Synthesis and evaluation of 4-(substituted)-acetylamino-3-mercapto-5-(4- substituted) phenyl-1,2,4-triazole derivatives as antimicrobial agents

Article abstract of DOI:10.1007/s00044-011-9708-z

Triazoles and its derivatives are found to possess diverse applications in the field of medicine and industry. A series of novel 1,2,4-triazole derivatives have been synthesized as novel antimicrobial agents starting from different 4-substituted benzoic acids. The chemical structures of these newly synthesized compounds were elucidated by Fourier transform infrared spectroscopy (FTIR), ¹H NMR, ¹³C NMR, FAB?-MS spectral data, and elemental analysis. Their antimicrobial activities were investigated against four bacterial strains S. aureus (ATCC-25923), P. aeruginosa (ATCC-27853), E. coli (ATCC-8739), B. subtilis (ATCC-6633) and three fungal strains C. albicans (MTCC-227), A. niger (MTCC-3323), and F. oxysporum (MTCC-2087). Preliminary results indicate that some of them exhibit promising activities and deserve further consideration.

Full text of DOI:10.1007/s00044-011-9708-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1967–1976
DOI 10.1007/s00044-011-9708-z
ORIGINAL RESEARCH
Synthesis and evaluation of 4-(substituted)-acetylamino-3-
mercapto-5-(4-substituted) phenyl-1,2,4-triazole derivatives
as antimicrobial agents
•
Neeraj Upmanyu Sanjay Kumar Pawan Porwal
•
•
•
Kamal Shah Pradeep Mishra
Received: 25 June 2010 / Accepted: 13 June 2011 / Published online: 9 July 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Triazoles and its derivatives are found to pos-
sess diverse applications in the field of medicine and
industry. A series of novel 1,2,4-triazole derivatives have
been synthesized as novel antimicrobial agents starting
from different 4-substituted benzoic acids. The chemical
structures of these newly synthesized compounds were
elucidated by Fourier transform infrared spectroscopy
Introduction
The treatment of infectious diseases still remain an
important and challenging problem because of a combi-
nation of factors including emerging infectious disease and
the increasing number of multi-drug resistant microbial
pathogens. In spite of a large number of antibiotics and
chemotherapeutics available for medical use, at the same
time the emergence of old and new antibiotic resistance
created in the last decades revealed a substantial medical
need for new classes of antimicrobial agents (Kaplancikli
et al., 2008). There is real perceived need for the discovery
of new compounds endowed with antimicrobial activity,
possibly acting through mechanism of action, which are
distinct from those of well-known classes of antibacterial
agents to which many clinically relevant pathogens are
now resistant.
1
(FTIR), H NMR, 13C NMR, FAB?-MS spectral data, and
elemental analysis. Their antimicrobial activities were inves-
tigated against four bacterial strains S. aureus (ATCC-25923),
P. aeruginosa (ATCC-27853), E. coli (ATCC-8739),
B. subtilis (ATCC-6633) and three fungal strains C. albi-
cans (MTCC-227), A. niger (MTCC-3323), and F. oxy-
sporum (MTCC-2087). Preliminary results indicate that
some of them exhibit promising activities and deserve
further consideration.
Keywords 1,2,4-Triazoles ꢀ Cyclization ꢀ
Zone of inhibition ꢀ Antibacterial ꢀ Antifungal
Through the various molecules designed and synthesized
for this aim, in recent years active research has been initiated
on heterocycles and the chemistry of 1,2,4-triazoles has
received considerable attention owing to their synthetic and
effective biological importance. 1,2,4-triazole moieties have
been incorporated into a wide variety of therapeutically
interesting drug candidates including anti-inflammatory,
analgesic antimicrobial agents (Mathew et al., 2006), and
antimycotic ones such as fluconazole, itraconazole, vorico-
nazole (Mishra et al., 2010). During the last few decades,
considerable attention has been devoted to synthesis of 1,2,4-
triazole derivatives possessing such comprehensive biolog-
ical activities such as antibacterial, antifungal (Holla et al.,
1994; Ulusoy et al., 2001; Muhi-Eldeen et al., 1991), anti-
tubercular (Shiradkar et al., 2007 and Mir and Siddiqui,
1970), anticancer, anti-tumor (Shivarama Holla et al., 2003;
Al-Soud et al., 2003), anti inflammatory (Wade et al., 1982;
Navidpour et al., 2006), anticonvulsant (Ainsworth et al.,
N. Upmanyu (&)
Division of Pharmaceutical Chemistry,
Department of Pharmaceutical Sciences,
Dr. H.S. Gour University, Sagar 470003, India
e-mail: neerajupmanyu@rediffmail.com
S. Kumar
Defence Research Development and Establishment,
Jhansi Road, Gwalior 474001, India
P. Porwal
Manipal College of Pharmaceutical Sciences,
Manipal 576104, Karnatka, India
K. Shah ꢀ P. Mishra
GLA Institute of Pharmaceutical Research,
Mathura 281406, India
123

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Med Chem Res (2012) 21:1967–1976
1962; Parmar et al., 1977), antidepressant (Kane et al.,
1988), hypoglycemic properties (Mhasalkar et al., 1970),
openers of Ca??-activated potassium (Maxi-K) channels
(Romine et al., 2002), anxiolytic (Gall et al., 1978), and
antiviral activity (Witkowski et al., 1972).
1(a, b), which was recrystallized from absolute alcohol and
melting point determined (Furniss et al., 1989).
Step 2 general procedure for the synthesis of hydrazides
Regarding antimicrobial activity, triazole is structurally
similar to imidazole molecule. Although triazole and
imidazole act by the same mechanism of action, triazole
possess advantages over imidazole, which have slow met-
abolic rate, oral bioavailability and less effect on human
sterol synthesis (Kharb et al., 2010). For these reasons
imidazoles are slowly being replaced by triazole mole-
cules. It was reported that incorporation of various sub-
stituent into heterocyclic ring systems augments biological
activities considerably (Wang and Shi, 2001). As second-
ary amine incorporated heterocycles like thiazole, oxadi-
azole, and 1,2,4-triazole displayed varied Pharmacological
properties. In our previous work, p-chloro benzoic acid and
p-nitro benzoic acid were used for synthesizing 1,2,4-tria-
zole (Mishra et al., 2006 and upmanyu et al., 2011) eval-
uated for in vitro antimicrobial evaluation. Prompted by
these investigations, it was thought to be interesting to
synthesize compounds containing 1,2,4-triazole on which
secondary amine group was attached and study their anti-
microbial activities.
Hydrazine hydrate (99%) (5.7 ml, 0.15 mol) was taken in a
flat-bottom flask and solution of methyl ester (0.1 mol) in
ethanol was added drop wise with gentle stirring. After
complete addition, the mixture was transferred into a
round-bottomed flask and refluxed for 4–6 h. Ethanol was
distilled off under reduced pressure. The precipitate of acid
hydrazide 2(a, b) found was filtered and recrystallise from
ethanol and melting point determined (Yale et al., 1953).
Step 3 synthesis of potassium 3-aroyl dithiocarbazate
A mixture of potassium hydroxide (0.15 mol), 100 ml of
absolute ethanol and (0.1 mol) of the acid hydrazide was
treated with (0.15 mol) of carbon-disulfide. This mixture
was diluted with 75 ml of absolute ethanol and stirred for
12–16 h. The solvent was distilled off under reduced
pressure. The salts 3(a, b), prepared as described above,
were obtained in nearly quantitative yield and were
employed without further purification (Reid and Heindel,
1976).
Step 4 synthesis of 4-amino-3-mercapto-5-(4-substituted)
phenyl-1,2,4-triazole
Materials and methods
Chemistry
A suspension of (0.1 mol) of the potassium salt in absolute
alcohol (0.2 mol) of 99% hydrazine hydrate and 6 ml of
water was refluxed for 2 to 3 h. The colour of the reaction
mixture changed to green with the evolution of hydrogen
sulfide gas and a homogenous solution resulted. Cold dis-
tilled water (100 ml) was added and the solution was
acidified with concentrated hydrochloric acid. The precip-
itated solid 4(a, b) was filtered, washed with two portions
30 ml each, of cold water and recrystallized from aqueous
ethanol (50%) (Heindel and Reid, 1980).
All the solvents were of LR grade and were obtained from
Merck, Rankem, Fluka, and S.D. fine chemicals. Melting
points were determined in open capillary tubes and are
uncorrected. Reaction sequence employed for the synthesis
of title compounds is shown in Scheme 1.
Step 1 general procedure for the synthesis of methyl esters
Required carboxylic acid viz. 4-methyl benzoic acid
(a) and 4-methoxy benzoic acid (b) (0.1 mol) was taken in
methanol (100 ml) in a round-bottom flask and concen-
trated sulphuric acid (5.7 ml) was added to that. The
mixture was refluxed for 4–6 h. Excess of methanol was
then distilled off. After cooling the contents were trans-
ferred to separating funnel containing 100 ml of distilled
water. The synthesized ester was repeatedly extracted
several times with carbon tetrachloride (30 ml). The
combined organic layer was washed with solution of
sodium-bi-carbonate (20%) to remove any unreacted acid.
After washing with distilled water the organic layer was
dried over anhydrous MgSO4. Carbon-tetrachloride was
then distilled off under reduced pressure to get the ester
Step 5 synthesis of 4-(chloro-acetyl amino)-3-mercapto-5-
(4-substituted) phenyl-1,2,4-triazole
Compound 4-amino-3-mercapto-5-(4-substituted) phenyl-
1,2,4-triazole (0.1 mol) was taken in a 50 ml of dioxane in
a two necked round-bottom flask fitted with reflux con-
denser and a separating funnel. Chloroacetyl chloride
8.75 ml (0.11 mol) was taken in dioxane (25 ml approx),
in the separating funnel. The chloroacetyl chloride was
added in small portions to the vessel. After the complete
addition, the contents of the flasks were refluxed for an
hour or so. After cooling the contents were poured on
crushed ice. The precipitated acyl product 5(a, b) was
123

Med Chem Res (2012) 21:1967–1976
1969
Conc. H2SO4
CH3OH
R
COOH
COOCH3
R
1
NH2NH2.H2O
S
CS2, KOH
-
+
R
CONHNH2
R
CONHNH-C-S K
2
3
NH2NH2.H2O
N
N
N
N
ClCOCH2Cl
R
SH
N
R
SH
N
NHCOCH2Cl
NH2
5
4
R'
N
N
R
SH
N
NHCOCH2R'
6-11
Where
R= (a) CH3, (b) OCH3 and
CH3
CH
CH3
CH3
N(CH CH
)
3
2
R'H =
N(CH2CH2CH3)2
N
,
2
N(CH2CH2CH2CH2)2
,
,
,
CH
CH3
CH3
N
N(CH2CH2CH2CH2CH3)2
,
CH2CH2CH2CH3
Scheme 1 Synthesis of 1,2,4-triazoles derivatives
filtered and washed several times with ice cold distilled
remove last traces of hydrochloride. Benzene was distilled
off under vacuum and the crude product was separated.
Purification of the title compounds 6–11 (a, b) was done by
repeated crystallization from appropriate solvents and
melting point was determined.
water (Eweiss et al., 1986).
Step 6 synthesis of the title compound
Compound 4-(chloroacyl-amino)-3-mercapto-5-(4-substi-
tuted) phenyl-1,2,4-triazole (0.025 mol) and respective amine
(0.030 mol) along with the triethylamine (0.030 mol) were
taken in a round-bottomed flask in benzene (75 ml approx).
The contents were refluxed for 3–4 h. The precipitated
triethylamine hydrochloride was separated out. The organic
layer was washed several times with distilled water to
Thin layer chromatography was used to reach the com-
pletion of the reaction and purity of the synthesized com-
pounds. Melting points were taken in open glass capillary
tubes by using melting point apparatus and were uncor-
rected. IR spectra in KBr were recorded on a Nicolet-6700
FTIR spectrophotometer. 13C NMR spectra were recorded
on Brucker aviance II 400 MHZ spectrophotometer in
123

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Med Chem Res (2012) 21:1967–1976
DMSO-d6/CDCl3 using TMS as an internal standard
(chemical shifts are expressed in d, ppm), mass spectra were
recorded on Jeol Sx 102/DA-600 mass spectrometer/Data
System using fast moving bombardment (FAB) technique
and nitrogen analysis were recorded using elemental ana-
lyzer Elementar Vario EL III Carlo Erba 1108. The purity of
the compounds was checked on silica gel-G coated plates
using a mixture of ethyl acetate and petroleum ether (1:1).
Visualization was done using iodine vapors. The log p val-
ues were determined using Hyperchem and Chemdraw
software. Substitution pattern and characterization data of
the synthesized compounds are reported in Table 1. The
spectral data are presented in Table 2.
drug. The inhibition zones were measured and compared
with the control and the results are summarized in Table 4
(These data includes the size of filter paper 6 mm).
Results and discussion
The synthesis of 4-(substituted)-acetylamino-3-mercapto-5-
(4-substituted) phenyl-1,2,4-triazole 6–11(a, b) was accom-
plished as presented in Scheme 1. Aromatic carboxylic acid
viz. 4-methyl benzoic acid (a) and 4-methoxy benzoic acid
(b) were converted into their respective methyl esters 1(a,
b). Esters were converted into their hydrazides 2(a, b) by
reacting with hydrazine hydrate. Hydrazides were reacted
with carob-di-sulphide and potassium hydroxide to give
their potassium 3-aroyl dithiocarbazate 3(a, b) and then
these potassium salt were converted into their respective
1,2,4-triazoles 4(a, b). These 1,2,4-triazoles were reacted
with chloroacetyl chloride to give their acyl derivatives 5(a,
b). These acyl derivatives were reacted with different sec-
ondary amines to give the titled compounds 6–11(a, b).
Synthesized compounds were characterized by elemental
Biological activities
Antibacterial activities
The newly synthesized compounds were screened for
their antibacterial activity against E. coli (ATCC-8793),
S. aureus (ATCC-25923), P. aeruginosa (ATCC-27853),
and B. subtilis (ATCC-6633) (recultured) bacterial strains
by paper disc diffusion method (Cruickshank et al., 1975)
at 70, 50, and 30 lg/ml concentrations, respectively. All
the bacterial strains were procured from (Hi-media) ATCC,
USA. A standard inoculum (1–2 9 107 c.f.u./ml 0.5
McFarland standards) was introduced onto the surface of
sterile agar plates and a sterile glass spreader was used for
even distribution of the inoculum. The discs measuring
6 mm in diameter were prepared from Whatman no. 1 filter
paper and sterilized by dry heat at 140°C for an hour. The
sterile discs previously soaked in a known concentration of
the test compounds (in DMSO) were placed in nutrient
agar medium. Solvent and growth controls were kept. The
plates were inverted and incubated for 24 h at 37°C.
Vancomycin and Amikacin were used as a standard drug.
The inhibition zones were measured and compared with the
controls and the results are summarized in Table 3 (These
data includes the size of filter paper 6 mm).
1
analysis, IR, H NMR, 13C NMR, and mass spectrum. The
IR spectrum exhibited characteristic bands for C–N, C=N,
SH, C=O, and N–H at 1330–1370, 1503–1548, 2520–2594,
1640–1711, and 3300–3413 cm-1
.
In 1H NMR spectra, a singlet of CONH was found in the
range of d 9.88–10.21 ppm and another singlet of thio
group was observed in the range of d 9.53–9.84 ppm. In
13C NMR spectra, C3 and C5 of the 1,2,4-triazole nucleus
were observed in the range of d 139–163 ppm. Carbonyl
carbon and methylene carbon of –NHCOCH2N\ were
found between d 161–178 and d 47–65 ppm, respectively.
A solvent peak of DMSO-d6 was observed at 44 ppm.
Analytical and spectral data were in good agreement with
the composition of synthesized compounds.
The investigation of antibacterial and antifungal screen-
ing data revealed that all the tested compounds 6–11(a,
b) showed moderate to good inhibition. The screening results
indicate that some of the compounds tested exhibited sig-
nificant antibacterial and antifungal activities when com-
pared with the reference drugs. It was observed that the
compound containing 4-methoxy phenyl group at position 5
of the triazole ring and n-butyl methyl group (at C2 of acet-
amido group) at position 4 of the triazole ring (9b) shows
maximum bactericidal as well as fungicidal activity as
compared with other compounds, whereas 9a and 7b showed
good activity. The compounds 7a and 10b showed moderate
activity as compared with 9b. The other compounds (6a, 6b,
8a, 8b, 11a, and 11b) showed lower fungicidal effects
compared with their bactericidal effects. Log p values
demonstrated the crucial role of lipophilicity in determining
the antimicrobial activity.
Antifungal activities
Newly prepared compounds were screened for antifungal
activity against C. albicans (MTCC-227), A. niger (MTCC-
3323), and F. oxysporum (MTCC-2087) by the same
method as in the antibacterial screening but different
mediums were used. All the fungal strains were procured
from Institute of Microbial Technology, Chandigarh. For
antifungal screening against A. niger, czapek yeast extract
agar was used. Malt yeast agar (&pH 7.0) was employed as
culture media against C. albicans and potato sucrose agar
was used as culture medium against F. oxysporum (Cata-
logue of strain, 2000). Clotrimazole was used as a standard
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Med Chem Res (2012) 21:1967–1976
1971
Table 1 Physico-chemical properties of the synthesized compounds
'
'
N N
N
3
2
R
SH
'
'
1
4
'
'
NHCOCH2R'
6
5
Code no.
R
R0
Yield (%)
M.P. (°C)
Molecular formula
Nitrogen estimation
found (calculated) (%)
Log P
6a
7a
8a
–CH3
–CH3
–CH3
–N(CH2CH3)2
41.5
71.2
61
152–154
112–114
142–144
C15H21N5SO
C17H25N5SO
C17H25N5SO
21.10 (21.92)
20.67 (20.15)
20.01 (20.15)
3.69
4.75
4.38
–N(CH2CH2CH3)2
CH3
CH
CH3
CH3
-N
CH
CH3
9a
–CH3
–CH3
–N(CH2CH2CH2CH3)2
74.7
74.2
120–122
102–104
C19H29N5SO
C16H23N5SO
18.58 (18.65)
21.03 (21.00)
5.81
4.22
10a
CH3
-N
CH2CH2CH2CH3
11a
6b
–CH3
–N(CH2CH2CH2CH2CH3)2
–N(CH2CH3)2
65.7
44.5
61.7
46.2
148–150
192–194
122–124
180–182
C21H33N5SO
C15H21N5SO2
C17H25N5SO2
C15H25N5SO2
16.50 (17.35)
20.97 (20.88)
19.12 (19.27)
19.23 (19.27)
6.87
3.39
4.49
4.09
–OCH3
–OCH3
–OCH3
7b
–N(CH2CH2CH3)2
8b
CH3
CH
CH3
CH3
-N
CH
CH3
9b
–OCH3
–OCH3
–N(CH2CH2CH2CH3)2
57.2
64
175–177
174–176
C19H29N5SO2
C16H23N5SO2
17.96 (17.89)
19.89 (20.04)
5.52
3.92
10b
CH3
-N
CH2CH2CH2CH3
11b
–OCH3
–N(CH2CH2CH2CH2CH3)2
62.3
159–161
C21H23N5SO2
16.73 (16.69)
6.58
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1975
Holla BS, Veerendra B, Shivananda MK, Poojary B (2003) Synthesis
characterization and anticancer activity studies on some Man-
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38:759–767
Kane JM, Dudley MW, Sorensen SM, Miller FP (1988) 2,4-Dihydro-
3H–1,2,4-triazole-3-thiones as potential antidepressant agents.
J Med Chem 31:1253–1258. doi:10.1021/jm00298a021
Kaplancikli ZA, Turan-Zitouni G, Ozdemir A, Revail G (2008) New
triazole and triazolothiadiazine derivatives as possible antimi-
crobial agents. Eur J Med Chem 43(1):155–159. doi:10.1016/
j.ejmech.2007.03.019
Kharb R, Sharma PC, Yar MS (2010) Pharmacological significance of
triazole scaffold. J Enz Inhib Med Chem 26(1):1–21. doi:
10.3109/14756360903524304
Mathew V, Keshavayya J, Vaidya VP, Reddy BM (2006) Heterocy-
clic system containing bridgehead nitrogen atom: Synthesis and
pharmacological activities of some substituted 1,2,4-triazol-
o[3,4-b]-1,3,4-thiadiazoles. Eur J Med Chem 41:1048–1058. doi:
10.1016/j.ejmech.2006.03.018
Conclusion
We report successful synthesis and antimicrobial activity
of a new 1,2,4-triazole moiety. The antimicrobial activity
study revealed that some of the tested compounds showed
moderate to good antibacterial and antifungal studies
against most abundant strains. Structure and biological
activity relationship of title compounds showed that
p-methoxy group is preferable in position 5-phenyl as
compare to p-methyl group. The antimicrobial activity was
enhanced serially with increase in number of carbon atom
(up to n-dibutyl amine) and decreased with branch chain
substitution.
The field is further open for study of these compounds
with respect to toxicity, chronic toxicity, pharmacokinetics,
and clinical studies to establish these molecules as drugs in
the market.
Mhasalkar MY, Shah MH, Nikam ST, Anantanarayanan KG,
Deliwala CV (1970) J Med Chem 13(4):672–674. doi:10.1021/
jm00298a021
Mir I, Siddiqui MT (1970) Antituberculosis agents-I:a-[5-(2-Furyl)-
1,2,4-triazol-3-ylthio] acethydrazide and related compounds.
Tetrahedron 26:5235–5238. doi:10.1016/S0040-4020(01)98
732-0
Mishra P, Upmanyu N, Mehta A (2006) In vitro anti-microbial
activity of some 5-aryl-4-(substituted amino)-3-mercapto-1,2,4-
triazole. Indian J Microbiol 46(4):401–404
Acknowledgments The authors are grateful to The Director,
Defence Research Development and Establishment, Gwalior for
providing necessary facility and also grateful to Head, Microbiology
Division, DRDE, Gwalior and Head, Department of Pharmaceutical
Sciences, Dr. H. S. Gour University, Sagar (M.P.). The author wish to
thanks SAIF, Lucknow for spectral analysis.
Mishra R, Kumar R, Kumar S, Majeed J, Rashid M, Sharma S (2010)
Synthesis and in vitro antimicrobial activity of some triazole
derivatives. J Chil Chem Soc 55(3):359–362
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