Synthesis and QSAR studies of some novel disubstituted 1,2,4-triazoles as antimicrobial agents

Article abstract of DOI:10.1007/s00044-013-0686-1

Disubstituted 1,2,4-triazoles 3a-k, 4a-k, and 6a-k have been synthesized from anthranilic acid and nicotinic acid, respectively, through a multi-step reaction sequence via their hydrazides. Synthesized compounds were evaluated for their in vitro antimicro

Full text of DOI:10.1007/s00044-013-0686-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:848–861
DOI 10.1007/s00044-013-0686-1
ORIGINAL RESEARCH
Synthesis and QSAR studies of some novel disubstituted
1,2,4-triazoles as antimicrobial agents
•
Siva S. Panda Subhash C. Jain
Received: 8 May 2013 / Accepted: 26 July 2013 / Published online: 7 August 2013
Ó Springer Science+Business Media New York 2013
Abstract Disubstituted 1,2,4-triazoles 3a–k, 4a–k, and
6a–k have been synthesized from anthranilic acid and nic-
otinic acid, respectively, through a multi-step reaction
sequence via their hydrazides. Synthesized compounds were
evaluated for their in vitro antimicrobial activity against two
gram-positive bacteria (S. aureus and B. subtilis), three
gram-negative bacteria (E. coli, S. typhi, and K. pneumonia)
as well as four fungi (A. niger, A. fumigatus, A. flavus, and
C. albicans). To explore computational approach, structure–
activity relationships were generated statistically using the
synthesized compounds and their respective quantitative
values of biological activities. These models can be used in
future for predicting antimicrobial activity on similar class of
compounds.
fluconazole (Tsukuda et al., 1998; Narayanan et al., 1993),
itraconazole (Bailey et al., 1990), ravuconazole (Roberts
et al., 2000), voriconazole (Sanati et al., 1997; Perea et al.,
2000; Espinel-Ingroff, 1998), ICI 153066 (Boyle et al.,
1988), and posaconazole (Oakley et al., 1997) contain
1,2,4-triazole moiety. The activity of these compounds is
based on the inhibition of biosynthesis of ergosterol (the
major steroid present in fungal membranes) by blocking
14-a-demethylation, which occurs with accumulation of
14-a-methyl-steroids and disruption of the fungal mem-
branes (Vanden Bossche et al., 1993; Massa et al., 1992;
Doignon and Rozes, 1992). Fluconazole also causes second
bronchialarch anomalies in mice (Tiboni, 1993).
Quantitative structure activity relationship (QSAR)
refers to a discipline in chemical informatics that addresses
the modeling of biological activities or chemical reactivity
based on the quantitative and chemical features of the
molecule. QSAR relies on the basic assumption that mol-
ecules with similar physicochemical properties or struc-
tures will have similar activities (Huang et al., 2007).
QSAR is one of the most important areas in chemometrics,
and is used extensively in drug design and medicinal
chemistry. Once a reliable QSAR model is established, we
can predict the activities of molecules, and know which
structural features play an important role in biological
processes (Mungalpara et al., 2010; Kumar et al., 2007,
2009; Narasimhan et al., 2006).
Keywords 1,2,4-Triazoles ꢀ Quinazoline ꢀ Pyridine ꢀ
Antibacterial ꢀ Antifungal ꢀ QSAR
Introduction
1,2,4-Triazoles constitute an important family of hetero-
cyclic compounds and find prominent place in medicinal
chemistry, pesticide chemistry, and polymer science. Since
many of these display remarkable biological activity,
therefore their syntheses and transformations have received
particular interest for a long time. 1,2,4-Triazoles were
known to possess important pharmacological activities
such as antifungal and antiviral. Some well-known anti-
fungal drugs (Yagisawa, 2004; Johnson et al., 1999) like
Inspired by the above facts and in continuation to our
on-going research program in the field of synthesis and
antimicrobial activity (Sakhuja et al., 2011; Panda et al.,
2012; Panda and Jain 2013), we got interested in exploring
the biological activity of such molecules through structural
modifications by introducing different moieties such as
quinazoline, pyridine, aryl, and heteroaryl in the frame-
work of triazoles. We report syntheses, characterization,
S. S. Panda ꢀ S. C. Jain (&)
Department of Chemistry, University of Delhi,
New Delhi 110 007, India
e-mail: jainsc48@hotmail.com
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Med Chem Res (2014) 23:848–861
849
H
studies microorganisms employed were Staphylococcus
aureus (MTCC 096), Bacillus subtilis (MTCC 441), Esche-
richia coli (MTCC 443), Salmonella typhi (MTCC 733), and
Klebsiella pneumoniae (MTCC 432). For antifungal screen-
ing, Aspergillus niger (MTCC 282), Aspergillus fumigatus
(MTCC 343), Aspergillus flavus (MTCC 277), and Candida
albicans (MTCC 227) were used. Both microbial studies
were assessed by recording minimum inhibitory concentra-
tion (MIC) by serial dilution method (Collee et al., 1989) and
by measuring zone of inhibition using Cup-plate method
(Barry, 1976; Muralidhar Reddy et al., 2009). Various con-
centrations (6.25, 12.5, 25, 50, 100 lg/ml) of each compound
were prepared by serially diluted with DMSO. For MIC, a
standard drop of the microbial culture, prepared for the assay,
was added to each of the dilutions, and were then incubated
for 16–18 h for bacteria and 28–30 h for fungi at 37 °C. MIC
is the minimum concentration of the compound, which
inhibits the visible growth of bacteria or fungi. For the
determination of zone of inhibition, inoculated MH agar for
bacteria and SD agar for fungi were separately poured onto
thesterilizedpetri dishes. The poured material was allowed to
set and thereafter the ‘CUPS’ (08 mm diameter) was made by
punching into the agar surface with a sterile cork borer and
scooping out the punched part of the agar. The test compound
solution was added into these cups with the help of a sterile
syringe. The plates were then incubated at 37 °C for 16 h for
bacteria and 28–30 h for fungi. Ciprofloxacin and Miconaz-
ole were used as standard drugs for bacteria and fungi,
respectively. The experiments were repeated three times to
reduce the error and the average value of antibacterial and
antifungal activity are presented in Tables 2 and 3.
N
O
N
N
Ar/Hetaryl
N
N
Ar/Hetaryl
N
N
H
N
N
CH3/CF3
Fig. 1 General structures of disubstituted 1,2,4-triazoles
antimicrobial activity, and QSAR studies of some new
disubstituted triazoles (Fig. 1) in this communication.
Results and discussion
Chemistry
The target compounds 3a–k, 4a–k, and 6a–k were synthe-
sized as illustrated in Schemes 1 and 2. Hydrazides (1a–b, 5)
were cyclocondensed with substituted aryl and heteroaryl
aldehyde in the presence of ammonium acetate in acetic acid
at room temperature to afford corresponding 3,5-disubsti-
tuted-1,2,4-triazole derivatives 3a–k, 4a–k, and 6a–k in
82–96 % yields (Schemes 1, 2; Table 1). 2-((2-Methylqui-
nazolin-4-yl)oxy)acetohydrazide 1a was prepared starting
from anthranilic acid and acetic anhydride by following the
literature method (Mohan et al., 1985). Similarly, 2-((2-(tri-
fluoromethyl)quinazolin-4-yl)oxy)acetohydrazide 1b was
prepared from anthranilic acid and trifluoroacetic anhydride,
whereas nicotinohydrazide 5 was prepared from nicotinic
acid (Jha et al., 2010). All the compounds were characterized
by analyticaland spectroscopicdata (IR, 1H NMR, 13C NMR,
and elemental analysis).
The data in Tables 3 and 4, revealed that triazoles 3a–k,
4a–k, and 6a–k could effectively, to some extent, inhibit
the growth of all tested strains in vitro. In antibacterial
studies, all the compounds tested have shown moderate
activity towards B. subtilis and S. typhi in comparison to
other three strains of bacteria. Of the four strains of fungi,
Antimicrobial studies
All the newly synthesized triazoles were screened for their
in vitro antibacterial and antifungal activity. For antibacterial
Scheme 1 Synthesis of 2-aryl-
4-(1,2,4-triazolyl)-quinazolines
3a–k and 4a–k
H
N
NH2
O
N
H
O
Ar
N
N
CH3COONH4
N
N
+
Ar
CHO
CH3COOH, 25 oC
N
R
N
R
2a-k
1a-b
3a-k R = CH3
4a-k R = CF3
Scheme 2 Synthesis of 2-aryl-
4-(1,2,4-triazolyl)-pyridines
6a–k
N
N
H
Ar
CH3COONH4
N
N
H
NH2
Ar
CHO
+
CH COOH 25 oC
,
3
N
N
2a-k
5
6a-k
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Med Chem Res (2014) 23:848–861
4k showed significant antibacterial activity against all the
strains whereas 3e, 3f, and 3g exhibited most promising
antifungal activity against all the fungal strains.
Table 1 Preparation of disubstituted 1,2,4-triazoles 3a–k, 4a–k, and
6a–k
Compound
R
Ar
Mp (°C)
Yield (%)
3a
3b
3c
3d
3e
3f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
–
–C6H5
238–239
241–243
184–186
234–235
291–292
246–248
228–229
208–210
244–245
180–182
175–176
212–213
259–261
176–177
236–238
301–302
222–223
216–218
224–226
238–239
216–217
235–236
116–117
177–179
181–183
157–159
221–223
93–95
92
94
92
95
90
94
95
92
96
85
82
92
94
95
91
92
92
95
94
96
96
98
90
92
90
92
96
95
92
95
94
82
85
Chemometrics—QSAR studies
4-FC6H4
4-ClC6H4
All the experimental data of the synthesized compounds
(Table 1) in our lab are considered as dataset for QSAR
studies with 1/log of MIC as unit of antibacterial and
antifungal activity. All the structures shown in Table 4
were drawn and converted to 3D using Marvin Sketch
(Marvin, 2011) and optimized using molecular mechanics
(UFF) in Argus Lab 4.0.1 (www.arguslab.com). Final
geometry optimization for all the compounds was carried
out by semi-empirical quantum mechanics using MOPAC
(Stewart, 2008) with AM1 parameterization (Dewar et al.,
1985). The optimized compounds are loaded in PaDEL-
Descriptor online tool to predict all possible 2D, 3D, and
Fingerprint molecular descriptors (Berhanu et al., 2012).
The MIC values of compounds are in lg/mL units and
were transformed to reciprocal logarithmic function for the
estimation of predicted values using statistical techniques.
Relative differences known to be residuals for each com-
pound are calculated from experimental and predicted
log(1/MIC) values. The generated dataset also briefs vari-
ation on data within the range of observed threshold,
assuming that the relative error covers approximately same
range for the whole dataset.
4-BrC6H4
4-OHC6H4
4-CH3C6H4
4-OCH3C6H4
3,4-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
2-Furanyl
3g
3h
3i
3j
3k
4a
4b
4c
4d
4e
4f
2-Thiophenyl
–C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
4-OHC6H4
4-CH3C6H4
4-OCH3C6H4
3,4-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
2-Furanyl
4g
4h
4i
4j
4k
6a
6b
6c
6d
6e
6f
2-Thiophenyl
–C6H5
–
4-FC6H4
A usual QSAR method needs several steps with the help
of several software packages. Hence the prediction of
QSAR model is not so easy and is a time-demanding
process (Berhanu et al., 2012). In the present study we used
freely available tools with manual assessment for better
interpretation of predicted models even though it was time
demanding. Using PaDEL descriptors (Yap, 2011) all
possible 2D, 3D descriptors were generated and these data
are used to perform regression analysis to correlate
between the biological activities. Here we have five strains
of antibacterial and four strains of antifungal activity data,
hence for QSAR model studies the average MIC values of
respective antibacterial and antifungal activity were con-
sidered for regression analysis. This average data helped to
minimize the consistency of QSAR approach to prove the
relative molecular descriptors for respective activity.
The optimization techniques used are as follows: (a) 2D
to 3D conversion using gradient optimize in Marvin
Sketch, (b) further optimization and conformational search
using Argus Lab, (c) final optimization using MOPAC
AM1 level of quantum theory, and all optimized structures
are uploaded to PaDEL tool, MM2 parameterization is used
for generating all descriptors.
–
4-Cl-C6H4
–
4-BrC6H4
–
4-OHC6H4
–
4-CH3C6H4
4-OCH3C6H4
3,4-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
2-Furanyl
6g
6h
6i
–
121–122
118–120
169–170
102–104
99–100
–
–
6j
–
6k
–
2-Thiophenyl
these triazoles have shown significant activity against
A. niger and C. albicans only and moderate activity against
rest of the two strains A. fumigatus and A. flavus.
Several structure–activity relationships (SAR) were
recognized from the results. Firstly, heterocyclic moieties
like quinazoline, pyridine, furan, and thiophene have
played an important role in enhancing the antimicrobial
activity. Especially quinazoline with trifluoromethyl sub-
stituent showed better antibacterial activity as compared to
the methyl. Secondly, the substituent on the phenyl ring
also significantly influenced the antibacterial and anti-
fungal activity of the compounds. Noticeably, the halogen
and methoxy derivatives showed better antimicrobial
property than the rest. Out of all the compounds 4c, 4j, and
The regression analysis was trained to all descriptors as
independent data and activity data log(1/MIC) as dependent
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851
Table 2 Antibacterial activity
data, MIC of 3a–k, 4a–k and
6a–k
Compound
MIC in lg/mL and zone of inhibition (in mm)
S. aureus
B. subtilis
E. coli
S. typhi
K. pneumonia
3a
12.5 (13–15)
12.5 (12–15)
12.5 (12–15)
12.5 (13–16)
25 (\10)
25 (\10)
12.5 (12–14)
25 (\10)
25 (\10)
25 (\10)
12.5 (12–15)
12.5 (12–15)
12.5 (12–14)
25 (\10)
25 (\10)
3b
6.25 (15–19)
6.25 (15–20)
6.25 (16–19)
12.5 (12–14)
25 (\10)
12.5 (12–15)
6.25 (15–19)
6.25 (16–18)
12.5 (13–16)
12.5 (12–15)
6.25 (16–20)
12.5 (12–15)
25 (\10)
3c
3d
12.5 (12–15)
50 (\10)
3e
3f
25 (\10)
25 (\10)
25 (\10)
3g
12.5 (13–16)
12.5 (12–15)
12.5 (13–17)
6.25 (15–18)
6.25 (14–18)
12.5 (13–15)
6.25 (15–21)
12.5 (14–16)
6.25 (15–20)
25 (\10)
25 (\10)
12.5 (12–15)
12.5 (13–15)
6.25 (15–18)
6.25 (15–20)
6.25 (16–19)
12.5 (12–15)
6.25 (16–20)
12.5 (13–16)
6.25 (15–17)
12.5 (14–16)
12.5 (12–15)
12.5 (13–15)
6.25 (16–18)
6.25 (15–20)
6.25 (15–19)
6.25 (15–20)
25 (\10)
25 (\10)
3h
25 (\10)
12.5 (13–15)
6.25 (15–18)
6.25 (15–19)
12.5 (13–15)
12.5 (12–15)
6.25 (16–20)
6.25 (15–20)
6.25 (15–18)
12.5 (12–16)
12.5 (12–15)
12.5 (12–15)
6.25 (15–18)
6.25 (15–20)
6.25 (15–20)
6.25 (14–17)
12.5 (14–16)
25 (\10)
3i
12.5 (12–15)
12.5 (13–15)
25 (\10)
3j
6.25 (15–20)
6.25 (16–20)
12.5 (12–15)
6.25 (15–20)
12.5 (12–15)
12.5 (12–16)
25 (\10)
3k
4a
12.5 (12–14)
6.25 (14–18)
6.25 (14–18)
12.5 (12–16)
12.5 (13–15)
25 (\10)
4b
4c
4d
4e
4f
12.5 (12–16)
12.5 (14–16)
6.25 (16–20)
6.25 (15–18)
6.25 (15–18)
6.25 (14–18)
12.5 (13–16)
12.5 (13–16)
12.5 (13–15)
6.25 (16–18)
25 (\10)
12.5 (14–16)
6.25 (16–18)
6.25 (16–19)
12.5 (12–16)
12.5 (13–15)
6.25 (15–18)
12.5 (12–15)
6.25 (15–20)
12.5 (13–15)
25 (\10)
4g
12.5 (12–14)
12.5 (12–15)
6.25 (15–20)
12.5 (12–15)
6.25 (15–18)
25 (\10)
4h
4i
4j
4k
6a
6b
12.5 (\10)
25 (\10)
25 (\10)
6c
12.5 (12–14)
6.25 (15–18)
25 (\10)
12.5 (12–15)
12.5 (14–16)
25 (\10)
6d
12.5 (13–15)
25 (\10)
6e
25 (\10)
6f
25 (\10)
25 (\10)
12.5 (12–15)
12.5 (12–15)
6.25 (14–18)
6.25 (16–18)
6.25 (15–20)
6.25 (15–20)
6.25 (18–22)
25 (\10)
12.5 (12–15)
6.25 (15–18)
6.25 (15–18)
12.5 (12–15)
12.5 (13–15)
6.25 (15–20)
6.25 (18–20)
6g
12.5 (12–16))
12.5 (14–16)
6.25 (14–18)
6.25 (15–18)
6.25 (15–20)
6.25 (17–22)
25 (\10)
50 (\10)
6h
12.5 (12–15)
12.5 (12–15)
12.5 (12–15)
12.5 (13–16)
6.25 (18–21)
25 (\10)
6i
25 (\10)
6j
25 (\10)
Values shown within the
parentheses represent zone of
inhibition
6k
25 (\10)
6.25 (18–21)
Ciprofloxacin
data. The molecular descriptors are independent because
descriptors contains (a) number, type, connectivity of atoms,
(b) electronic and physical features of molecules, (c) topo-
logical features, and (d) 3D features of molecule which helps
molecular structures to correlate closely with activity data.
Thus for QSAR models, we do not require any physico-
chemical experimental data, as all molecular descriptors
(features) are derived from molecular structures.
was iterated with 2, 3, 4, 5 descriptors (N) progressively to
find better R2 coefficient. The square of the correlation
coefficient (R2), cross-validated correlation coefficient
(R2cv), Fisher criterion (F), and squared deviation (s2) were
used to compare the robustness and optimal stability of the
correlation models.
QSAR model for antibacterial activity
The multi-linear regression technique encoded in
xlStatistician add-in (www.xlstatistician.com) for Micro-
soft Excel was used to choose significant descriptors based
on iterative calculations to generate correlations to build
QSAR models. The procedure for predicting correlation
The calculated statistical parameters for antibacterial
activity with desired quality of the model and having
minimum difference on cross-validated correlation coeffi-
cient (Table 5a; Fig. 2)
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Table 3 Antifungal activity
data of 3a–k, 4a–k, and 6a–k
Compound
MIC in lg/mL and zone of inhibitiona (in mm)
A. niger
A. fumigatus
A. flavus
C. albicans
3a
3b
3c
12.5 (12–15)
12.5 (12–15)
25 (\10)
50 (\10)
50 (\10)
25 (\10)
50 (\10)
50 (\10)
25 (\10)
25 (\10)
50 (\10)
50 (\10)
50 (\10)
25 (\10)
25 (\10)
25 (\10)
25 (\10)
25 (\10)
25 (\10)
25 (\10)
50 (\10)
50 (\10)
25 (\10)
25 (\10)
12.5 (13–15)
12.5 (12–15)
25 (\10)
50 (\10)
25 (\10)
25 (\10)
25 (\10)
50 (\10)
25 (\10)
25 (\10)
12.5 (12–15)
6.25 (15–17)
6.25 (14–16)
12.5 (12–15)
6.25 (17–20)
12.5 (12–15)
6.25 (15–18)
6.25 (15–17)
12.5 (12–15)
12.5 (14–16)
6.25 (15–17)
6.25 (15–20)
6.25 (15–19)
6.25 (15–17)
12.5 (12–14)
6.25 (16–20)
12.5 (12–14)
6.25 (15–19)
6.25 (15–20)
6.25 (15–18)
12.5 (12–15)
12.5 (13–16)
12.5 (13–15)
6.25 (15–20)
6.25 (14–18)
6.25 (16–20)
6.25 (15–20)
12.5 (12–15)
6.25 (15–18)
25 (\10)
50 (\10)
3d
3e
12.5 (13–16)
25 (\10)
25 (\10)
50 (\10)
3f
25 (\10)
50 (\10)
3g
3h
3i
12.5 (12–15)
12.5 (12–14)
12.5 (13–15)
6.25 (14–18)
12.5 (12–15)
25 (\10)
25 (\10)
25 (\10)
25 (\10)
3j
12.5 (12–14)
12.5 (12–15)
25 (\10)
3k
4a
4b
4c
25 (\10)
25 (\10)
12.5 (12–14)
12.5 (12–15)
25 (\10)
25 (\10)
4d
4e
12.5 (12–14)
50 (\10)
4f
12.5 (13–15)
25 (\10)
50 (\10)
4g
4h
4i
25 (\10)
12.5 (14–16)
12.5 (13–15)
12.5 (12–15)
6.25 (14–17)
12.5 (12–14)
12.5 (12–15)
12.5 (14–16)
25 (\10)
50 (\10)
50 (\10)
4j
25 (\10)
4k
6a
6b
6c
12.5 (12–15)
50 (\10)
6.25 (15–17)
25 (\10)
6d
6e
25 (\10)
25 (\10)
12.5 (12–14)
12.5 (12–15)
6.25 (15–18)
6.25 (15–20)
6.25 (15–20)
6.25 (15–18)
6.25 (15–20)
6.25 (17–22)
25 (\10)
12.5 (13–15)
12.5 (12–15)
12.5 (12–14)
12.5 (12–15)
6.25 (14–18)
6.25 (15–20)
6.25 (15–20)
6.25 (17–22)
6f
25 (\10)
6g
6h
6i
25 (\10)
25 (\10)
6.25 (14–16)
12.5 (12–14)
12.5 (13–15)
12.5 (14–17)
6j
Values shown in within the
parentheses represent zone of
inhibition
6k
Miconazole
R2 ¼ 0:7015; Rc2v ¼ 0:664; F ¼ 32:10; s2 ¼ 0:0717;
N ¼ 3; n ¼ 34
presence of negative charged halogens has a better
dependency for biological activity (Katritzky et al., 2008).
Equation 1 can be used for predicting the antibacterial
activity for homogenous compounds similar to dataset
chemical class.
Threshold: Observed (-1.35218 to -0.79588); Predicted
(-1.2873 to -0.754793)
Antibacterial activity ¼ I0 þ ðd1x ꢁ 1:039Þ
þ ðd2x ꢁ 0:197Þ þ ðd3x ꢁ 0:580Þ
QSAR model for antifungal activity
ð1Þ
The calculated statistical parameters for antifungal activity
with desired quality of the model and having minimum
difference on cross validated correlation coefficient
(Table 5b; Fig. 3)
The descriptor ‘Relative Negative charges’ in the model
is related to hetero atom binding affinity. Negative
coefficient showed the increase in the activity and the
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Med Chem Res (2014) 23:848–861
853
Table 4 Structural data,
observed and predicted in
log(1/MIC) values, and their
differences of dataset
ID Antibacterial activity
Antifungal activity
Obs. log(1/MIC) Pred. log(1/MIC) Residual Obs. log(1/MIC) Pred. log(1/MIC) Residual
3a -1.352
3b -1.051
3c -1.097
3d -1.000
3e -1.398
3f -1.352
3g -1.211
3h -1.176
-1.235
-1.058
-1.081
-1.070
-1.167
-1.250
-1.176
-1.086
-1.159
-1.017
-1.027
-1.050
-0.983
-0.997
-0.990
-1.090
-1.053
-1.115
-0.900
-0.907
-0.822
-0.877
-1.282
-1.240
-1.199
-1.184
-1.225
-1.285
-1.287
-1.202
-1.133
-1.047
-1.070
-0.117
0.007
-1.301
-1.376
-1.419
-1.176
-1.352
-1.419
-1.273
-1.273
-1.138
-1.051
-1.051
-1.243
-1.211
-1.138
-1.051
-1.439
-1.398
-1.243
-1.273
-1.211
-1.051
-1.000
-1.398
-1.000
-1.243
-1.301
-1.301
-1.176
-1.138
-1.051
-0.699
-0.796
-1.301
-1.411
-1.422
-1.466
-1.222
-1.356
-1.362
-1.203
-1.264
-1.199
-1.110
-0.980
-1.278
-1.276
-1.277
-1.277
-1.246
-1.254
-1.225
-1.180
-1.147
-1.031
-0.912
-1.187
-1.146
-1.150
-1.158
-1.122
-1.151
-1.104
-1.028
-0.974
-0.893
-1.411
0.110
0.046
-0.016
0.070
0.047
0.046
-0.231
-0.102
-0.035
-0.090
0.062
0.004
-0.057
-0.070
-0.009
0.061
3i
-1.097
3j -0.875
3k -1.051
4a -1.097
4b -0.796
4c -1.000
4d -0.942
4e -1.243
4f -1.176
4g -1.051
4h -0.875
0.142
0.058
-0.024
-0.047
0.187
-0.071
0.035
0.065
-0.003
0.048
0.138
0.226
-0.153
-0.123
0.064
-0.193
-0.144
-0.018
-0.093
-0.064
-0.021
-0.088
-0.211
0.146
0.025
4i
-0.875
0.032
4j -0.942
4k -0.796
6a -1.243
6b -1.211
6c -1.176
6d -1.097
6e -1.398
6f -1.301
6g -1.327
6h -1.097
-0.120
0.081
0.039
0.029
0.023
-0.093
-0.143
-0.179
-0.026
-0.034
-0.023
0.275
0.087
-0.172
-0.016
-0.040
0.105
6i
-1.097
0.036
6j -1.097
6k -1.051
-0.050
0.019
0.097
0.110
Table 5 Descriptor values and
parameters of regression
analysis for (a) antibacterial
dataset and (b) antifungal
dataset
Coefficient
Std error
t Ratio
Descriptors
Constant
(a)
I0
-1.039
-0.197
0.064
0.087
0.036
0.009
0.293
-11.965
-5.484
6.840
d1
d2
d3
(b)
I0
Number of benzene rings
Total dipole of molecule
Relative negative charges
-0.580
-1.980
3.381
-2.066
-1.083
-2.617
1.339
0.352
0.152
0.770
2.523
-5.868
-7.106
-3.396
Constant
d4
d5
d6
Max antibonding contribution
Average valence of H atom
Relative number of C atoms
123

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Med Chem Res (2014) 23:848–861
Fig. 2 Scatter plot of predicted
versus observed values
log(1/MIC) for antibacterial
dataset
Fig. 3 Scatter plot of predicted
versus observed values
log(1/MIC) for antifungal
dataset
Fig. 4 Residual plot for
residuals versus predicted
(fitted) values log(1/MIC)
for antibacterial dataset
123

Med Chem Res (2014) 23:848–861
855
Fig. 5 Residual plot for
residuals versus predicted
(fitted) values log(1/MIC)
for antifungal dataset
R2 ¼ 0:7072; Rc2v ¼ 0:634; F ¼ 25:76; s2 ¼ 0:1157;
N ¼ 3; n ¼ 34
against gram-positive and gram-negative bacteria as well as
fungi. Some of the compounds have been found to possess
good to significant antibacterial and antifungal activity. The
above results suggested that the presence of a halogen,
methoxy group and heterocyclic moieties like furan and
thiophene are important for the antimicrobial activity and
therefore such kind of compounds may be further developed
to discover a potent pharmacophore for future.
Threshold: Observed (-1.43933 to -0.69897); Predicted
(-1.466 to -0.687956)
Antifungal activity ¼ I0 þ ðd4x ꢁ 2:066Þ þ ðd5x ꢁ 1:083Þ
þ ðd6x ꢁ 2:617Þ
ð2Þ
Predicted QSAR model with three respective descriptors
for two activities was obtained and evaluated the ability of
predictive models. Molecular descriptors of the antibacterial
dataset resembles the polarity and binding affinities of com-
pounds and for antifungal dataset descriptors resembles the
donor–acceptor abilities including the anti-bonding contri-
bution of molecules which were calculated from structural
features with certain physicochemical meaning related to the
biological activities. The usage of multiple tools and manual
interpretation managed to provide more attention for all sta-
tistical predictions and generation of QSAR equation.
For QSAR validation, the whole synthesized compounds
including reference compound was divided into training set
and test set, 34 compounds were treated as training set and 8
compounds were treated as test set as the data points are
considerably low. Randomization test was performed with
random resampling of activity data to understand the model
stability. The descriptors for our model are ‘Relative number
if C atoms’ which denotes the ratio between carbon atoms and
all other atoms in molecule and the value depends on number
of double and triple bonds which can enhance the property.
Next descriptor, ‘Maximum antibonding contribution’ is
dependent on donor–acceptor abilities is that larger overlap-
ping between donor atoms and H atoms can decrease the
chances for stronger donor–acceptor bonds. The ‘Average
valence of H atom’ descriptor is the stability of bonds formed
between H atoms and molecular backbone. Higher regression
coefficients indicate more stability and antifungal effect
(http://www.xlstatistician.com/). Equation 2 can be used for
predicting the antifungal activity for compounds similar to the
dataset. The residual plots are given below, antibacterial
activity model (Fig. 4) and antifungal activity model (Fig. 5),
where the residuals are normally distributed.
Experimental section
Melting points were determined in open capillary tubes and
are uncorrected. Reaction courses were monitored by TLC
on silica gel-precoated F254 Merck plates. Infrared (FTIR)
spectra were determined on a Perkin Elmer-2000 Spec-
1
trophotometer instrument. H NMR spectra were recorded
on a Bruker Avance (400 MHz) and 13C NMR spectra
were recorded on Bruker Avance (100 MHz) using tetra-
methylsilane (TMS) as an internal standard and DMSO-d6
as solvent. TOF ES ? Mass spectra (m/z) were recorded on
Micromass Autospec LCTKC455.
Conclusion
General procedure for the synthesis of 3,5-disubstituted
1,2,4-triazoles
We have synthesized new series of 3,5-disubstituted 1,2,4-
triazoles bearing quinazoline, pyridine, and substituted aryl
moieties and evaluated them for antimicrobial activity
To a mixture of hydrazide (1 eq) and aryl/heteroaryl
aldehyde (1 eq) in glacial acetic acid, ammonium acetate
123

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Med Chem Res (2014) 23:848–861
4-((5-(4-Bromophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
(1.5 eq) was added. The reaction mixture was stirred for a
period of 4–6 h at room temperature. The progress of the
reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was poured into ice cold
water and neutralize with liquid ammonia. The precipitate
obtained was filtered, washed with water, and crystallized
from methanol/chloroform to give the desired product in
excellent yield.
methylquinazoline (3d)
White solid, 95 % yield, mp 234–235 °C, IR (KBr) mmax
3406, 2926, 1671, 1604, 1459, 1411, 1275, 1234, 1180,
1
1050, 996, 875, 754, 694, 482; H NMR (d, DMSO-d6,
400 MHz): 11.81 (s, 1H, [NH, D2O exchangeable), 8.12
(m, 1H), 7.70 (m, 2H), 7.61 (m, 1H), 7.49 (m, 2H), 7.45 (m,
2H), 5.29 (s, 2H, OCH2), 2.50 (s, 3H, CH3); 13C NMR (d,
DMSO-d6, 100 MHz): 168.3, 155.4, 148.1, 143.3, 134.5,
133.1, 131.8, 128.8, 126.2, 123.3, 119.6, 45.2 (OCH2), 22.9
(CH3). Anal. Calcd for C18H14BrN5O: C, 54.56; H, 3.56;
N, 17.67. Found: C, 55.20; H, 3.84; N, 17.52.
:
2-Methyl-4-((5-phenyl-4H-1,2,4-triazol-3-
yl)methoxy)quinazoline (3a)
White solid, 92 % yield, mp 238–239 °C, IR (KBr) mmax
:
3385, 2968, 1679, 1601, 1474, 1411, 1341, 1276, 1245,
1
1181, 1084, 982, 944, 876, 841, 758, 695; H NMR (d,
4-((5-(4-Hydroxyphenyl)-4H-1,2,4-triazol-3-yl)methoxy)-
2-methylquinazoline (3e)
DMSO-d6, 400 MHz): 11.76 (s, 1H, [NH, D2O
exchangeable), 8.26 (m, 1H), 8.08 (m, 2H), 7.73 (m, 1H),
7.60 (m, 1H), 7.43 (m, 2H), 6.86 (m, 2H), 5.27 (s, 2H,
OCH2), 2.51 (s, 3H, CH3); 13C NMR (d, DMSO-d6,
100 MHz): 168.3, 144.5, 134.3, 130.6, 129.0, 125.9, 119.1,
117.3, 115.4, 45.6 (OCH2), 22.3 (CH3). Anal. Calcd for
C18H15N5O: C, 68.13; H, 4.76; N, 22.07. Found: C, 68.24;
H, 4.51; N, 22.01.
White solid, 90 % yield, mp 291–292 °C, IR (KBr) mmax
:
3429, 2957, 1662, 1605, 1475, 1442, 1389, 1345, 1271,
1243, 1187, 1063, 989, 958, 872, 838, 773, 692, 663, 527;
1H NMR (d, DMSO-d6, 400 MHz): 11.63 (s, 1H, D2O
exchangeable), 9.98 (brs, 1H, OH, D2O exchangeable),
8.09 (m, 2H), 7.80 (m, 2H), 7.58 (d, 2H, J = 7.8 Hz), 6.84
(d, 2H, J = 7.8 Hz), 4.85 (s, 2H, OCH2), 2.53 (s, 3H,
CH3); 13C NMR (d, DMSO-d6, 100 MHz): 166.3, 159.9,
155.9, 148.0, 145.2, 134.9, 129.4, 127.0, 126.6, 125.3,
120.1, 116.1, 46.0 (OCH2), 22.3 (CH3). Anal. Calcd for
C18H15N5O2: C, 64.86; H, 4.54; N, 21.01. Found: C, 64.91;
H, 4.40; N, 21.00.
4-((5-(4-Fluorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
methylquinazoline (3b)
White solid, 94 % yield, mp 241–243 °C, IR (KBr) mmax
:
3403, 2928, 1671, 1605, 1475, 1414, 1295, 1264, 1180,
987, 943, 875, 774, 694, 486; 1H NMR (d, DMSO-d6,
400 MHz): 11.42 (s, 1H, [NH, D2O exchangeable), 8.10
(m, 1H), 7.96 (d, 2H, J = 7.8 Hz), 7.69 (m, 2H), 7.41 (m,
1H), 6.88 (d, 2H, J = 7.8 Hz), 5.25 (s, 2H, OCH2), 2.49 (s,
3H, CH3); 13C NMR (d, DMSO-d6, 100 MHz): 168.1,
143.8, 134.8, 130.6, 129.3, 126.8, 119.8, 115.8, 45.5
(OCH2), 22.4 (CH3). Anal. Calcd for C18H14FN5O: C,
64.47; H, 4.21; N, 20.88. Found: C, 64.84; H, 4.51; N,
22.11.
2-Methyl-4-((5-(p-tolyl)-4H-1,2,4-triazol-3-
yl)methoxy)quinazoline (3f)
White solid, 94 % yield, mp 246–248 °C, IR (KBr) mmax
:
3374, 2966, 1680, 1601, 1474, 1413, 1340, 1277, 1246,
1181, 1035, 982, 934, 876, 818, 773, 696, 519; 1H NMR (d,
DMSO-d6, 400 MHz): 11.67 (s, 1H, [NH, D2O
exchangeable), 8.16 (m, 1H), 7.72 (m, 1H), 7.60 (m, 1H),
7.51 (d, 2H, J = 8.0 Hz), 7.42 (m, 1H), 7.14 (d, 2H,
J = 8.0 Hz), 5.27 (s, 2H, OCH2), 2.49 (s, 3H, CH3), 2.29
(s, 3H, CH3); 13C NMR (d, DMSO-d6, 100 MHz): 167.9,
145.2, 140.2, 134.7, 131.3, 127.5, 126.8, 125.8, 119.8, 45.5
(OCH2), 22.8, 21.5 (CH3). Anal. Calcd for C19H17N5O: C,
68.87; H, 5.17; N, 21.13. Found: C, 70.01; H, 5.10; N,
21.40.
4-((5-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
methylquinazoline (3c)
White solid, 92 % yield, mp 184–186 °C, IR (KBr) mmax
:
3430, 2963, 1679, 1603, 1475, 1411, 1288, 1183, 1069,
1
1008, 956, 824, 774, 698, 512; H NMR (d, DMSO-d6,
400 MHz): 11.92 (s, 1H, [NH, D2O exchangeable), 8.18
(m, 1H), 7.92 (d, 2H, J = 7.8 Hz), 7.74 (m, 2H), 7.58 (m,
1H), 7.33 (d, 2H, J = 7.8 Hz), 5.39 (s, 2H, OCH2), 2.48 (s,
3H, CH3); 13C NMR (d, DMSO-d6, 100 MHz): 168.1,
155.2, 148.4, 142.8, 134.5, 133.0, 128.5, 126.2, 123.1,
119.6, 45.4 (OCH2), 22.9 (CH3). Anal. Calcd for
C18H14ClN5O: C, 61.45; H, 4.01; N, 19.91. Found: C,
61.10; H, 4.00; N, 20.01.
4-((5-(4-Methoxyphenyl)-4H-1,2,4-triazol-3-yl)methoxy)-
2-methylquinazoline (3g)
White solid, 95 % yield, mp 228–229 °C, IR (KBr) mmax
3447, 2969, 1674, 1604, 1472, 1442, 1389, 1313, 1290,
1
1257, 1169, 1027, 980, 937, 834, 787, 700, 604, 485; H
:
NMR (d, DMSO-d6, 400 MHz): 11.51 (s, 1H, D2O
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Med Chem Res (2014) 23:848–861
857
2-Methyl-4-((5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)
exchangeable), 8.11 (m, 1H), 7.68 (m, 1H), 7.64 (d, 2H,
J = 7.8 Hz), 7.59 (m, 1H), 7.45 (m, 1H), 6.94 (d, 2H,
J = 7.8 Hz), 5.31 (s, 2H, OCH2), 3.82 (s, 3H, OCH3), 2.54
(s, 3H, CH3); 13C NMR (d, DMSO-d6, 100 MHz): 168.1,
161.1, 155.4, 145.7, 143.6, 133.4, 129.8, 126.1, 119.9,
115.5, 56.5 (OCH3), 45.8 (OCH2), 22.3 (CH3). Anal. Calcd
for C19H17N5O2: C, 65.69; H, 4.93; N, 20.16. Found: C,
65.51; H, 5.05; N, 20.08.
methoxy)quinazoline (3k)
White solid, 82 % yield, mp 175–176 °C, IR (KBr) mmax
3431, 2948, 1674, 1607, 1474, 1392, 1291, 1221, 1185,
1
1043, 985, 949, 871, 777, 716; H NMR (d, DMSO-d6,
:
400 MHz): 11.79 (s, 1H, [NH, D2O exchangeable), 8.14
(m, 1H), 7.82 (m, 2H), 7.72 (m, 1H), 7.53 (m, 1H), 6.84 (m,
1H), 6.72 (m, 1H), 5.21 (s, 2H, OCH2), 2.51 (s, 3H, CH3);
13C NMR (d, DMSO-d6, 100 MHz): 167.6, 161.0, 148.4,
137.1, 138.3, 133.6, 128.1, 127.0, 125.8, 120.8, 46.3
(OCH2), 22.2 (CH3). Anal. Calcd for C16H13N5OS: C,
59.43; H, 4.05; N, 21.66. Found: C, 59.11; H, 3.90; N,
22.51.
4-((5-(3,4-Dimethoxyphenyl)-4H-1,2,4-triazol-3-
yl)methoxy)-2-methylquinazoline (3h)
White solid, 92 % yield, mp 208–210 °C, IR (KBr) mmax
:
3403, 2927, 1672, 1605, 1465, 1413, 1295, 1254, 1144,
981, 871, 744, 634, 481; 1H NMR (d, DMSO-d6,
400 MHz): 11.66 (s, 1H, D2O exchangeable), 8.14 (m, 1H),
7.61 (m, 1H), 7.45 (d, 2H, J = 7.8 Hz), 7.34 (m, 1H), 6.94
(d, 2H, J = 7.8 Hz), 5.33 (s, 2H, OCH2), 3.86 (s, 6H, 29
OCH3). 2.55 (s, 3H, CH3); 13C NMR (d, DMSO-d6,
100 MHz): 168.0, 151.0, 149.2, 133.3, 127.0, 125.3, 122.9,
119.9, 110.3, 107.6, 58.7 (OCH3), 45.8 (OCH2), 22.3
(CH3). Anal. Calcd for C20H19N5O3: C, 63.65; H, 5.07; N,
18.56. Found: C, 63.70; H, 4.94; N, 18.11.
4-((5-Phenyl-4H-1,2,4-triazol-3-yl)methoxy)-2-
(trifluoromethyl)quinazoline (4a)
White solid, 92 % yield, mp 212–213 °C, IR (KBr) mmax
3428, 2928, 1671, 1609, 1475, 1392, 1274, 1222, 1185,
1
1044, 985, 956, 871, 752, 626; H NMR (d, DMSO-d6,
:
400 MHz): 11.81 (s, 1H, [NH, D2O exchangeable), 8.37
(m, 1H), 8.14 (m, 1H), 8.05 (m, 1H), 7.82 (m, 1H), 7.69 (d,
2H, J = 7.8 Hz), 7.53 (m, 1H), 7.43 (d, 2H, J = 7.8 Hz),
5.22 (s, 2H, OCH2); 13C NMR (d, DMSO-d6, 100 MHz):
168.7, 163.9, 160.7, 149.0, 148.5, 147.7, 144.7, 134.9,
130.5, 129.3, 127.8, 127.4, 126.5, 121.9, 47.4 (OCH2).
Anal. Calcd for C18H12F3N5O: C, 58.22; H, 3.26; N, 18.86.
Found: C, 58.48; H, 3.44; N, 19.05.
2-Methyl-4-((5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazol-
3-yl)methoxy)quinazoline (3i)
White solid, 96 % yield, mp 244–245 °C, IR (KBr) mmax
:
3400, 2928, 1674, 1605, 1477, 1443, 1282, 1264, 1174,
987, 921, 876, 774, 694, 524; 1H NMR (d, DMSO-d6,
400 MHz): 11.67 (s, 1H, [NH, D2O exchangeable), 8.14
(m, 1H), 7.61 (m, 1H), 7.44 (m, 2H), 7.36 (s, 2H), 5.29 (s,
2H, OCH2), 3.89 (s, 6H, 29 –OCH3), 3.75 (s, 3H, OCH3),
2.53 (s, 3H, CH3); 13C NMR (d, DMSO-d6, 100 MHz):
167.5, 151.1, 148.2, 135.4, 133.4, 127.1, 124.8, 122.9,
117.3, 58.9 (OCH3), 56.8 (OCH3), 45.3 (OCH2), 22.2
(CH3). Anal. Calcd for C21H21N5O4: C, 61.91; H, 5.20; N,
17.19. Found: C, 61.69; H, 5.33; N, 17.11.
4-((5-(4-Fluorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
(trifluoromethyl)quinazoline (4b)
White solid, 94 % yield, mp 259–261 °C, IR (KBr) mmax
3429, 2928, 1711, 1663, 1612, 1471, 1358, 1291, 1244,
1
1185, 1052, 995, 871, 767, 681; H NMR (d, DMSO-d6,
:
400 MHz): 11.78 (s, 1H, [NH, D2O exchangeable), 8.18
(m, 1H), 8.07 (m, 1H), 7.82 (m,1H), 7.89 (d, 2H,
J = 7.6 Hz), 7.53 (m, 1H), 7.39 (d, 2H, J = 7.6 Hz), 5.17
(s, 2H, OCH2); 13C NMR (d, DMSO-d6, 100 MHz): 168.5,
160.7, 148.3, 147.5, 144.7, 134.2, 132.1, 129.3, 128.0,
127.4, 125.2, 119.9, 47.2 (OCH2). Anal. Calcd for
C18H11F4N5O: C, 55.53; H, 2.85; N, 17.99. Found: C,
55.18; H, 3.00; N, 18.20.
4-((5-(Furan-2-yl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
methylquinazoline (3j)
White solid, 85 % yield, mp 180–182 °C, IR (KBr) mmax
:
3402, 2925, 1672, 1609, 1476, 1390, 1226, 1063, 1014,
977, 780; 1H NMR (d, DMSO-d6, 400 MHz): 11.81 (s, 1H,
[NH, D2O exchangeable), 8.16 (m, 1H), 7.81 (m, 2H),
7.69 (m, 1H), 7.57 (m, 1H), 6.89 (m, 1H), 6.69 (m, 1H),
5.19 (s, 2H, OCH2), 2.49 (s, 3H, CH3); 13C NMR (d,
DMSO-d6, 100 MHz): 167.9, 160.1, 148.1, 137.1, 138.0,
134.1, 128.8, 127.4, 126.3, 120.7, 46.1 (OCH2), 22.3
(CH3). Anal. Calcd for C16H13N5O2: C, 62.53; H, 4.26; N,
22.79. Found: C, 62.88; H, 4.01; N, 23.00.
4-((5-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
(trifluoromethyl)quinazoline (4c)
White solid, 95 % yield, mp 176–177 °C, IR (KBr) mmax
:
3420, 2929, 1671, 1607, 1475, 1342, 1271, 1246, 1185, 1147,
1054, 990, 871, 757, 680; 1H NMR (d, DMSO-d6,
400 MHz): 11.78 (s, 1H, [NH, D2O exchangeable), 8.17
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Med Chem Res (2014) 23:848–861
4-((5-(4-Methoxyphenyl)-4H-1,2,4-triazol-3-yl)methoxy)-
(m, 1H), 8.08 (m, 1H), 7.82 (m, 1H), 7.88 (d, 2H,
J = 7.8 Hz), 7.54 (m, 1H), 7.32 (d, 2H, J = 7.8 Hz), 5.15 (s,
2H, OCH2); 13C NMR (d, DMSO-d6, 100 MHz): 167.8,
160.0, 149.0, 148.1, 146.5, 144.7, 133.6, 130.5, 129.0, 127.8,
124.5, 120.1, 47.5 (OCH2). Anal. Calcd for C18H11ClF3N5O:
C, 53.28; H, 2.73; N, 17.26. Found: C, 55.50; H, 2.73; N,
17.01.
2-(trifluoromethyl)quinazoline (4g)
White solid, 95 % yield, mp 216–218 °C, IR (KBr) mmax
:
2950, 1675, 1609, 1570, 1513, 1474, 1369, 1304, 1252,
1170, 1028, 957, 831, 774; 1H NMR (d, DMSO-d6,
400 MHz): 11.64 (s, 1H, [NH, D2O exchangeable), 8.34
(m, 1H), 8.14 (m, 1H), 7.81 (m, 1H), 7.65 (d, 2H,
J = 7.8 Hz), 7.52 (m, 1H), 6.98 (d, 2H, J = 7.8 Hz), 5.21
(s, 2H, OCH2), 3.81 (s, 3H, OCH3); 13C NMR (d, DMSO-
d6, 100 MHz): 170.4, 150.7, 147.6, 145.5, 135.6, 131.9,
129.9, 128.6, 127.4, 124.0, 117.8, 115.7, 56.8 (OCH3), 49.4
(OCH2).Anal. Calcd for C19H14F3N5O2: C, 56.86; H, 3.52;
N, 17.45. Found: C, 56.99; H, 3.88; N, 17.18.
4-((5-(4-Bromophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
(trifluoromethyl)quinazoline (4d)
White solid, 91 % yield, mp 236–238 °C, IR (KBr) mmax
:
3214, 2929, 1710, 1612, 1598, 1474, 1339, 1268, 1181,
1111, 1013, 918, 852, 774; 1H NMR (d, DMSO-d6,
400 MHz): 11.81 (s, 1H, [NH, D2O exchangeable), 8.45
(m, 1H), 8.14 (m, 1H), 7.89 (m, 1H), 7.75 (d, 2H,
J = 7.8 Hz), 7.54 (m, 1H), 7.57 (d, 2H, J = 7.8 Hz), 5.20
(s, 2H, OCH2); 13C NMR (d, DMSO-d6, 100 MHz): 167.1,
160.0, 151.1, 148.2, 145.8, 136.2, 130.0, 125.1, 122.8,
120.5, 112.2, 110.0, 45.2 (OCH2). Anal. Calcd for
C18H11BrF3N5O: C, 48.02; H, 2.46; N, 15.56. Found: C,
48.35; H, 2.40; N, 15.80.
4-((5-(3,4-Dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)
methoxy)-2-(trifluoromethyl)quinazoline (4h)
White solid, 94 % yield, mp 224–226 °C, IR (KBr) mmax
:
2956, 1699, 1675, 1615, 1522, 1477, 1409, 1370, 1332,
1263, 1167, 1134, 1024, 808, 777; 1H NMR (d, DMSO-d6,
400 MHz): 11.49 (s, 1H, [NH, D2O exchangeable), 8.15
(m, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.42 (m, 1H), 7.25 (s,
1H), 7.08 (d, 1H, J = 7.4 Hz), 6.84 (d, 1H, J = 7.4 Hz),
5.18 (s, 2H, OCH2), 3.81 (s, 6H, 29 –OCH3); 13C NMR (d,
DMSO-d6, 100 MHz): 167.9, 150.7, 149.3, 145.8, 135.1,
133.0, 128.0, 126.2, 122.8, 121.7, 120.6, 112.2, 109.3, 56.7
(OCH3), 54.8 (OCH3), 45.2 (OCH2). Anal. Calcd for
C20H16F3N5O3: C, 55.09; H, 3.74; N, 16.23. Found: C,
55.78; H, 4.00; N, 16.10.
4-((5-(4-Hydroxyphenyl)-4H-1,2,4-triazol-3-yl)methoxy)-
2-(trifluoromethyl)quinazoline (4e)
White solid, 92 % yield, mp 301–302 °C, IR (KBr) mmax
:
3321, 2926, 1723, 1605, 1563, 1511, 1474, 1262, 1129,
1
1067, 845; H NMR (d, DMSO-d6, 400 MHz): 11.57 (s,
1H, [NH, D2O exchangeable), 9.63 (brs, 1H, OH, D2O
exchangeable), 8.29 (m, 1H), 8.13 (m, 1H), 7.87 (m, 1H),
7.74 (d, 2H, J = 8.0 Hz), 7.65 (m, 1H), 7.46 (d, 2H,
J = 8.0 Hz), 5.20 (s, 2H, OCH2); 13C NMR (d, DMSO-d6,
100 MHz): 167.4 160.3, 150.1, 148.2, 143.6, 135.4, 128.1,
126.2, 125.1, 122.0, 121.7, 119.5, 112.2, 110.0, 45.7
(OCH2). Anal. Calcd for C18H12F3N5O2: C, 55.82; H, 3.12;
N, 18.08. Found: C, 56.01; H, 3.50; N, 17.81.
2-Trifluoromethyl-4-((5-(3,4,5-Trimethoxyphenyl)-4H-
1,2,4-triazol-3-yl)methoxy)quinazoline (4i)
White solid, 96 % yield, mp 238–239 °C, IR (KBr) mmax
:
2940, 1701, 1672, 1617, 1582, 1500, 1464, 1420, 1369,
1325, 1293, 1230, 1129, 1014, 957, 771; 1H NMR (d,
DMSO-d6, 400 MHz): 11.65 (s, 1H, [NH, D2O
exchangeable), 8.17 (m, 1H), 7.73 (m, 1H), 7.67 (m, 1H),
7.48 (m, 1H), 6.87 (s, 2H), 5.20 (s, 2H, OCH2), 3.80 (s, 6H,
29 –OCH3), 3.78 (s, 3H, OCH3); 13C NMR (d, DMSO-d6,
100 MHz): 168.0, 160.5, 153.4, 148.4, 144.8, 139.5, 134.6,
129.5, 126.7, 104.1, 60.7 (OCH3), 56.1 (OCH3-), 47.4
(OCH2). Anal. Calcd for C21H18F3N5O4: C, 54.67; H, 3.93;
N, 15.18. Found: C, 54.65; H, 4.04; N, 14.98.
4-((5-(p-Tolyl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
(trifluoromethyl)quinazoline (4f)
White solid, 92 % yield, mp 222–223 °C, IR (KBr) mmax
:
2926, 1671, 1612, 1541, 1425, 1393, 1322, 1222, 1174,
1114, 1054, 986, 847, 751; 1H NMR (d, DMSO-d6,
400 MHz): 11.80 (s, 1H, [NH, D2O exchangeable), 8.32
(m, 1H), 8.14 (m, 1H), 7.79 (m, 1H), 7.58 (d, 2H,
J = 7.8 Hz), 7.50 (m, 1H), 7.21 (d, 2H, J = 7.6 Hz), 5.21
(s, 2H, OCH2), 2.21 (s, 3H, CH3); 13C NMR (d, DMSO-d6,
100 MHz): 168.3, 160.6, 150.1, 147.3, 143.6, 140.0, 135.6,
130.6, 128.2, 127.4, 126.0, 125.2, 121.8, 47.2 (OCH2), 22.2
(CH3). Anal. Calcd for C19H14F3N5O: C, 59.22; H, 3.66; N,
18.17. Found: C, 59.61; H, 4.01; N, 17.98.
4-((5-(Furan-2-yl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
(trifluoromethyl)quinazoline (4j)
White solid, 96 % yield, mp 216–217 °C, IR (KBr) mmax
:
3221, 1668, 1611, 1560, 1545, 1472, 1367, 1325, 1221,
1173, 1067, 936, 881, 766; 1H NMR (d, DMSO-d6,
400 MHz): 11.80 (s, 1H, [NH, D2O exchangeable), 8.36
123

Med Chem Res (2014) 23:848–861
859
(m, 1H), 8.17 (d, 1H, J = 7.8 Hz), 7.81 (m, 1H), 7.69 (m,
1H), 7.54 (m, 1H), 6.88 (m, 1H), 6.59 (m, 1H), 5.17 (s, 2H,
OCH2); 13C NMR (d, DMSO-d6, 100 MHz): 167.9, 160.1,
148.4, 139.5, 138.0, 134.1, 128.8, 127.5, 126.3, 121.1, 47.4
(OCH2). Anal. Calcd for C16H10F3N5O2: C, 53.19; H, 2.79;
N, 19.38. Found: C, 52.97; H, 3.00; N, 19.44.
7.72 (m, 2H), 7.37 (m, 2H); 13C NMR (d, DMSO-d6,
100 MHz): 162.1, 152.4, 149.1, 144.9, 140.6, 136.8, 130.5,
128.2, 127.4, 127.2, 123.9, 122.1. Anal. Calcd for
C13H9ClN4: C, 60.83; H, 3.53; N, 21.83. Found: C, 70.01;
H, 3.11; N, 21.55.
3-(5-(4-Bromophenyl)-4H-1,2,4-triazol-3-yl)pyridine (6d)
4-((5-(Thiophen-2-yl)-4H-1,2,4-triazol-3-yl)methoxy)-2-
(trifluoromethyl)quinazoline (4k)
White solid, 92 % yield, mp 157–159 °C, IR (KBr) mmax
:
3375, 3032, 1654, 1603, 1595, 1489, 1402, 1363, 1298,
1
1152, 1129, 1089, 1013, 915, 826, 725, 519; H NMR (d,
White solid, 98 % yield, mp 235–236 °C, IR (KBr) mmax
:
2946, 1672, 1613, 1473, 1424, 1360, 1320, 1292, 1222,
1169, 1041, 952, 778, 698; 1H NMR (d, DMSO-d6,
400 MHz): 11.68 (s, 1H, [NH, D2O exchangeable), 8.24
(m, 1H), 7.80 (m, 1H), 7.52 (m, 1H), 7.51 (m, 2H), 7.28 (m,
1H), 7.06 (m, 1H), 5.19 (s, 2H, OCH2); 13C NMR (d,
DMSO-d6, 100 MHz): 167.9, 163.2, 160.3, 148.1, 139.5,
138.5, 134.5, 128.8, 127.1, 126.0, 121.4, 47.5 (OCH2).
Anal. Calcd for C16H10F3N5OS: C, 50.93; H, 2.67; N,
18.56. Found: C, 51.17; H, 2.65; N, 18.19.
DMSO-d6, 400 MHz): 11.99 (s, 1H, [NH, D2O
exchangeable), 9.09 (s, 1H), 8.69 (m, 2H), 8.27 (m, 1H),
7.60 (m, 2H), 7.45 (m, 2H); 13C NMR (d, DMSO-d6,
100 MHz): 163.3, 152.1, 147.9, 145.0, 136.3, 130.6, 129.0,
121.2, 116.4. Anal. Calcd for C13H9F3N4: C, 51.85; H,
3.01; N, 18.60. Found: C, 51.55; H, 3.00; N, 18.91.
3-(5-(4-Hydroxyphenyl)-4H-1,2,4-triazol-3-yl)pyridine
(6e)
3-(5-Phenyl-4H-1,2,4-triazol-3-yl)pyridine (6a)
White solid, 96 % yield, mp 221–223 °C, IR (KBr) mmax
:
3422, 3065, 1651, 1607, 1517, 1480, 1376, 1291, 1261,
1
1172, 1060, 920, 812, 710, 527; H NMR (d, DMSO-d6,
White solid, 90 % yield, mp 116–117 °C, IR (KBr) mmax
:
3270, 3060, 1650, 1610, 1587, 1551, 1355, 1284, 1131,
1
400 MHz): 11.63 (s, 1H, [NH, D2O exchangeable), 9.58
(s, 1H, OH, D2O exchangeable), 9.05 (s, 1H), 8.64 (m, 1H),
8.27 (m, 2H), 7.52 (m, 2H), 6.76 (m, 2H); 13C NMR (d,
DMSO-d6, 100 MHz): 163.8, 152.2, 148.5, 146.9, 135.8,
130.3, 128.7, 123.5, 115.6. Anal. Calcd for C13H10N4O: C,
65.54; H, 4.23; N, 23.52. Found: C, 65.19; H, 4.55; N,
23.59.
1064, 1021, 956, 913, 830, 753, 691, 612; H NMR (d,
DMSO-d6, 400 MHz): 11.86 (s, 1H, D2O exchangeable),
9.11 (s, 1H), 8.67 (m, 1H), 8.27 (m, 1H), 7.69 (m, 2H), 7.52
(m, 1H), 7.41 (m, 1H), 7.32 (m, 2H); 13C NMR (d, DMSO-
d6, 100 MHz): 162.3, 151.7, 150.2, 148.5, 136.4, 134.0,
130.4, 128.7, 127.6, 123.6. Anal. Calcd for C13H10N4: C,
70.26; H, 4.54; N, 25.21 Found: C, 70.55; H, 4.33; N,
25.51.
3-(5-(p-Tolyl)-4H-1,2,4-triazol-3-yl)pyridine (6f)
3-(5-(4-Fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine (6b)
White solid, 95 % yield, mp 93–95 °C, IR (KBr) mmax
:
3375, 3023, 1671, 1604, 1363, 1300, 1150, 1094, 1067,
970, 916, 816, 717, 517; 1H NMR (d, DMSO-d6,
400 MHz): 11.94 (s, 1H, D2O exchangeable), 9.02 (s, 1H),
8.64 (m, 1H), 8.36 (m, 1H), 8.20 (m,1H), 7.58 (d, 2H,
J = 7.5 Hz), 7.21 (d, 2H, J = 7.5 Hz), 2.42 (s, 3H, CH3);
13C NMR (d, DMSO-d6, 100 MHz): 162.1, 152.7, 149.0,
144.9, 140.2, 135.9, 130.5, 129.7, 128.8, 127.2, 124.0,
123.4, 21.5 (CH3). Anal. Calcd for C14H12N4: C, 71.17; H,
5.12; N, 23.71. Found: C, 71.51; H, 5.18; N, 23.45.
White solid, 92 % yield, mp 177–179 °C, IR (KBr) mmax
3462, 2924, 1653, 1601, 1593, 1509, 1363, 1303, 1231,
1
1154, 1101, 945, 918, 838, 705, 532; H NMR (d, DMSO-
d6, 400 MHz): 11.82 (s, 1H, [NH, D2O exchangeable),
9.01 (s, 1H), 8.62 (m, 2H), 8.17 (m, 1H), 7.73 (m, 2H), 7.37
(m, 2H); 13C NMR (d, DMSO-d6, 100 MHz): 165.0, 152.2,
148.9, 147.9, 135.8, 130.6, 129.6, 123.5, 115.9. Anal.
Calcd for C13H9FN4: C, 64.99; H, 3.78; N, 23.32. Found:
C, 64.87; H, 4.05; N, 23.01.
:
3-(5-(4-Methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridine
3-(5-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)pyridine (6c)
(6g)
White solid, 90 % yield, mp 181–183 °C, IR (KBr) mmax
:
White solid, 92 % yield, mp 121–122 °C, IR (KBr) mmax
:
3378, 3023, 1661, 1607, 1593, 1559, 1485, 1421, 1360,
1297, 1151, 1129, 1068, 1009, 915, 823, 725, 512; 1H
NMR (d, DMSO-d6, 400 MHz): 12.01 (s, 1H, [NH, D2O
exchangeable), 9.12 (s, 1H), 8.70 (m, 2H), 8.32 (m, 1H),
3449, 2925, 1683, 1607, 1515, 1378, 1297, 1252, 1177,
1
1069, 1018, 829, 731; H NMR (d, DMSO-d6, 400 MHz):
11.90 (s, 1H, D2O exchangeable), 9.05 (s, 1H), 8.74 (m,
1H), 8.23 (m, 1H), 7.67 (d, 2H, J = 7.6 Hz), 7.54 (m, 1H),
123

860
Med Chem Res (2014) 23:848–861
6.99 (d, 2H, J = 7.6 Hz), 3.78 (s, 3H, OCH3); 13C NMR
(d, DMSO-d6, 100 MHz): 162.1, 152.6, 149.0, 144.7,
137.6, 130.4, 129.7, 128.8, 127.0, 124.0, 123.4, 114.8, 55.7
(OCH3). Anal. Calcd for C14H12N4O: C, 66.65; H, 4.79; N,
22.21. Found: C, 70.01; H, 4.88; N, 22.05.
9.09 (s, 1H), 8.67 (m, 1H), 8.24 (m, 1H), 7.52 (m, 2H), 7.39
(m, 1H), 7.10 (m, 1H); 13C NMR (d, DMSO-d6, 100 MHz):
163.1, 152.2, 148.3, 145.9, 135.9, 131.3, 128.7, 124.6,
113.8. Anal. Calcd for C11H8N4S: C, 84.18; H, 3.53; N,
30.68. Found: C, 84.50; H, 3.19; N, 31.00.
Acknowledgments Siva S. Panda is thankful to UGC (New Delhi)
for financial assistance. Authors also thank Girinath G. Pillai, Tech-
nical Consultant, Mumbai, India (2009) currently working as
Research Scholar, University of Florida, Gainesville, FL, USA (2011)
for his support in the prediction of QSAR models using freely
accessible software. G.G. Pillai is grateful to Dr. Alexander Drijver,
ChemAxon Kft., Hungary for Marvin Suite Licenses.
3-(5-(3,4-Dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridine
(6h)
White solid, 95 % yield, mp 118–120 °C, IR (KBr) mmax
:
3413, 2928, 1671, 1603, 1422, 1329, 1309, 1269, 1237,
1168, 1139, 1071, 1023, 898, 752; 1H NMR (d, DMSO-d6,
400 MHz): 11.86 (s, 1H, [NH, D2O exchangeable), 9.06
(s, 1H), 8.69 (m, 1H), 8.24 (m, 2H), 7.48 (m, 2H), 7.35 (s,
1H), 3.83 (s, 6H, 29 –OCH3); 13C NMR (d, DMSO-d6,
100 MHz): 161.9, 151.8, 152.1, 149.4, 148.7, 136.0, 129.7,
127.2, 123.9, 122.6, 111.3, 55.9 (OCH3). Anal. Calcd for
C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 64.11;
H, 5.08; N, 19.51.
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3065, 1672, 1644, 1609, 1584, 1561, 1475, 1421, 1284,
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d6, 400 MHz): 11.92 (s, 1H, [NH, D2O exchangeable),
9.08 (s, 1H), 8.67 (m, 1H), 8.25 (m, 1H), 7.54 (m, 2H), 7.39
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:
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1220, 1147, 1095, 904, 854, 708, 629; 1H NMR (d, DMSO-
d6, 400 MHz): 11.94 (s, 1H, [NH, D2O exchangeable),
123

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