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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
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 245
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.
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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
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 247
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,
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 248
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.
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 249
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 .
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 250
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.
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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 .
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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
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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 .
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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 .
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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.
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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.
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 257
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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 258
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 .
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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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 260
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
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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 .
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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 .
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 263
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
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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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 265
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 .
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 266
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.
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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.
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 268
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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 269
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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 270
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).
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 271
(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
): 3343.48(O-H str),3320.62(N-H-str), 1620.81 (C=N str), 1488.94
(Ar-C=C str), 1380.00(C=S str),1179.50 (C-O-C str). 1
H-NMR(400 MHz, ppm):
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
+); Anal. Calcd (found) for
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).
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 272
(E)-5-((2,4-dichlorophenoxy)methyl)-4-(2-hydroxybenzylideneamino)-2H-1,2,4-
triazole-3(4H)-thione (5e)
IR(KBr)(cm-1
): 3350.48(O-H str), 3222.00(N-H-str), 3010.07(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),1152.03 (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, 7H, Ar-H), 5.2(s, 2H, OCH2). MS(m/z): 395 (M
+);
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
): 3350.48(O-H str), 3200.00(N-H-str), 3017.07(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),1180.18 (C-O-C str).1
H-NMR(400 MHz, ppm): δ11.3(s,1H,O-H), 10.6(s, 1H, N-
H), 9.3 (s, 1H, N=CH), 7.8-6.8 (m, 6H, Ar-H), 5.3(s, 2H, OCH2). MS(m/z): 429 (M
+);
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
): 3370.48(O-H str),3319.62(N-H-str), 1636.81 (C=N str), 1434.94
(Ar-C=C str), 1380.00(C=S str),1160.50 (C-O-C str). 1
H-NMR(400 MHz, ppm):
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),
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 273
5.3(2H, s, OCH2),2.3(3H, s, CH
3). MS(m/z): 356 (M
+); Anal. Calcd (found) for
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
): 3433.06(O-H str), 3247.90(N-H-str), 3001.03(Ar-C-H str), 2923.88
(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
+); Anal. Calcd (found) for
C23H28N6O2S,C, 61.06(60.00);H, 6.19(6.13);N, 18.58(18.52);S, 7.07(7.01).
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 274
(E)-4-(2-hydroxybenzylideneamino)-5-(phenoxymethyl)-2-(piperazin-1-ylmethyl)
-2H-1,2,4-triazole-3(4H)-thione (6b)
IR(KBr)(cm-1
): 3456.20(O-H str), 3433.06(N-H-str), 3047.32(Ar-C-H str), 2923.88
(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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 275
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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 276
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-
tolyloxymethyl)-2H-1,2,4-triazole-3(4H)-thione (5b).
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 277
Fig-7.6: Mass spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-(p-
tolyloxymethyl)-2H-1,2,4-triazole-3(4H)-thione (5b).
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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 278
Fig-7.8: NMR spectrum of (E)-5-((2-chlorophenoxy)methyl)-4-(2-hydroxybenzy-
lideneamino)-2H-1,2,4-triazole-3(4H)-thione (5d).
Fig-7.9: Mass 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
OH2C
N
NHN
N
OH
SCl
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 279
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-
methylpiperazin-1-yl)methyl)-5-(p-tolyloxymethyl)-2H-1,2,4-triazole-3(4H)-
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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 280
Fig-7.12: Mass 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-7.13: 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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 281
Fig-7.14: NMR spectrum of (E)-4-(2-hydroxybenzylideneamino)-5-
(phenoxymethyl)-2-(piperazin-1-ylmethyl)-2H-1,2,4-triazole-3(4H)-thione (6b)
Fig-7.15: Mass 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 NH
OH2C
N
NN
N CH
OH
S
H2C N NH
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 282
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.
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 283
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.
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 284
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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 285
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
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Dept. of Chemistry, MIT, Manipal University, Manipal. Page 286
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.
Triazole derivatives
Dept. of Chemistry, MIT, Manipal University, Manipal. Page 287
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