal screening data showed that substituted schiff bases 1f (R = -4-Cl) against

C. albicans show highly promising activity compare with standard drug while 1d (R = -4-

N,N(CH3)2 , and 1h (R = H) against C. albicans, 1k (R = -4-F) against A.niger while 1i (R = -

4-OCH3) against A.niger and A.clavatus shows very good activity compare with standard

drug. The remaining compounds exhibited only moderate to poor activity.

Schiff Bases…


49

SECTION II

SYNTHESIS AND BIOLOGICAL EVALUATION OF (E)-N-(1-((Z)PHENYL)

ETHYLIDENE)-1H-PYRAZOLO[3,4-b]PYRIDIN-3-AMINE

Schiff base play a vital role owing of their wide range of biological activity and

with an aim to getting better drug, it was considered worthwhile to synthesize some

azomethine derivatives of Type (III) by the condensation of 1H-Pyrazolo[3,4-b]Pyridine-

3-amine Type (I) with different aromatic acetophenones in order to study their

biodynamic behavior.

REACTION SCHEME

N

N

NH

NH2

O

CH3

N

N

NH

N

CH3

R

R

12.0 Hrs., Reflux

Ethanol

+

(Type III)

gl. CH3COOH

R = OH, Cl, NH2, CH3, OCH3 etc.

(Type I)

Schiff Bases…


50

The constitution of the synthesized products have been characterized by using

elemental analysis, infrared and 1H-nuclear magnetic resonance spectroscopy and further

supported by mass spectroscopy.





standard drugs.

Schiff Bases…


51

IR SPECTRAL STUDIES OF 2-((E)-1-(1H-PYRAZOLO[3,4-b]PYRIDIN-3-YL -

IMINO)ETHYL)PHENOL

Instrument: SHIMADZU FTIR 8400 Spectrophotometer; Frequency range:

4000-400 cm-1 (KBr disc.)

Frequency cm-1

Type

N NH

N

N C

CH3

HO

Vibration

Mode Observed Reported Ref.

Alkane

(Methane)

C-H str. (asym.)

C-H str. (sym.)

C-H def. (asym.)

C-H def. (sym.)

3022

2875

1467

1388

2975-2920

2880-2860

1470-1435

1395-1370

100

”

”

”

Aromatic

C-H str.

C=C

C-H i.p. def.

C-H o.o.p. def.

3091

1539

1157

846

3100-3000

1585-1480

1125-1090

860-810

”

”

”

”

Azomethine N=C str.

C-N str.

1666

1284

1650-1580

1350-1200

”

”

O-H str. 3414 3650-2590 ”

” Hydroxy

O-H def. 1346 1410-1310

Schiff Bases…


52

1H NMR SPECTRAL STUDIES OF 2-((E)-1-(1H-PYRAZOLO[3,4-b]PYRIDIN-3-

YLIMINO)ETHYL)PHENOL

Internal Standard: TMS; Solvent: CDCl3 Instrument: BRUKER Spectrometer (400

MHz)

Signal

No.

Signal Position

δppm

Relative No.

of Protons Multiplicity Inference

1

2

3

4

5

6

2.58

6.92-6.96

7.02-7.04

7.35-7.40

7.63-7.66

13.26

3H

3H

1H

2H

1H

1H

singlet

multiplet

-CH3

Ar-H(e,f,g)

doublet Ar-H(b)(J=8.0 Hz)

multiplet Ar-H(c,d)

multiplet Ar-H(a)

singlet -NH

Schiff Bases…


53

EXPANDED REGION

Schiff Bases…


54

MA

SS S

PEC

TR

UM

OF

N-(

1-(2

-HY

DR

OX

YPH

EN

YL

)ET

HY

LID

EN

E)-

1H-P

YR

AZ

OL

O[3

,4-b

]PY

RID

IN-3

-AM

INE

N

NH

NN

CH3C

HO

M/Z

= 2

52.1

Schiff Bases…


55

EXPERIMENTAL

SYNTHESIS AND BIOLOGICAL EVALUATION OF N-(1-

((Z)PHENYL)ETHYLIDENE)-1H-PYRAZOLO[3,4-b]PYRIDIN-3-AMINE

[A] SYNTHESIS OF 1H-PYRAZOLO[3,4-b]PYRIDINE-3-AMINE

See, Part-I Experimental [A].

[B] SYNTHESIS OF N-(1-(2-HYDROXYPHENYL)ETHYLIDENE)-1H-

PYRAZOLO[3,4-b]PYRIDIN-3-AMINE

A mixture of 1H-Pyrazolo[3,4-b]pyridine-3-amine (0.01 mol, 1.34 gm) and 2-

hydroxy acetophenone (0.01 mol, 1.36 gm) was taken in ethanol using catalytic amount

of gla. acetic acid. The reaction mixture was refluxed for 12 hrs. The product was isolated

and crystallized from absolute ethanol. Yield 87%; m.p.2020C.

Similarly other N-(1-((Z)phenyl)ethylidene)-1H-pyrazolo[3,4-b]pyridin-3-amine

were obtained. Various physical constants for all the synthesized compounds are given in

Table 3.

[C] BIOLOGICAL EVALUATION OF N-(1-((Z)PHENYL)ETHYLIDENE)-1H-

PYRAZOLO [3,4-b]PYRIDIN-3-AMINE

Antimicrobial testing were carried out as described in Experimental Section-I [C].

The results of test solutions are recorded in Table 4.

Schiff Bases…


56

Sr

.

R

Mol

ecul

ar

Mol

ecul

ar

M

.P.

Y

ield

% o

f Nitr

ogen

R

f

So

lven

t

N

o.

F

orm

ula

W

eigh

t

0 C

%

Cal

cd.

F

ound

Val

ue

Sys

tem

2

d

4-M

ethy

l

C

15H

14N

4

250

.30

150

85

2

2.38

22

.41

0

.62

S1

2

e

4-N

itro

C

14H

11N

5O2

2

81.2

7

29

5

7

0

24.

90

24.9

2

0.5

2

S

1

2

f

4

-Chl

oro

C14

H11

ClN

4

270

.72

241

78

2

0.70

20

.69

0

.50

S1

2

g

4

-Flu

oro

C

14H

11FN

4

25

4.26

232

9

0

22.

04

22.0

0

0.49

S 1

2

h

H

C

14H

12N

4

2

36.2

7

16

5

76

23.

71

23.7

2

0.5

7

S

1

1

2

3

4

5

6

7

8

9

10

2

a

2-H

ydro

xy

C14

H12

N4O

25

2.27

202

87

2

2.21

22

.20

0

.46

S1

2

b

4-H

ydro

xy

C14

H12

N4O

25

2.27

220

68

2

2.21

22

.23

0

.48

S1

2

i

4

-Met

hoxy

C15

H14

N4O

266

.30

180

91

2

1.04

21

.03

0

.51

S1

2

j

2

-Chl

oro

C14

H11

ClN

4

270

.72

1

92

83

2

0.70

20

.75

0

.53

S1

2

c

4-A

min

o

C

14H

13N

5

251.

29

19

8

60

27.

87

27.8

5

0.4

0

S

1

TA

BL

E 3

: PH

YSI

CA

L C

ON

STA

NT

S N

-(1-

((Z

)PH

EN

YL

)ET

HY

LID

EN

E)-

1H-P

YR

AZ

OL

O [3

,4-b

]PY

RID

IN-3

-AM

INE

S 1-H

exan

e : E

thyl

acet

ate-

7 :

3

Schiff Bases…


57

TABLE 4: BIOLOGICAL EVALUATION OF N-(1-((Z)PHENYL)

ETHYLIDENE)-1H-PYRAZOLO [3,4-b]PYRIDIN-3-AMINE Antibacterial Activity Antifungal activity

Minimal bactericidal concentration μg/ml

Gram +ve Bacteria Gram –ve Bacteria

Minimal fungicidal concentration μg/ml Sr.

No. Code

S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus

1 2a 100 1000 250 500 1000 200 200 2 2b 250 500 100 100 200 500 500 3 2c 250 250 200 200 250 1000 250 4 2d 200 1000 250 1000 >1000 >1000 >1000 5 2e 1000 100 250 200 500 500 200 6 2f 200 62.5 1000 100 200 250 500 7 2g 500 250 62.5 1000 500 >1000 1000 8 2h 200 200 100 100 1000 250 200 9 2i 1000 100 500 1000 1000 250 250

10 2j 100 200 250 200 250 500 500

MINIMAL INHIBITION CONCENTRATION

E.coli P.aeruginosa S.aureus S.pyogenus Standard Drugs

(microgramme/ml) Gentamycin 0.05 1 0.25 0.5 Ampicillin 100 100 250 100 Chloramphenicol 50 50 50 50 Ciprofloxacin 25 25 50 50 Norfloxacin 10 10 10 10

MINIMAL FUNGICIDAL CONCENTRATION

C.Albicans A.Niger A.Clavatus Standard Drugs

(microgramme/ml) Nystatin 100 100 100 Greseofulvin 500 100 100

Schiff Bases…


58

ANTIBACTERIAL ACTIVITY:

From screening results, substituted Schiff base 2f (R= -4-Cl) against S.pyogenus

while 2g (R= -4-F) against E-coli possesses excellent activity as compared with

ampicillin. 2a (R= -2-OH) and 2j (R= -2-Cl) against S.aureus, 2e (R= -4-NO2) against

S.pyogenus, 2b (R= -4-OH) and 2f (R= -4-Cl) against E-coli, 2b (R= -4-OH) and 2h (R=

-H) against P.aeruginosa possesses good activity against E-coli, The remaining schiff

bases possesses moderate to poor activity against all four bacterial species.

ANTIFUNGAL ACTIVITY:

Antifungal screening data showed that substituted schiff bases 2b (R= -4-OH) and

2f (R = -4-Cl) against C.albicans, 2a (R = -2-OH) against A.niger, 2e (R = -4-NO2)

against A.clavatus shows highly promising activity compare with standard drug. 2c (R = -

4-NH2) and 2j (R= -2-Cl) against C.albicans, 2c (R = -4-NH2) and 2f (R = -4-Cl) against

A.niger while 2i (R = -4-OCH3) against A.clavatus possesses good activity compare to

standard drug. The remaining compounds exhibited only moderate to poor activity.

Schiff Bases…


59

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Schiff Bases…

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