CHAPTER-7shodhganga.inflibnet.ac.in/bitstream/10603/32217/16... · inflammatory[1-6], inspite of...

Triazole derivatives

Dept. of Chemistry, MIT, Manipal University, Manipal. Page 244

CHAPTER-7

Contents Page no

Abstract 245

List of Tables 246

List of Figures 246

Section-1

7.1 Introduction 247-248

Section-2

7.2 Objective 248-249

Section-3

7.3 Review of literature 249-266

Section-4

7.4 Methodology

Experimental section

Synthetic procedure

266-269

Section-5

7.5 Results and Discussion

Physical Data

Characterization

Antimicrobial activity with data

Discussion

270-285

Section-6

7.6 Summary & Conclusion 285-286

Section-7

7.7 References 287-295



ABSTRACT

A new series of Schiff bases were obtained, after refluxing 4-amino-5-(substituted

phenoxymethyl)-2H-1, 2, 4-triazole-3(4H)-thione with salicyladehyde in ethanol in

the presence of catalytic amount of Conc. H2SO4. . The resulted Schiff bases were

stirred at room temperature for 48 hours in 40% HCHO / 20amine to get mannich

bases. The newly synthesized compounds were characterized by C, H, N analyses,

FT- IR, NMR and Mass spectroscopic techniques. Melting points were determined by

open capillary method and are uncorrected. All the newly synthesized compounds

were tested for their antimicrobial activities. Few of them exhibited significant and

highly significant activities with MIC at 125 μ/mL.



LIST OF TABLES

Sl.no Table Page no

7.1 Physical data of Schiff bases & Mannich bases 270

7.2 Antimicrobial activity data of Schiff bases &

Mannich bases

284

LIST OF FIGURES

Sl. no Figure Page no

7.1 IR spectrum of the compound 5a 274

7.2 1HNMR spectrum of the compound5a 275

7.3 Mass spectrum of the compound 5a 275

7.4 IR spectrum of the compound 5b 276

7.5 1HNMR spectrum of the compound 5b 276

7.6 Mass spectrum of the compound 5b 277

7.7 IR spectrum of the compound 5d 277

7.8 1HNMR spectrum of the compound 5d 278

7.9 Mass spectrum of the compound 5d 278

7.10 IR spectrum of the compound 6a 279

7.11 1HNMR spectrum of the compound 6a 279

7.12 Mass spectrum of the compound 6a 280

7.13 IR spectrum of the compound 6b 280

7.14 1HNMR spectrum of the compound 6b 281

7.15 Mass spectrum of the compound 6b 281



7.1INTRODUCTION

The 1, 2, 4-triazole is a five membered heterocyclic compound containing two

carbons and three nitrogens with a molecular formula of C2H3N3. It exists in two

tautomeric forms. 1H and 4H-1, 2, 4-triazole is considered to be pharmacologically

important nucleus. Schiff base, named after Hugo Schiff, is a compound that contains

the –C=N- (azomethine) group, synthesized by the condensation of primary/secondary

amines and active carbonyl groups. The reaction between Schiff base and secondary

amine in presence of catalytic amount of formaldehyde produces the corresponding

mannich base. Schiff bases and mannich bases have attracted much interest in the

development of pharmacologically active compounds. The present investigation is

concerned with synthesis of Schiff bases & Mannich bases with the objective of

discovering novel and potent antimicrobial agents. 1,2,4-triazoles and their derivatives

have been reported to show varied biological activities such as mainly anti-

inflammatory[1-6],

inspite of that antimicrobial, anticonvulsant, anticancer, analgesic,

anti HIV and properties were also exhibited. A literature search on recent years

suggest that there has been sustained interest in the application of Vilsmeier- Haack

reagent in organic synthesis. It has proved to be a mild and efficient reagent for the

formylation of reactive aromatic and hetero-aromatic substrates [7-8].

In this chapter we

reported some novel Schiff bases bearing salicylaldehyde moiety. Furthermore 1, 2, 4-

triazole derived schiff bases are used as substrates in the preparation of a number of

industrial and biologically active compounds via ring closure, cycloaddition and

replacement reactions [9].

Moreover, Schiff bases derived from various heterocycles

have been reported to possess cytotoxic [10],

anticonvulsant [11]

, anti-proliferative [12],

antimicrobial[13],

anticancer [14],

and antifungal [15],

anti-inflammatory activities[16].

Mannich bases were well known for their biological activity as antibacterial,



antifungal, anticancer and antiviral agents [17-18].

Schiff bases appear to be important

intermediates in a number of enzymatic reactions involving interaction of enzyme

with an amino or a carbonyl group of the substrate. Schiff bases derived from

aromatic amines and aromatic aldehydes have a great utility in important fields such

as medicine, agriculture, cosmetic products and wide variety of applications in

inorganic and analytical chemistry [19].

Some Schiff bases bearing aryl groups or

heterocyclic residues like triazole possess excellent pharmacological [20-63]

activities.

These biological data prompted us to synthesize new Schiff base derivatives bearing

1, 2, 4-triazole ring and the newly synthesized compounds were characterized by

C,H,N analyses, FT- IR,1HNMR& Mass spectral data. The newly synthesized

Mannich bases have shown significant antimicrobial activity as compare to newly

synthesized Schiff bases.

7.2 OBJECTIVE

It is clear from the literature review that a number of substituted triazole

derivatives are known for their antibacterial, anti-inflammatory, antifungal, antiviral,

antitubercolous, cyclo-oxygenase inhibitors, antinociceptive, hypoglycemic and

anticancer activities.

The present studies were performed with the following objectives:

1. To synthesize new substituted Schiff bases and Mannich bases bearing

salicylaldehyde moiety.

2. To characterize the structures of newly synthesized compounds by analytical

and spectral methods; viz, elemental analysis, Infrared spectra (IR spectra),

Nuclear Magnetic Resonance spectra (NMR spectra) and Mass spectra.



3. Screening for the antibacterial activity of the newly synthesized compounds

using gram-positive and gram-negative strains. Antifungal activity was carried

on Candida albicans.

7.3 REVIEW OF LITERATURE

As Antibacterial and Antifungal agents: Xin-Ping Hui et.al, prepared

variety of 5-(5-methylisoxazol-3-yl)-1, 3, 4-thiadiazoles, 1, 2, 4-triazoles and 1, 3, 4-

oxadiazoles and evaluated for their antibacterial potency .

B. Shivarama Holla et al, prepared variety of diaryloxymethyl-substituted-

1,2,4-triazolo [3, 4-b]-1, 3, 4-thiadiazoles and evaluated for antibacterial activity .

NN

NS

N

CH2 O Ar1

CH2

OAr

B. Shivarama Holla et al, prepared a series of 6-(5-aryl-2-furyl)-1, 2, 4-

triazolo [3, 4-b]-1, 3, 4-thiadiazoles and investigated for antibacterial potency .

2



NN

NS

N

R

Ar

B. Shivarama Holla et al, reported the synthesis of N-bridged heterocycles

such as triazolothiadiazoles, bistriazolothiadiazoles, triazolothiadiazines,

triazolothiadiazinones derived from 3-aryloxymethyl-4-amino-5-mercapto-1, 2, 4-

triazoles and evaluated for their antibacterial activity .

B. ShivaramaHolla et al, reported the synthesis of various bis–(4-amino-5-

mercapto-triazol-3-yl)alkanes, theirschiffs bases and bis-(1,2,4-triazolo[3, 4-b]-1, 3,

4- thiadiazol-4-yl]alkanes and investigated as potential bacterial agents.

3



K. Mogilaiah et al, prepared a series of 1-arylazetidino[2, 3-b][1, 8]

napthyridin2-(1H)-ones and 1-aryl-4-carbethoxy-1,2,4-triazolo[4, 3-a][1, 8]

naphthyridines and tested for antibacterial potency.

B. S. Sudha et al, reported the synthesis of 5-[(4-aroyl)aryloxymethyl]-2-(4-

methylphenylamino)-1,3,4-thiadiazoles and 5-[(4-aroyl)aryloxymethyl]-4-(4-methyl)-

3-mercapto-4H-1,2,4-triazoles and investigated as antibacterial agents.

O

N

NN

SH

CH3

RO

R1

T. K. Ravi et al, reported the synthesis of 1, 2, 4-triazoles derivatives of

anthranalic acid and for their antibacterial activity .

7



H2N

N

NN

R1

SH

V. V. Mulwad et al, had reported the synthesis of a series of

oxadiazolo(1,3,5)-triazines, 1,2,4-triazoles and thiadiazolo 1, 3, 4-oxadiazole

analogues and investigated for their antibacterial activity .

Umesh Kumar et al, reported the synthesis of 4-amino-5-aryl-1, 2, 4-

triazoles and screened for their antibacterial activity .

NN

N

NH2

SHR

Nizamuddin et al, reported the synthesis of 2-Aryl/aryloxy methyl-1, 3, 4-

oxa/thiadiazolo[4,5-b]1,2,4-triazolo[5,4-c]thiazolo-spiro-7-cyclohexanes and

investigated as fungicidal agents .

8

10



NN

O

N

N

S

R

Anees A Siddiqui et al, reported the synthesis of a series of 3-(p-substituted

anilinoethyl)-4-(p-substituted phenyl)-5-thioxo-1, 2, 4-triazoles and investigated as

active antifungal agents .

Qing-Yan Sun et al, prepared various 1, 2, 4-triazol-1-yl)-2-(2,4-

difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl)-propan-2-olsand

investigated for their antifungal potency .

11



NN

NH

N

N N

OH

F

F

R R1

Yong Sun et al, synthesized 2-alkylamino-3-aryl-6-(1H)-1,2,4-triazol-1-yl)-

thieno (2, 3-d)-pyrimidin-4(3H)-ones and evaluated for fungicidal activity.

F3C

N

N

N

N

CH3

OR

Jag Mohan et al, synthesized s-triazolo[3,4 b)[1,3,4]thiadizoles, s-

triazolo(3, 4 – b)[1, 3, 4]thiadiazines and triazolo(3’, 4’-2, 3)[1, 3, 4-thiadizino[5, 6-

b]quinoxalines and evaluated for antimicrobial potency .

13

14



N

N

N NH

S

N

N

N

S

NH

S

Ph

Ph

Jagmohan et al, prepared s-triazolo[3, 4-b][1, 3, 4] thiadiazoles and s-

triazolo[3, 4-b][1, 3, 4]thiadiazines and evaluated for antifungal and antibacterial

activities .

N

N

NS

HN

OR

N

N

NS

N

R

R

NN

N

S

HN

SH

R

H. M. Hirpara et al, synthesized a series of 6-aryl-3-pyridin-4-yl-5, 6-

dihydro[1, 2, 4]-triazolo[3, 4-b][1, 3, 4]-thiadiazoles and investigated for

antimicrobial activity.

15

16



G. M. Srinivasa et al, reported the synthesis of 8-fluoro-9-substituted (1,3)-

benzothiazolo(5,1-b)-3-substituted triazoles and investigated for their antimicrobial

activities .

Arun Kumar Wahi et al, prepared N-(substituted benzylidene)-2-(N-(4H-

1,2,4-triazole-4-yl)benzamido)acetohydrazides and N-((5-substitutedaryl)-1, 3, 4-

oxadiazole-2-yl)methyl-N-(4H-1, 2, 4-triazole-4-yl)benzamides and screened for

antibacterial and antifungal activity .

Mudasir Rashid Banday et al, reported the synthesis of substituted triazoles

and thiazolidinones from fatty acids and screened for antimicrobial activity.



B. A. Baviskar et al, synthesized thiazolyltriazole substituted azetidinone

derivatives and evaluated for their antimicrobial activity.

N

S

CH3

N

N

N

N R

HNOCH3C

Bahittin Kahveci et al, reported the synthesis of 3-alkyl-4-

(arylmethyleneamino) 4,5-dihydro-1H-1, 2, 4-triazol-5-one derivatives and screened

for the antimicrobial activity.

NN

N

CONHNH2

O

HN

Ar

21

22



R. Shivakumar et al, synthesized 3-aryl-oxymethyl-4-[2-

(benzimidazolylthio)acetamide]-5-mercapto-1,2,4-triazoles and evaluated for their

antimicrobial activities.

Jag Mohan prepared a series of s-triazolo(3, 4-b)(1, 3, 4)thiadiazoles, s-

triazolo (3, 4-b)(1, 3, 4) thiadiazines and screened for their antibacterial and

antifungal activities.

N

S

HN

N

N

OH

ON

N

N

OH

S

N

Cl

Chang–Hu Chu et al, prepared a series of ω-(5-arylamino-1, 3, 4-thiadiazol-

2-thiol)-ω-(1H-1, 2, 4-triazol-yl)acetophenones and screened for antifungal and

growth regulatory activities .

24



N

S

N

N

S

NN

NH

Ar

O

Balakrishna Kalluraya et al, prepared 3-alkyl-/aryl-9-substituted 1, 2, 4-

triazolo[3, 4-b][1, 3, 4]quinolinothiadiazipines and selected compounds were screened

for their antibacterial and antifungal activities .

S

N

N

N

N

R1

R

Nasser S. A. M. Kalil synthesized N-and S-α-Larabinopyranosyl [1, 2,

4]triazolo[3, 4-b][1 ,3, 4]thiadiazoles and investigated for antimicrobial potency .

S

N

N

NN

S

OOH

OH

OH

R

D. K. Swamy et al, synthesized 3-substituted(1, 2, 4)-triazolo[3,4-b]1, 2-

benzisoxazole derivatives and tested for their antimicrobial activity .

25

27

26



N

O

NN

SH

As diuretic agents: Jag Mohan reported the synthesis of 3-(2-thienyl)-s-

triazolo[3,4-b][1, 3, 4]-thiadiazole, 2-(2-thienyl)thiazolo[3,2-b]-s-triazole and

isomeric 3-(2-thienyl)-thiazolo(2,3-c)-s-triazole and screened for their diuretic,

antibacterial and antifungal activities.

As anti-inflammatoty agents: Arun K. Wahi et al, synthesized the series of

N-substituted benzylidene)-2-N-(4H-1, 2, 4-triazole-4yl) benzamidoacetohydrazides

and evaluated for antimicrobial and anti-inflammatory activities.

N NHNH

N

NN

O

O

R

Ram Janam Singh et al, synthesized 1, 2, 4-triazolothiadiazines, 1, 2, 4-

triazolothiadiazinones and evaluated for anti-inflammatory activity .

28

30



N

N S

N

N

NAr

PhPh

O

N

N S

N

N

NAr

PhO

O

As anticancer agents: Olcay Bekircan et al, reported the synthesis of various

4-arylidenamino-4H-1, 2, 4-triazoles, 4-(1-aryl)ethylidenamino-4H-1, 2, 4-triazoles,

4-arylmethyl amino-4H-1, 2, 4-triazoles, 4-(1-aryl)ethylamino-4H-1, 2, 4-triazoles

and investigated as weak anticancer agents .

Wageeshl Hamouly et al, reported the synthesis of N-substituted sulphonyl,

1, 2, 4-triazole, N-substituted benzylidene and pyrazole analogues bearing 4-

(benzo(d)thiazol-2-yl)benzohydrazide and evaluated for antibreast cancer activity .

31



Hend A. A. Abd El-Wahab et al, synthesized substituted 1, 2, 4- triazole-3-

acetic acid derivatives and evaluated for antitumor and anti-inflammatory activities .

As antitubercular agents: Shashikant Patten et al, reported the synthesis of

5-mercapto 1, 2, 4-triazolederivatives and evaluated for antimicrobial,

antiinflammatory, antitubercular activities .

Mahendra Ramesh Shiradkar et al, reported the synthesis of various

derivatives of N-{4-[(4-amino-5-sulphanyl-4H-1, 2, 4-triazol-3-yl)methyl]-1,3-

thiazol-2-yl}-2-substituted amides and tested for antibacterial and antitubercular

potency .



Mahendra Shiradkaretal, synthesized analogues of thiazolyltriazoles and

tested for their antimycobacterial and antimicrobial activities.

N

S NN

N

HN

S

N

NN

R

O

NH2

SH

As anticonvulsant agents: Hong Guang Jin et al.,reported the synthesis of 7-

alkoxy-4,5-dihydro[1, 2, 4]triazolo[4,3-a]quinoline1(2H)-ones and investigated for

anticonvulsant activity and neurotoxicity.

N

NH

N

OR

O

37

38



S. Moreau et al., reported the synthesis of 3-amino-7-(2,6-dichlorobenzyl)-

6-methyltriazolo[4,3-b]pyridine derivatives of amide and carboxylic acid and

investigated for their anticonvulsant potency.

Dayanand Kadadevar et al., reported the synthesis and evaluation of N-

(substitutedphenyl)-2-[5-phenyl-2H-1, 2, 4-triazol-3-yl-amino]acetamide for their

anticonvulsant activity .

NHN

NNH

HN

R1

R2

R3

R4

O

Ph

As Anxiolytic agents: Anil M. Manikaro et al, synthesized

carboxamidoethylthio-(4H)-1, 2, 4-triazolesand evaluated for anxiolytic, anti-

inflammatory, analgesic activity .

NN

NH

S HN R

O

41

40



As Antioxidant agents: M. Suresh et al, reported the synthesis of 8-chloro-

1,4-substituted (1, 2, 4[4, 3-a]quinoxalines and evaluated for antioxidant and

antimicrobial activity .

As Human V1A receptor antagonists: Akio Kakefuda et al, synthesized 5-

(4-biphenyl)-3-methyl 4-phenyl-1, 2, 4-triazole derivatives and investigated as

selective antagonists for the human vasopression V1A receptor.

As PPAR α-agonists: Yan Ping Xu et al., reported the design and synthesis

of various 2, 4-dihydro-3H-1, 2, 4-triazol-3-one, and investigated as most potent and

selective PPAR α-agonist .



N

NH

NO

OH

H3C

CH3

O

O

H3C

As Analgesic agents: P. K. Goyal et al., were synthesized s-substituted -4-

(3-disubtituted-1-triazenyl)-4H-1, 2, 4-triazol-5-thiol and tested for analgesic activity .

N

N

N

R SH

N N N

R1

R2

7.4 MEHODOLOGY

7.4.1 EXPERIMENTAL SECTION

Melting points were taken in open capillaries and are uncorrected. Infra-red

spectra (KBr in cm-1

) were recorded on 8400S, Shimadzu FT-IR spectrophotometer.

1H-NMR spectra were measured by Bruker Ascend-TM 400MHz-NMR spectrometer,

deuterated solvents such as dimethyl-sulphoxide (DMSO-d6), methanol (CD3OD) and

also chloroform (CDCl3) were used as solvents and the chemical shifts were quoted as

δ-value relative to tetramethylsilane (TMS, δ=O) as an internal standard. Mass

spectra were recorded on LC-MS Schimadzu 2010A spectrometer. The elemental

analysis was carried out on a Perkin Elmer CHN analyzer. The purity of the

compounds was monitored by thin layer chromatography on silica gel plates and

iodine was used as a visualizing agent.

44

45



7.4.2 SYNTHETIC PROCEDURE

7.4.2.1 Synthesis of ortho & para substituted ethyl phenoxy acetate (1)

A mixture of phenol (0.05 mol), ethylchloroacetate (0.05mol) was refluxed in

dry acetone in presence of potassium carbonate for 24 hours on water bath. The

reaction mixture was cooled and filtered, the excess solvent was distilled and the solid

thus separated was recrystallized from ethanol.

7.4.2.2 Synthesis of substituted 2-phenoxyacetohydrazide (2)

A mixture of compound (1) (0.05 mol), hydrazine hydrate (0.07 mol) in

ethanol was refluxed for 6 hours. The excess of solvent is distilled off and the solid

thus separated was recrystallized from ethanol.

7.4.2.3 Synthesis of potassium 2-(2-(substituted phenoxy) acetyl)

hydrazinecarbodithioate (3)

Compound 2(0.001mol) was dissolved in alcoholic KOH, then drop wise CS2(0.001

mol) was added to get 2-(2-(substitutedphenoxy)acetyl)hydrazinecarbodithioate. After

few minutes solid was obtained, filtered and dried to get salt.

7.4.2.4 Synthesis of 4-amino-5-((substituted phenoxy)methyl)-4H-1,2,4-triazole-3-

thiol (4)

A mixture of Salt 3 (0.001 mol) and hydrazine hydrate (0.001 mol) was

refluxed for 24 hrs. After complete evolution of carbondisuphide, the mixture was

poured into ice cold water. The solid separated was filterd, dried and recrystallized

from ethanol.



7.4.2.5 Synthesis of(E)-5-((substituted phenoxy)methyl)-4-(2-hydroxybenzy-

lideneamino)-2H-1, 2, 4-triazole-3(4H)-thione (5a-h)

A mixture of 4-amino-5-((substituted phenoxy)methyl)-4H-1, 2, 4-triazole-3-

thiol (4) and salicyladehyde was refluxed in ethanol for 10 hours in catalytic amount

of Conc. H2SO4.Then solvent was distilled off and residue was poured to crushed ice.

The solid separated was filtered, dried and recrystallized from ethanol.

7.4.2.6 Synthesis of (E)-5-((substituted phenoxy)methyl)-4-(2-hydroxybenzy-

lideneamino)-2-((substituted lpiperazin-1-yl)methyl)-2H-1, 2, 4-triazole-3(4H)-

thione (6a-b)

Schiff base (0.001 mol) (5) was dissolved in 1,4-dioxan, then 40% HCHO

(0.001 mol) was added in dropwise followed by the addition of secondary amine

(0.001 mol), then stirred for 48 hours to get (E)-5-((substituted phenoxy)methyl)-4-(2-

hydroxybenzylideneamino)-2-(substituted lpiperazin-1-yl)methyl)-2H-1, 2, 4-triazole-

3(4H)-thione. The resultant mixture was poured to crushed ice, filtered, dried and

recrystallized from DMF.

OH + CLCH2COOC2H5

K2CO3, AcetoneOCH2COOC2H5

OCH2-C=O

NH-NH2

Alc KOH,CS2

OCH2C=O

NH-NH-C=S

S K-

+

H2N-NH2

N

N N

NH2

SHO

OH + CLCH2COOC2H5

K2CO3, AcetoneOCH2COOC2H5

OCH2-C=O

NH-NH2

Alc KOH,CS2

OCH2C=O

NH-NH-C=S

S K-

+

H2N-NH2

N

N N

NH2

SH

RR

RR

R

Stirring 24 hrs

NH2 NH2



OCH2

NN

NSH

NH2

+

CHO

OH

Conc.H2SO4

OCH2

NHN

S

N CH

OH

40%HCHO/Piperzine

OCH2

NN

NS

N

H2C N

CH

OH

NH

OCH2

NN

NS

N

H2C N

CH

OH

N CH3

40%HCHO/N-methyl Piperzine

4

5

6

R

R

RR



7.5 RESULTS AND DISCUSSION

Table-7.1: Physical properties of Schiff bases (2a-h) & Mannich bases (3a-b).

Code R Molecular

Formula

M.W M.P(0

C) Yield

(%)

5a -H C16

H14

N4O

2S 326 120 72

5b 4-CH3 C

17H

16N

4O

2S 340 156 65

5c 2-CH3 C

17H

16N

4O

2S 340 162 60

5d 2-Cl C16

H13

ClN4O

2S 360 170 74

5e 2,4-Cl C16

H12

Cl2N

4O

2S 395 175 72

5f 2,4,6-Cl C16

H11

Cl3N

4O

2S 429 181 65

5g 4-OCH3 C

17H

16N

4O

3S 356 156 67

5h 4-NO2 C

16H

13N

5O

4S 371 123 35

6a 4-CH3 C

23H

28N

6O

2S 452 157 45

6b -H C21

H24

N6O

2S 424 153 50

CHARACTERISATION

(E)-4-(2-hydroxybenzylideneamino)-5-(phenoxymethyl)-2H-1,2,4-triazole-3(4H)-

thione(5a)

IR(KBr)(cm-1

): 3340.48(O-H str), 3309.62(N-H-str), 2916.17 (alkyl C-H str),

1620.09 & 1596.95 (C=N str), 1488.94 (Ar-C=C str),1300.00(C=S str),1064.63 (C-O-

C str). 1

H-NMR(400 MHz, ppm): δ11.8(1H, s, O-H), 10.3(1H, s, N-H), 9.8(1H, s,

N=CH), 7.8-6.8 (9H, m,Ar-H), 5.2(2H, s, OCH2). MS(m/z): 326 (M

+); Anal. Calcd

(found) for C17H16N4O2S, C,60.00(59.01);H, 4.70(4.68);N,16.47(16.38);S, 9.41(9.00).



(E)-4-(2-hydroxybenzylideneamino)-5-(p-tolyloxymethyl)-2H-1,2,4-triazole-

3(4H)-thione (5b)

IR(KBr)(cm-1

): 3340.48(O-H str),3309.62(N-H-str), 1627.81 (C=N str), 1488.94

(Ar-C=C str), 1380.00(C=S str),1149.50 (C-O-C str). 1

H-NMR(400 MHz, ppm):

11.8(1H, s, O-H), 10.6(1H, s, N-H), 9.7(1H, s, N=CH), 7.8-6.8 ( 8H, m, Ar-H),

5.2(2H, s, OCH2),2.3(3H, s, CH

3). MS(m/z): 340 (M

+); Anal. Calcd (found) for

C17H16N4O2S, C,60.00(59.01); H,4.70(4.68); N, 16.47(16.38); S, 9.41(9.00).

(E)-4-(2-hydroxybenzylideneamino)-5-(o-tolyloxymethyl)-2H-1,2,4-triazole-

3(4H)-thione (5c)

IR(KBr)(cm-1




11.3(1H, s, O-H), 10.2 (1H, s, N-H), 9.6(1H, s, N=CH), 7.8-6.8 ( 8H, m, Ar-H),

5.2(2H, s, OCH2),2.3(3H, s, CH

3). MS(m/z): 340 (M


C16H13ClN4O2S, C,53.33(52.28); H,3.61(3.47); N, 15.55(15.51);S, 8.88(8.83),

(E)-5-((2-chlorophenoxy)methyl)-4-(2-hydroxybenzylideneamino)-2H-1,2,4-

triazole-3(4H)-thione(5d)

IR(KBr)(cm-1

): 3350.48(O-H str), 3200.00(N-H-str), 3000.00(Ar-C-H str), 2970.00

(alkyl C-H str), 1640.95 & 1596.95 (C=N str), 1434.94 (Ar-C=C str),1350.00(C=S

str),1150.00 (C-O-C str).1

H-NMR(400 MHz, ppm): δ11.1(s,1H,O-H), 10.1(s, 1H, N-

H), 9.0 (s, 1H, N=CH), 7.8-6.8 (m, 8H, Ar-H), 5.2(s, 2H, OCH2). MS(m/z): 360 (M

+);

Anal. Calcd (found) for C16H12Cl2N4O2S,C, 48.60(47.52);H, 3.03(3.00); N,

14.17(14.11); S, 8.10(8.07).



(E)-5-((2,4-dichlorophenoxy)methyl)-4-(2-hydroxybenzylideneamino)-2H-1,2,4-

triazole-3(4H)-thione (5e)

IR(KBr)(cm-1



str),1152.03 (C-O-C str).1



+);

Anal. Calcd (found) for C16H11Cl3N4O2S,C, 44.75(43.70);H, 2.56(2.51);N,

13.05(13.00);S, 7.45(7.40).

(E)-4-(2-hydroxybenzylideneamino)-5-((2,4,6-trichlorophenoxy)methyl)-2H-

1,2,4-triazole-3(4H)-thione (5f)

IR(KBr)(cm-1



str),1180.18 (C-O-C str).1



+);

Anal. Calcd (found) for C17H16N4O3S,C, 57.30(56.25);H, 4.49(4.47);N,15.73(15.70);

S, 8.98(8.90).

(E)-4-(2-hydroxybenzylideneamino)-5-((4-methoxyphenoxy)methyl)-2H-1,2,4-

triazole-3(4H)-thione (5g)

IR(KBr)(cm-1




12.1(1H, s, O-H), 10.4(1H, s, N-H), 9.3(1H, s, N=CH), 7.8-6.8 ( 8H, m, Ar-H),



5.3(2H, s, OCH2),2.3(3H, s, CH

3). MS(m/z): 356 (M


C16H13N5O4S, C, 51.75(50.70);H, 3.50(3.48);N,18.61(18.55); S,8.62(8.58).

(E)-4-(2-hydroxybenzylideneamino)-5-((4-nitrophenoxy)methyl)-2H-1,2,4-

triazole-3(4H)-thione (5h)

IR(KBr)(cm-1

): 3390.48(O-H str), 3327.62(N-H-str), 2916.17 (alkyl C-H str),

1620.09 & 1598.95 (C=N str), 1487.94 (Ar-C=C str),1338.00(C=S str),1164.63 (C-O-

C str). 1

H-NMR(400 MHz, ppm): δ11.9(1H, s, O-H), 10.2(1H, s, N-H), 9.6(1H, s,

N=CH), 7.8-6.8 (8H, m,Ar-H), 5.3(2H, s, OCH2). MS(m/z): 371 (M

+); Anal. Calcd

(found) for C16H14N4O2S,C, 58.89(57.85);H,4.29(4.24); N, 17.17(17.13);S,

9.80(9.72).

(E)-4-(2-hydroxybenzylideneamino)-2-((4-methylpiperazin-1-yl)methyl)-5-(p-

tolyloxymethyl)-2H-1,2,4-triazole-3(4H)-thione (6a)

IR(KBr)(cm-1


(alkyl C-H str), 1620.09 & 1596.95 (C=N str), 1473.51 (Ar-C=C str), 1326.93(C=S

str). 1

H-NMR(400 MHz, ppm): δ9.8(1H, s, O-H), 8.7(1H, s, N=CH), 7.8-6.8 (8H,

m, Ar-H), 5.3( 2H, s, >N-CH2-N<), 5.2( 2H, s , OCH

2), 2.6(4H, s, -N-CH

2-CH

2-N-),

2.3(3H, s, CH3), 2.2(3H, s, >N-CH

3). MS(m/z): 452 (M


C23H28N6O2S,C, 61.06(60.00);H, 6.19(6.13);N, 18.58(18.52);S, 7.07(7.01).



(E)-4-(2-hydroxybenzylideneamino)-5-(phenoxymethyl)-2-(piperazin-1-ylmethyl)

-2H-1,2,4-triazole-3(4H)-thione (6b)

IR(KBr)(cm-1


(alkyl C-H str), 1620.09 (C=N str), 1481.23 (Ar-C=C str), 1326.93(C=S str). 1

H-

NMR(400 MHz, ppm): 12.6(1H, s, O-H), 9.7(1H, s, N-H), 8.7(1H, s, N=CH), 7.8-

6.8 (9H, m, Ar-H), 5.2(2H, s, >N-CH2-N<), 5.1(2H, s, OCH

2), 2.6( 4H, s, -N-CH

2-

CH2-N-). MS(m/z): 424 (M

+); Anal. Calcd (found) for C21H24N6O2S, C,

59.43(58.40);H, 5.66(5.61);N,17.81(17.78);S,7.54(7.50)

Fig-7.1: IR spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-(phenoxymethyl)-

2H-1,2,4-triazole-3(4H)-thione (5a).

OH2C

N

NHN

N

OH

S



Fig-7.2: NMR spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-

(phenoxymethyl)-2H-1,2,4-triazole-3(4H)-thione (5a).

Fig-7.3: Mass spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-

(phenoxymethyl)-2H-1,2,4-triazole-3(4H)-thione (5a).

OH2C

N

NHN

N

OH

S

OH2C

N

NHN

N

OH

S



Fig-7.4: IR spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-(p-

tolyloxymethyl)-2H-1,2,4-triazole-3(4H)-thione (5b).

Fig-7.5: NMR spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-(p-




Fig-7.6: Mass spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-(p-


Fig-7.7: IR spectrum of (E)-5-((2-chlorophenoxy)methyl)-4-(2-hydroxybenzy-

lideneamino)-2H-1,2,4-triazole-3(4H)-thione (5d).

OH2C

N

NHN

N

OH

SCl



Fig-7.8: NMR spectrum of (E)-5-((2-chlorophenoxy)methyl)-4-(2-hydroxybenzy-


Fig-7.9: Mass spectrum of (E)-5-((2-chlorophenoxy)methyl)-4-(2-hydroxybenzy-


OH2C

N

NHN

N

OH

SCl

OH2C

N

NHN

N

OH

SCl



Fig-7.10: IR spectrum of (E)-4-(2-hydroxybenzylideneamino)-2-((4-

methylpiperazin-1-yl)methyl)-5-(p-tolyloxymethyl)-2H-1,2,4-triazole-3(4H)-

thione (6a).

Fig-7.11: NMR spectrum of (E)-4-(2-hydroxybenzylideneamino)-2-((4-


thione (6a).

OH2C

N

NN

N CH

OH

S

H2C N N CH3

H3C

OH2C

N

NN

N CH

OH

S

H2C N N CH3

H3C



Fig-7.12: Mass spectrum of (E)-4-(2-hydroxybenzylideneamino)-2-((4-


thione (6a).

Fig-7.13: IR spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-

(phenoxymethyl)-2-(piperazin-1-ylmethyl)-2H-1,2,4-triazole-3(4H)-thione (6b)

OH2C

N

NN

N CH

OH

S

H2C N N CH3

H3C

OH2C

N

NN

N CH

OH

S

H2C N NH



Fig-7.14: NMR spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-


Fig-7.15: Mass spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-


OH2C

N

NN

N CH

OH

S

H2C N NH

OH2C

N

NN

N CH

OH

S

H2C N NH



Antimicrobial activity

Medium: Mueller Hinton agar (MHA) (For antibacterial activity)

Medium: Sabaroud Dextrose Broth (SDB) (For antifungal activity)

Bacteriaselected: Basillus subtilis, Staphylococcus aureus, Seretia marcescens,

Escheritia coli, Salmonella typhi.

Fungus selected: Candida albicans.

StdDrug: Ciprofloxacin (For bacteria).

Stddrug: Amphoterecin B ( For fungus).

Procedure of antibacterial activity

Preparation of MHA solution: In 250 mL conical flask a known weight of MHA

powder (2.1g) was taken, then dissolved it in 100 ml distilled water. To the mixture

about 2.8% agar was added. Then mouth of the conical flask was covered with cotton

and paper. The conical flask was transferred to autoclave for sterilization at 1210C

(15lbs PSIG) for 15 minutes.

Approximately 20ml of molten MHA was added in 100 mm sterile glass

petriplate. Plates were allowed to cool at room temperature until agar was solidified.

50 μ/L of test culture was added on solidified agar surface of 100 mm petriplate.

Entire surface of agar was swabbed using sterile spreader ensuring an equal

distribution of inoculum. Finally the edges of agar were swabbed. Wells were

punched in the agar using sterile borer. 50 μl of test compound & standard drug were

dispensed in respective wells. Plates were then kept in a refrigerator for 30-45 minutes

& then incubated at 370C for 18-24 hours. After incubation, diameters of zone of

complete inhibition (including diameter of the well) were measured in mm using

antibiotic zone reader.



Procedure for antifungal activity:

Preparation of SDA solution: In 250 mL conical flask a known weight of Saboraud

Dextrose Broth powder (1.5g) was taken, then dissolved it in 50 ml distilled water. To

the mixture about 2.8% agar was added. Then mouth of the conical flask was covered

with cotton and paper. The conical flask was transferred to autoclave for sterilization

at 1210C (15lbs PSIG) for 15 minutes. Approximately 20ml of molten SDB was

added in 100mm sterile glass petriplate. Plates were allowed to cool at room

temperature until agar was solidified. 50 μ/L of test culture was added on solidified

agar surface of 100 mm petriplate.

Entire surface of agar was swabbed using sterile spreader ensuring an equal

distribution of inoculum. Finally the edges of agar were swabbed. Wells were

punched in the agar using sterile borer. 50 μl of test compound & standard drug were

dispensed in respective wells. Plates were then kept in a refrigerator for 30-45 minutes

& then incubated at 370C for 18-24 hours. After incubation, diameters of zone of

complete inhibition (including diameter of the well) were measured in mm using

antibiotic zone reader.



Table-7.2: Antimicrobial activity data of Schiff bases (5a-h) & Mannich bases

(6a-b)

Code R Antibacterial activity Zone of inhibition (in mm)

Antifungal

activity Zone of

inhibition (in

mm)

B.

subtilis S.

marcescens E.

Coli S.

typhi S.

aureus C.

albicans

5a 4-CH3 -- 12 12 13 8 ---

5b 2-CH3 _ 10 12 15 7 ---

5c 4-Cl _ 10 10 15 10 ---

5d 2,4-Cl _ 13 12 15 13 ---

5e 2,4,6-Cl _ 11 13 15 13 ---

5f 4-OCH3 _ 9 8 13 12 ---

5g 4-NO2 -- --- --- 15 10 ---

5h -H 5 _ 12 10 13 ---

6a 4-CH3 30 26 23 28 32 ---

6b -H 5 _ _ 10 15 ---

Ciplofloxacin --- 37 33 37 36 35 ---

Amphoterecin

B --- --- --- --- --- 23

DISCUSSION

1,2,4-triazole derivatives have shown significant various pharmacological activity.

Schiff bases i.e., (E)-5-((substituted phenoxy)methyl)-4-(2-hydroxybenzy-

lideneamino)-2H-1,2,4-triazole-3(4H)-thione derived from 1,2,4-triazole played

important role as new medicinal agents. Keeping this in view some Schiff bases and

mannich bases are synthesized from 1, 2, 4-triazole derivatives. The newly



synthesized Schiff and Mannich bases were obtained with good yield. The derivatives

have shown sharp melting points, which is carried out by open capillary method and

are uncorrected. All the synthesized compounds are characterized by IR, 1NMR, Mass

and elemental analysis. In the IR spectra the peak observed at 1600-1640 cm-1

indicates the presence of –N=CH- (imine) & peak observed at about 1350 cm-1

confirms the presence C=S in the Schiff base. The peak observed in the 1NMR spectra

at 9-10 ppm due to the presence of –CH- proton in the imine functional group. The

peak observed at 12-13 ppm for triazole is due to the presence of –SH proton, which

is disappeared in the 1NMR spectra of Schiff & Mannich bases. All the newly

synthesized compounds are tested for antimicrobial activity. The compound 6a has

shown significant antibacterial activity against all selected bacteria due to n-methyl

piperzine moiety. The remaining compounds have shown moderate activity against

some of microorganisms. It is not showing any activity against fungus. Hence further

fungal study has’nt been done, because C. albican is the most susceptible for most of

the drug.

7.6 SUMMARY & CONCLUSION

The objective of the present study is aimed to synthesize, characterize and also

to evaluate the antimicrobial activity of some new Schiff and Mannich bases derived

from 1,2,4-triazole derivatives.

The synthesis of the 1, 2, 4-derivatives comprises of six steps which are as

follows



1. Synthesis of ortho & para substituted ethyl phenoxy acetate (1) after refluxing a

mixture of phenol & ethylchloroacetate in dry acetone in presence of potassium

carbonate for 24 hours on water bath.

2. Substituted 2-phenoxyacetohydrazide (2) was obtained after refluxing a mixture

of compound (1) and hydrazine hydrate in ethanol.

3. Synthesis of potassium 2-(2-(substituted phenoxy)acetyl)hydrazinecarbodithioate

(3), When the Compound (2) was stirred in alcoholic KOH with CS2.

4. 4-amino-5-((substituted phenoxy)methyl)-4H-1,2,4-triazole-3-thiol (4) was

obtained from a mixture of Salt (3) and hydrazine hydrate.

5. Schiff bases i.e., (E)-5-((substituted phenoxy)methyl)-4-(2-hydroxybenzy-

lideneamino)-2H-1,2,4-triazole-3(4H)-thiones (5) were obtained after refluxing a

mixture of 4-amino-5-((substituted phenoxy)methyl)-4H-1,2,4-triazole-3-thiol (4)

and salicyladehyde in ethanol.

6. (E)-5-((substitutedphenoxy)methyl)-4-(2-hydroxybenzylideneamino)-2-

((substitutedpiperazin-1-yl)methyl)-2H-1,2,4-triazole-3(4H)-thiones (6) were

obtained, when a mixture of Schiff bases were dissolved in 1,4-dioxan, then 40%

formaldehyde was added in dropwise followed by the addition of secondary

amine. The present study revealed that 1, 2, 4-triazole derivatives are the

significant class of heterocyclic compounds and showed promising

pharmacological activities like antibacterial, antifungal, antitubercular,

antioxidant, anticancer, antiinflammatory, analgesic, anticonvulsant, anxiolytic,

activities. These observations have been useful for the development of 1, 2, 4-

triazole nucleus which can be taken as a lead for future development to get safer

and effective compounds.



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