A click chemistry strategy to synthesize geraniol-coupled 1,4-disubstituted 1,2,3-triazoles and exploration of their microbicidal and antioxidant potential with molecular docking profile

Article abstract of DOI:10.1007/s00044-015-1329-5

The present paper elicits an unprecedented synthesis of a novel series of 1,2,3-triazole compounds using geraniol as the precursor via 1,3-dipolar cycloaddition using click chemistry strategy. All the synthesized compounds were screened to evaluate their

Full text of DOI:10.1007/s00044-015-1329-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1329-5
ORIGINAL RESEARCH
A click chemistry strategy to synthesize geraniol-coupled 1,4-
disubstituted 1,2,3-triazoles and exploration of their microbicidal
and antioxidant potential with molecular docking profile
Nitin Dubey
Pratibha Sharma
•
Mukesh C. Sharma
•
Ashok Kumar
•
Received: 23 August 2014 / Accepted: 19 January 2015
Ó Springer Science+Business Media New York 2015
Abstract The present paper elicits an unprecedented
synthesis of a novel series of 1,2,3-triazole compounds
using geraniol as the precursor via 1,3-dipolar cycloaddi-
tion using click chemistry strategy. All the synthesized
compounds were screened to evaluate their microbicidal
and antioxidant potentials. The antibacterial activity of all
the new compounds was assessed by the micro-broth
dilution technique against a panel of Gram-positive
Staphylococcus aureus (MTCC 3160), Bacillus cereus
Introduction
During the past decade, the incidence of microbial infec-
tion has increased to alarming levels around the world. The
main culprit probably is the resistance developed against
existing antimicrobial drugs (Barbuceanu et al., 2012). In
particular, multidrug-resistant Gram-positive bacteria are
major concerns to the public health (Thomas et al., 2010).
Therefore, a prudent way to combat this challenge is the
conscious usage of the currently marketed antibiotics
(Bandyopadhyay et al., 2011). Today, design and devel-
opment of new compounds to deal with bacterial resistance
has become one of the most important challenging areas of
antibacterial research (Guzeldemirci and Kucukbasmaci,
2010). Furthermore, according to the modern theory of free
radical biology and medicine, reactive oxygen species
(ROS) are involved in several disorders, such as cardio-
vascular diseases and cancers (Harini et al., 2012). Reac-
tive oxygen species capable of causing damage to DNA has
been associated with carcinogenesis, coronary heart disease
and many other health problems related to growing age.
Therefore, in order to cater the need of potential antioxi-
dative agents, a focus of the major thrust relies on to
develop some new molecules of such a biological
significance.
(
MTCC 430), and Gram-negative Escherichia coli (MTCC
610) and Pseudomonas aeruginosa (MTCC 2295). Fur-
1
thermore, evaluation of their antioxidative behavior mani-
fested the remarkable free radical scavenging activity using
DPPH assay. Also, the docking study of the compounds
was performed on complex structure of E.coli FabH
(
1HNJ. pdb) using VLife MDS 3.5 software. Significant
dock score of 5g (-80.121 kcal/mol) in comparison with
the standard ciprofloxacin (-88.263 kcal/mol) has been
figured out upon molecular docking.
Keywords Geraniol ꢀ Triazole ꢀ Antibacterial ꢀ
Antioxidant ꢀ Molecular docking
Out of a number of heterocyclic compounds, the triazole
derivatives have attracted the attention of medicinal
chemists to develop its unexplored potentials (Zoumpou-
lakis et al., 2012). These have been known to exhibit wide
range of therapeutic properties, viz. antimicrobial (Sudh-
eendran et al., 2014), antitumor (Demirbas and Ugurluoglu,
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-015-1329-5) contains supplementary
material, which is available to authorized users.
N. Dubey ꢀ A. Kumar ꢀ P. Sharma (&)
School of Chemical Sciences, Devi Ahilya University, Khandwa
Road, Indore 452 001, MP, India
e-mail: drpratibhasharma@yahoo.com
2
002), anti-inflammatory (Reddy et al., 2008), antihyper-
tensive (Siddiqui et al., 2011), analgesic (Vijesh et al.,
013), anticonvulsant (Almasirad et al., 2004), antiviral
(De Clercq, 2004), antidepressant (Radhika et al., 2012),
M. C. Sharma
School of Pharmacy, Devi Ahilya University, Khandwa Road,
Indore 452 001, MP, India
2
123

Med Chem Res
antitubercular (Kucukguzel et al., 2001), sedative (Delgado
and Remers, 1998) and antioxidant activities (Trakossas
et al., 2011). Also, a number of potent drugs possessing
triazole nucleus have been investigated as important
medicinal agents, viz. fluconazole, itraconazole and terco-
nazole (antifungal agents), and triazolam (sedative and
hypnotic) (Fig. 1; Khalil, 2010). It was observed that 1,2,3-
triazole coupled to other pharmacophores has resulted in
potent antibacterial agents. Therefore, coupling of triazole
nucleus with pharmaceutically important geraniol molecule
has turned out to be potentially significant antibacterial
agent. Geraniol (3,7-dimethylocta-2,6-dien-1-ol) is recog-
nized as safe GRAS by FDA (Kim et al., 2011). It is a
natural acyclic monoterpenoid derived from herb oils. This
monoterpenoid alcohol is widely used as fragrance material
in the perfumes, cosmetics, soap and flavor industries. It is
used in flavors, especially as peach, raspberry, grapefruit,
orange, lemon, watermelon, pineapple and blueberry. Also,
it has been used as insect repellants or deterrents (Bakkali
et al., 2008). In addition to this, experimental studies
demonstrated several pharmacological activities including
antioxidant and antibacterial potential of geraniol (Tiwari
and Kakkar, 2009).
Therefore, in continuation of our enduring research on the
synthesis of biologically significant compounds (Sharma
et al., 2004; 2005a, b, 2008, 2010; Kumar et al., 2006), we
have synthesized novel 1,2,3-triazole–geraniol coupled
hybrid compounds via click strategy followed by the
evaluation of their antibacterial and antioxidant assays
(Ji et al., 2013). This study demonstrated a worthy com-
bination of a natural entity with a synthesized compound.
The final series of synthesized compounds were also
docked on the enzyme E.coli FabH. However, to the best of
our knowledge, this combination has not been reported and
studied. For the first time our team has reported the syn-
thesis of 1,2,3-triazole–geraniol derivative and explored
their pharmacological activities.
Results and discussion
Chemistry
The synthesis of 1-azido-3,7-dimethylocta-2,6-diene 3 was
carried out as per the literature method (Singh et al., 2011)
involving a base-assisted reaction between geraniol and
tosyl chloride to yield the corresponding 3,7-dimethylocta-
2,6-dienyl 4-methylbenzenesulfonate 2, followed by sub-
sequent reaction with sodium azide in DMF at 60 °C. The
second precursor 4 was prepared by the literature method
(Scheme 1) (Ishikawa et al., 1997, Pal et al., 2003; Joshi
et al., 2006). The target compounds 5a–s were synthesized
through azide–alkyne cycloaddition reaction of appropriate
precursors 3 and 4 in the presence of copper catalyst
(Scheme 2). The purification of the reaction mixture, after
usual workup via column chromatography resulted in the
isolation of desired scaffolds. The structures of all the
compounds were assigned on the basis of spectral data and
analytical evidences (Table 1).
Successively, interest in the development of efficient
methods for the synthesis of triazole, bearing multiple and
diverse substitution patterns, has aroused. In this regard,
Huisgen cycloaddition reaction (Huisgen, 1963) of dipol-
arophiles with 1,3-dipoles was the first set of reactions that
drew the attention of synthetic organic chemists to syn-
thesize five-membered heterocycles including triazoles
without the use of fancy reagents. Among various cyclo-
addition reactions, the azide–alkyne cycloaddition reaction
was quickly identified as the most efficient approach to
conjugation of two or more molecules. Later, Sharpless and
co-workers set a milestone in discovering copper-catalyzed
alkyne–azide cycloaddition with exceptional regioselec-
tivity and introduced the philosophy of ‘‘click chemistry’’
(
Kolb et al., 2001) Hence, keeping in view the increasing
In vitro antibacterial activity
necessity of new molecules which can combat these
pharmaceutical ailments, it was our endeavor to develop
hybrid molecules composed of geraniol and triazole nuclei.
The antibacterial activity (zone of growth inhibition) of
the tested 1, 4-disubstituted triazoles (5a–s) against two
N
N
N
N
N
O
N
N
N
HO
N
N
N
N
N
O
N
N
N
N
N
N
O
O
N
Cl
N
F
O
Cl
O
H
N
O
Cl
N
Cl
F
Itraconazole
Triazolam
Terconazole
Fluconazole
Fig. 1 Structures of some medicinal agents containing triazole moiety
1
23

Med Chem Res
antibacterial activity of the compounds 5h–j and 5l.
Compound 5a having CHO group at the para position of
the phenyl ring exhibit potent antibacterial activity against
B. cereus and S. aureus (zone of inhibition 32 and 28 mm),
while it has been less active against Gram-negative bac-
teria. When we substitute at para position of the phenyl
ring by methyl or chloro group, we found very good anti-
bacterial activity of these compounds 5c and 5e with zone
of inhibition 30, 32, 19 and 33, 31, 21 in mm against
B. cereus S. aureus and P. aerogenasa. But there is no zone
of inhibition in case of E. coli. In compound 5f, wherein
electron-withdrawing substituent –Cl is attached, ortho to
phenyl group of triazole ring shows moderate biological
activity. The compound with nitro group at para position
possesses slightly better activity as compared to its ortho
part (5m, 5n). It is remarkable that compounds 5a, 5o and
Scheme 1 Synthetic pathway for precursor aryl prop-2-yn-1-yl ether
5p possessed a significant activity against Gram-positive
bacteria. From structural subset of 19 compounds, it is
evident from Table 3 that substitution at ortho position of
the phenyl ring has negative effect on the antibacterial
activity (5b, 5d and 5f), while without any substitution in
phenyl ring compound 5o shows good antibacterial activ-
ity. Similarly, compound 5p having phenyl group directly
attached with the triazole ring exhibits potent antibacterial
activity. The bactericidal activity of compounds 5q and 5r
can be due to more rigidity resulting from the presence of
pyridine nucleus, which is also directly attached with the
triazole ring. It is noteworthy to mention that compound 5s
was found to be selectively active against diarrhea causing
bacteria E. coli.
Scheme 2 Synthetic pathway of (1-(3,7-dimethylocta-2,6-dienyl)-4-
(
arylmethyl)-1H-1,2,3-triazole) (5a–s)
Finally, five compounds 5g, 5c, 5d, 5a and 5e have
shown better and equal antibacterial activity against
Gram-positive strains than that of ciprofloxacin, which
was used as the standard drug in this study. Our results
showed that B. cereus was the most susceptible species to
triazole derivates tested in this work. Despite relatively
small number of synthesized derivatives, it is still possible
to observe significant dependences between their structure
and activity. All synthesized compounds differ from each
other by the type of substituents in position C-4 of the
1,2,3-triazole ring. From the microbiological point of
view, the key factor is the presence of phenyl ring in
position C-4 of triazole ring in 10 out of 19 derivatives.
Alkyl substituent derivative in position C-4 of triazole
ring (5l) showed devoid activity. Additionally, the more
the alkyl fragment was extended, the activity decreased
more and more (5k). Besides the presence of phenyl ring
(in position C-4 of triazole ring), an extremely important
factor is the electronic nature of substituent attached to
this ring. The structure–activity relationship study reveals
that the substituents with electron-withdrawing effect such
Gram-negative (E. coli, P. aeruginosa) and two Gram-positive
S. aureus, B. cereus) bacterial strains was determined
(
according to the literature protocol, and their results are
presented in Table 2. This process was determined by
Kirby-Bauer disk diffusion method on Mueller–Hinton
agar according to the guidelines of Clinical Laboratory
Standards Institute, 2007, USA. The obtained results were
compared to control drug ciprofloxacin. Among all the
tested compounds, most of the compounds exhibited
moderate-to-excellent activity.
Compound 5g was found to be the most potent against
Gram-positive as well as Gram-negative bacteria with zone
of inhibition in the range 32–22 mm; specifically, it was
found to be more potent against B. cereus than the refer-
ence drug ciprofloxacin. Structure and biological activity
relationship of compound showed that the presence of
hydroxyl groups in the side chain attached to the triazole
ring of the compound is responsible for good antibacterial
activity. Furthermore, incorporation of CH group in 5k
2
deteriorates its antibacterial activity. In the same way,
substitution of OH by OMe, OCOEt, tetrahydropyran or Br
functional group in compound 5g resulted in the loss of
as –NO , –Cl and –OH has resulted in the improved
2
activity.
123

Med Chem Res
Table 1 Synthesized triazole derivatives (5a–s)
Entry
R
Product
Yield (%)*
O
N
N
N
O
5a
5b
5c
5d
5e
5f
p-CHO-Ph
75
70
73
68
75
70
O
N
N
N
N
N
O
o-CHO-Ph
p-Me-Ph
o-Me-Ph
p-Cl-Ph
N
N
N
O
CH3
H C
3
N
N
O
N
N
N
O
Cl
Cl
N
N
O
o-Cl-Ph
5
g
OH
Me
N
N
82
79
HO
N
5
h
N
N
H C
3
O
N
N
N
5i
COEt
74
O
C O
N
1
23

Med Chem Res
Table 1 continued
O
N
N
5j
THP
66
O
N
5
k
l
CH
2
CH
2
OH
N
N
80
81
HO
N
5
CH
2
Br
N
Br
N
N
O N
2
N
N
N
O
5m
2
o-NO -Ph
69
N
N
N
O
NO2
5
n
o
p-NO
2
-Ph
74
72
N
N
N
O
5
Ph
Ph
5
5
5
p
q
r
N
N
78
66
62
N
N
2-Pyridine
3-Pyridine
N
N
N
N
N
N
N
5s
1-Cyclohexanol
69
N
N
O
N
*
Isolated yield
123

Med Chem Res
Table 2 Antibacterial activity of geraniol–triazole conjugates (5a–s)
Table 3 Inhibition of DPPH radical by synthesized compounds
S. No.
Zone of inhibition (mm)
Gram-positive bacteria Gram-negative bacteria
N
N
R
N
B. cereus S. aureus
MTCC
30
E. coli
MTCC
1610
P.
MTCC
3160
aeruginosa
MTCC 2295
4
a
a
Compounds
IC50 (lM)
Compound
IC50 (lM)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
32
28
12
32
14
31
13
27
–
12
–
–
b
Ascorbic acid
3.09
6.81
7.68
7.93
8.68
14.68
18.28
4.61
5.76
6.49
5j
19.34
4.27
15
30
11
33
12
32
–
10
19
–
5
5
5
5
5
5
5
5
5
a
a
b
c
d
e
f
5k
5l
–
19.84
15.28
14.28
10.47
10.18
13.22
11.44
3.35
18
–
5m
5n
5o
5p
5q
5r
5s
21
–
08
27
–
g
h
i
22
–
g
h
i
–
–
–
–
j
–
–
–
–
k
l
–
–
–
–
IC50 values were determined by linear regression analysis using at
–
–
–
–
least five different concentrations in triplicate
b
Antioxidant potential of the synthesized geraniol–triazole hybrid
compounds was compared to the standard antioxidant Ascorbic acid
m
n
o
p
q
r
s
12
23
35
28
18
27
–
13
21
23
24
21
25
–
08
17
–
05
15
–
Bold value indicate best results
–
–
–
21
17
–
–
more susceptible having only an outer peptidoglycan layer
which is not an effective permeability barrier, whereas the
Gram-negative bacteria possess an outer phospholipidic
membrane carrying the structural lipopolysaccharide
components. This makes the cell wall impermeable to drug
constituents. The results for the antibacterial activity of the
selected synthesized compounds against S. aureus MTCC
17
28
ciprofloxacin* 29
30
26
Concentration of compounds was 0.2 mg/mL in DMSO. The tests
were repeated in triplicate, and the average values were taken to show
the inhibitory activity of the synthesized triazole derivatives against
the selected sets of bacteria
* Antibacterial activity of the synthesized compounds was compared
to the standard antibacterial drug ciprofloxacin
3
160, B. cereus MTCC 430, P. aeruginosa MTCC 2295
and E. coli MTCC 1610 are graphically represented in
Fig. 2.
It is obvious that different compounds respond in dif-
ferent ways against bacteria. Gram-positive bacteria seem
to be more susceptible in these compounds than Gram-
negative species. The susceptibility of a microorganism
depends, first of all, on the properties of the agents and
second on the microorganism itself (Ezabadi et al., 2008).
These observations are in conformity to our obtained
results. All the compounds showed good-to-moderate
antibacterial activity against Gram-positive bacteria and
moderate to lack of activity against selected Gram-negative
bacterial strains. The increase in activity of new triazole
derivatives toward Gram-positive bacteria may be related
to the permeation process of drug molecules across the
bacterial cell wall. This may be due to the absence of a
unique outer membrane in Gram-positive bacteria, and
hence, the wall of Gram-positive bacteria is permeable to
these derivatives. Generally, the Gram-positive bacteria are
Fig. 2 Percent inhibition (% inhibition) of antibacterial activity for
triazole derivatives (5a–s) as compared to the standard drug
ciprofloxacin
1
23

Med Chem Res
In vitro antioxidant activity
compound 5b in which aldehyde group is attached at ortho
position. Similar trend activity was followed in case of
compounds 5c and 5d. In addition, compounds 5p and 5o
displayed effective DPPH radical scavenging activity with
IC50 values 8.68 and 10.18 lM, whereas the compounds 5r
and 5q showed moderate antioxidant activity. The intro-
The synthesized molecules (5a–s) can quench DPPH free
radical (i.e., by providing hydrogen atoms or by electron
donation, conceivably via a free radical attack on the
DPPH molecule) and convert them to a colorless/bleached
product (i.e., 2,20-diphenyl- 1-picryl-hydrazine, or a
substituted analogous hydrazine), resulting in a decrease in
absorbance at 517 nm. Hence, the more rapidly the
absorbance decreases, the more potent the radical scav-
enging activity of the compound. The inhibitory concen-
tration (IC ) value (Koparir et al., 2013), representing the
duction of groups such as –Cl and –NO on the phenyl ring
2
at C-4 position demonstrated no contribution in the
enhancement of radical scavenging capacity (5n and 5e).
The reason might be the electron-withdrawing capabilities
of these groups. Remaining compounds displayed mild
antioxidant activity. The order of antioxidant potencies was
found to be 5s > 5k > 5g > 5i > 5h > 5a > 54 > 5c > 5d
> 5o > 5p > 5r > 5q > 5n > 5e > 5 m > 5f > 5j > 5l. All
the synthesized compounds (5a–s) with IC50 values in the
range of 1.76–27.74 lM showed moderate-to-good radical
scavenging activities in comparison with ascorbic acid as
standard which was attributed to the presence of different
substituted functional groups attached to triazole ring (that
can donate hydrogen atoms) and governs the main factor
behind their ability to be scavenged by DPPH. After
donating a hydrogen atom, compounds exist in its radical
form and the electron conjugation effect in the structure
stabilizes the radical that favors the reaction to occur. On
the basis of the above observation, the electron-donating
groups such as phenol, hydroxyl groups showed positive
influence on DPPH scavenging activities, while the elec-
tron-withdrawing groups such as nitro, chloro and bromine
groups exhibited negative effect.
5
0
concentration required to exhibit 50 % antioxidant activity,
was extrapolated from the graph plotted with percentage
DPPH free radical scavenging activity (Fig. 3). Results of
these findings are presented in Table 3.
From all the synthesized derivatives, compounds 5s, 5k
and 5g showed very good scavenging activities which were
very much close to the reference antioxidant compound.
Due to the presence of hydroxyl group, these three com-
pounds exhibited highest radical scavenging activity as
compared to other compounds of the series with minimum
IC50 values (3.09–4.27 lM). Also incorporation of
–
OCOC H and –OCH groups on the triazole ring at the
2 5 3
C-4 position, (5h and 5i) exhibited good antioxidant
activity. Compounds 5a, 5b, 5c, and 5d with the IC50
values 6.49, 6.81, 7.68 and 7.93, respectively, have also
shown hydrogen-donating ability on reaction with DPPH
radical. It is inferred from the results that the antioxidant
potential of compounds is associated with the position of
the substituents on the phenyl ring. In compound 5a,
aldehyde group is attached to para position in phenyl ring
showing more antioxidant activity as compared to the
Molecular docking studies
The molecular docking of the synthetic triazole derivatives
and E.coli FabH was performed on the binding model
based on the E.coli FabH-CoA complex structure (1HNJ.
pdb) by using the VLife MDS 3.5 software, in order to go
the better understanding on the potency of compounds and
to explore further SAR studies. Docking studies showed
that various amino acid residues, viz. THR21A, TRP32A,
ARG36A, CYS112A, ARG151A, GLY152A, ILE155A,
PHE157A, LEU189A, MET207A, GLY209A, ASN210A,
VAL212A, ARG249A, PHE304A and GLY305A present
in the E.coli FabH binding pocket (in cavity ‘‘1’’) (Fig. 4),
are highly conserved and may play a major role in substrate
binding. Standard ciprofloxacin is also found to bind to
these amino acids (Fig. 6).
AA
5
5
5
5
s
k
g
i
8
7
6
5
4
3
2
0
0
0
0
0
0
0
5h
5
5
5
5
5
a
b
c
d
o
G7
g
6
F
f
5p
E5
e
5
5
q
r
D4
d
C3
c
5n
5
m
B2
b
Docking alterations was based on the interaction force
field scoring that includes van der Waals, hydrophobic, pi-
stacking and hydrogen bond interaction between active site
and ligands. After completion of the docking process, the
minimum interaction energy between each ligand and
E.coli FabH enzyme for the best ligand pose inside the
receptor cavity was obtained as the dock score, which is
1
A
a
5e
5f
5j
A1
a
5
l
0
5
10
Concentration
15
20
Fig. 3 Graphical representation of percentage (%) DPPH radical
scavenging activity for triazole derivatives (5a–s)
123

Med Chem Res
compound (1-(3,7-dimethylocta-2,6-dienyl)-1H-1,2,3-tria-
zole-4yl)methanol (5g) (Table 4; Fig. 4) has exhibited
comparable dock score (-80.121 kcal/mol) to the standard
ciprofloxacin (-88.263 kcal/mol), while left compounds
5a–5s except 5g (Table 4) displayed significant dock score
in the range -79.606 to -60.602 kcal/mol. Docking
energy gives an idea about the energy required to cover the
entire protein by a ligand molecule. Lower the value of the
docking energy, efficient will be the molecule. So this
study indicates that compound 5g binds effectively and
uniquely at the active site and interact with amino acid
residues into the FabH binding pocket.
Moreover, in the binding model of 5g, it is nicely bound
to the 1HNJ via van der Waals (VDW), hydrophobic,
pi-stacking and hydrogen bond interactions (Table 5) lead
Fig. 4 Representation of interactions between the E.coli FabH
binding pocket (PDB code: 1HNJ) and highly active compound
Table 5 van der Waals (VDW), hydrophobic, hydrogen bond and
pi-stacking interactions between compound 5g and E.coli FabH
(1-(3,7-dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4yl)methanol (5g),
which has a strong resemblance with standard drug
S. no.
Residue
Distance
Interaction type
1
2
3
4
.
.
.
.
THR28A
3.647
3.162
3.426
3.448
3.387
3.315
3.349
3.203
3.448
3.135
3.181
3.740
3.443
3.721
3.142
4.063
4.203
4.643
4.884
4.466
4.865
4.987
4.113
4.975
4.798
3.865
1.627
2.456
2.265
1.332
4.975
VDW
TRP32A
VDW
Table 4 Dock score of substituted triazole derivatives
ARG36A
THR37A
VDW
S. no.
Compound
Dock score (Kcal/mol)
VDW
1
5a
-79.6064
-71.5177
-75.4762
-68.3918
-72.5381
-72.1438
-80.1211
-70.4844
-68.8439
-60.6029
-77.5275
-73.9965
-74.6156
-64.2304
-67.5477
-70.6254
-75.4951
-76.7435
-72.7335
-88.2633
5.
CYS112A
ARG151A
GLY152A
ILE155A
PHE157A
LEU189A
MET207A
GLY209A
ASN210A
ARG249A
GLY305A
THR28A
VDW
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
.
5b
6.
VDW
.
5c
7.
VDW
.
5d
8.
VDW
.
5e
9.
VDW
.
5f
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
VDW
.
5g
VDW
.
5h
VDW
.
5i
VDW
0.
1.
2.
3.
4.
5.
6.
7.
8.
9.
0.
5j
VDW
5k
VDW
5l
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrogen Bond
Hydrogen Bond
Hydrogen Bond
Hydrogen Bond
pi-Stacking
5m
TRP32A
5n
CYS112A
ARG151A
GLY152A
ILE155A
LEU189A
MET207A
ALA208A
VAL212A
GLY305A
THR28A
5o
5p
5q
5r
5s
Standard (ciprofloxacin)
2
2
2
2
2
3
3
5.
6.
7.
8.
9.
0.
1.
presented in Table 4. The highest scoring orientations for
each ligand proposed a feasible binding mode of the
inhibitor in the active site of E.coli FabH; especially,
compound 5g with the most effective inhibitory activity
displayed the maximum dock score and thereby easily
docked with E. coli FabH. The binding model of compound
ARG151A
GLY209A
PHE304A
PHE157A
5
g with 1HNJ is depicted in Fig. 4. It was observed that the
Bold values indicate best results
1
23

Med Chem Res
the binding model of 5g, it is inferred that the introduction
of triazole moiety facilitate the ligand easier to combine
with E.coli FabH. Hence, high binding affinities led to
potent antimicrobial activity, and the attempt to obtain new
potential antibacterial E.coli FabH were verified with the
expected results (Fig. 6).
Conclusion
All the synthesized compounds have been investigated for
their microbicidal and antioxidant activities. Most of the
compounds showed good-to-moderate antibacterial activity
against Gram-positive bacteria and moderate to lack of
activity against selected Gram-negative bacterial strains.
Meanwhile, the results of structure–activity relationships
and molecular modeling study confirm compound 5g as a
lead molecule with best dock score (-80.121 kcal/mol)
compared with other compounds. The investigation of
antioxidant screening data reveals that compounds 5k, 5j,
Fig. 5 Highly active compound 5g (pink color) bound with the active
binding sites of line ribbon-shaped E.coli FabH binding pocket (PDB
code: 1HNJ)
5d and 5e showed excellent activity, almost equivalent to
that of standard. The remaining compounds showed mod-
erate-to-mild inhibition activity. Moreover, these results
oriented us toward further studies with a positive note for
the construction of novel chemical entities having better
pharmacological profiles.
Experimental section
Materials and methods
All chemicals used in the syntheses were purchased from
Sigma-Aldrich and were used without purification. Thin-
layer chromatography was used to monitor the progress of
the reactions. Melting points were determined by open
capillary using Veego Precision Digital Melting Point
apparatus (MP-D) and were uncorrected. IR spectra were
recorded on a Shimadzu D-8001 spectrophotometer. The
Fig. 6 Interactions with various residues of E.coli FabH protein
(
PDB code: 1HNJ) with ciprofloxacin (pink color)
to identification of active binding sites of E.coli FabH in
the docked complex (Fig. 4), and all the above residues are
also shown in ribbon model (Fig. 5), respectively. From
Table 2, it is deduced that the triazole derivative (com-
pound 5g) is surrounded by van der Waals residues. The
hydroxyl substituent at C4-position of the triazole moiety is
bounded by a VDW pocket consisting of residues such as
LEU189A, ASN247A and VAL212A, which strengthened
the binding affinity, leading to the increased antimicrobial
activity of the compound. It is also inferred from the
docking results that the geraniol fraction of the triazole is
located near to the deep VDW pocket formed by TRP32A,
ARG36A, GLY152A, ILE155A and ASN210A. Some
other conserved hydrophobic residues surrounding the
binding site are CIS112A, MET207A and ALA208A. From
1
13
H and C NMR spectra of the synthesized compounds
were recorded at 400 MHz and 100 MHz, respectively,
using Bruker Avance 400 MHz NMR spectrometer in
DMSO-d and CDCl solvent, and the chemical shifts were
6
3
expressed in d relative to TMS as internal standard and
coupling constants (J) in Hz. Splitting patterns are indi-
cated as s: singlet, d: doublet, t: triplet, m: multiplet, dd:
doubledoublet, ddd: doublet of a doublet of a doublet and
br: broad peak. Mass spectra were recorded on Shimadzu
GCMS-QP-2000 mass spectrometer. Elemental analyses
were performed on Heraeus CHN-O-Rapid Elemental
Analyzer. TLC was performed using precoated aluminum
sheets with silica gel 60 F254. Column chromatography was
performed on a silica gel (60–120 mesh) glass column.
123

Med Chem Res
1
1,696, 1,630, 1,605, 1,495, 1,140, 1,050, 1,030. H NMR
General procedure for the preparation of 3,7-
dimethylocta-2,6-dienyl 4-methylbenzenesulfonate (2)
(400 MHz, DMSO-d ): d 1.58 (s, 3H, CH ), 1.67 (s, 3H,
6
3
CH ), 1.76 (s, 3H, CH ), 2.15 (m, 4H, CH ), 4.97 (d,
3
3
2
In a 50-cc two-neck round-bottomed flask, KOH (0.64 g,
J = 7.45 Hz, 2H, CH ), 5.02 (m, 1H, CH), 5.32 (s, 2H,
2
5
mmol) and tosyl chloride (0.45 g, 2.2 mmol) dissolved in
THF (8 mL) were taken. The suspension was cooled to
°C, and the required geraniol (2 mmol) was added. The
CH ), 5.43 (t, J = 7.8 Hz, 1H, CH), 7.23 (d, J = 8 Hz, 2H,
2
Ar–H), 7.95 (d, J = 8.0 Hz, 2H, Ar–H), 8.09 (s, 1H, tria-
1
3
0
zole-H), 9.33 (s, 1H, CHO). C NMR (100 MHz, DMSO-
d6): d 16.5, 18.9, 24.2, 26.6, 49.9, 72.6, 114.3, 117.5, 123.2,
123.7, 129.6, 131.9, 132.5, 136.8, 142.1, 164.4, 191.2.
mixture was stirred for 2 h at room temperature. In the end
of reaction, the aqueous phase was washed with ethyl
acetate (2 9 30 mL), the organic phase obtained was dried
with sodium sulfate, filtered and the solvent evaporated
under vacuum. The crude product was purified by column
chromatography using as eluant a mixture of hexane/ethyl
acetate (7/3).
?
ESI–MS: 340 [M ? H] ; Anal. Calcd. For C H N O :
20 25 3 2
C, 70.77; H, 7.42; N, 12.38 %. Found: C, 70.91; H, 7.53;
N, 12.09 %.
2-((1-(3,7-Dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4-yl)
methoxy)benzaldehyde (5b) Dark green solid, yield:
7
0
1
0 %; m.p.180–182 °C; 20 % EtOAc in hexane, R =
f
General procedure for the preparation of 1-azido-3,7-
-1
.33; IR (KBr, cm ); 3,057, 2,961, 2,923, 2,872, 2,854,
dimethylocta-2,6-diene (3)
1
,702, 1,618, 1,609, 1,487, 1,132, 1,053, 1,024. H NMR
(
400 MHz, DMSO-d ): d 1.55 (s, 3H, CH ), 1.65 (s, 3H,
6
3
In a 50-cc two-neck round-bottomed flask under a nitrogen
atmosphere, the starting material (0.5 mmol) was added
with sodium azide (1.1 equiv, 0.55 mmol) dissolved in
DMF. The mixture was stirred until the starting material
was consumed, followed by TLC. The reaction was worked
up by dilution with diethyl ether and washed with water
CH ), 1.78 (s, 3H, CH ), 2.12 (m, 4H, CH ), 4.94 (d,
3
3
2
J = 7.43 Hz, 2H, CH ), 5.05 (m, 1H, CH), 5.33 (s, 2H,
2
CH ), 5.41 (t, J = 7.80 Hz, 1H, CH), 7.08-7.13 (m, 1H,
2
Ar–H), 7.40 (d, J = 6 Hz, 1H, Ar–H), 7.65–7.72 (m, 2H,
13
Ar–H), 8.04 (s, 1H, triazole-H), 10.33 (s, 1H, CHO).
C
NMR (100 MHz, DMSO-d ): d 16.3, 18.8, 23.9, 27.1, 50.1,
7
6
(
2 9 30 mL). The aqueous layer was further washed with
2.2, 113.9, 117.8, 121.2, 123.4, 125.6, 131.5, 132.2,
EtOAc (2 9 30 mL), and the combined organic extracts
were washed with brine (1 9 30 mL). After drying over
sodium sulfate, filtration and evaporation of the solvent, the
crude was purified by column chromatography using PE/
EtOAc 95:5 as eluant to give 600 mg of the corresponding
azide 3 as brown color oil (65 %).
1
35.1, 136.8, 142.7, 160.9, 190.6. ESI–MS: 340
?
M ? H] ; Anal. Calcd. For C H N O : C, 70.77; H,
[
2
0 25 3 2
7.42; N, 12.38 %. Found: C, 70.97; H, 7.56; N, 12.21 %.
1-(3,7-Dimethylocta-2,6-dienyl)-4-(p-tolyloxymethyl)-1H-1,
2,3-triazole (5c) Reddish green solid, yield: 73 %;
m.p.142 °C; 20 % EtOAc in hexane, R = 0.27; IR (KBr,
f
-
cm ); 3,072, 2,970, 2,926, 2,875, 2,853, 1,632, 1,611,
1
General procedure for the preparation of (1-(3,7-
1
1,498, 1,138, 1,049, 1,027. H NMR (400 MHz, DMSO-
dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4-yl)methanol
(
5)
d
6
): d 1.52 (s, 3H, CH ), 1.65 (s, 3H, CH ), 1.75 (s, 3H,
3 3
CH ), 1.84 (s, 3H, CH ), 2.15 (m, 4H, CH ), 4.94 (d,
3
3
2
In a 50-cc two-neck round-bottomed flask under a nitrogen
J = 7.28 Hz, 2H, CH ), 5.03 (m, 1H, CH), 5.07 (s, 2H,
2
atmosphere, azide derivatives 3 (1 mmol), alkyne 4
1 mmol) and the copper catalyst (1.0 equiv, 0.5 mmol)
CH
), 5.42 (t, J = 7.52 Hz, 1H, CH), 6.84 (d, J = 8.0 Hz,
2
(
2H, Ar–H), 7.04 (d, J = 8.0 Hz, 2H, Ar–H), 8.02 (s, 1H,
1
triazole-H). C NMR (100 MHz, DMSO-d ): d 15.8, 18.6,
6
3
were mixed under vigorous stirring. On completion of the
reaction, as monitored by TLC, water (15 mL) was added
to the reaction mixture and extracted with chloroform
21.1, 24.5, 26.9, 49.5, 72.6, 114.3, 118.2, 122.8, 123.6,
130.5, 131.1, 132.2, 136.7, 142.5, 155.9. ESI–MS: 326
?
[M ? H] ; Anal. Calcd. For C20
(
2 9 30 mL). Combined organic layers were dried over
H
27
N
3
O: C, 73.81; H,
anhydrous sodium sulfate and concentrated under reduce
pressure to result in a crude product which was recrystal-
lized using chloroform: methanol (10:2) mixture.
Spectral data for newly synthesized substituted triazole
derivatives are given below:
8.36; N, 12.91 %. Found: C, 73.74; H, 8.53; N, 12.83 %.
1
2
-(3,7-Dimethylocta-2,6-dienyl)-4-(o-tolyloxymethyl)-1H-1,
,3-triazole (5d) Reddish green solid, yield: 68 %;
m.p.134–136 °C; 20 % EtOAc in hexane, R = 0.27; IR
f
-1
KBr, cm ); 3,078, 2,959, 2,920, 2,867, 2,852, 1,630,
(
1
4
-((1-(3,7-Dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4-yl)
1,609, 1,498, 1,137, 1,052, 1,025. H NMR (400 MHz,
DMSO-d ): d 1.55 (s, 3H, CH ), 1.63 (s, 3H, CH ), 1.72 (s,
3H, CH ), 1.78 (s, 3H, CH ), 2.13 (m, 4H, CH ), 4.89 (d,
J = 7.3 Hz, 2H, CH ), 5.04 (m, 1H, CH), 5.10 (s, 1H,
methoxy)benzaldehyde (5a) Dark green solid, yield:
6
3
3
7
5 %; m.p.180–182 °C; 20 % EtOAc in hexane, R =
3
3
2
f
-
.33; IR (KBr, cm ); 3,060, 2,967, 2,924, 2,872, 2,853,
1
0
2
1
23

Med Chem Res
CH ), 5.40 (t, J = 7.64 Hz, 1H, CH), 6.84 (m, 1H, Ar–H),
2
1-(3,7-Dimethylocta-2,6-dienyl)-4-(methoxymethyl)-1H-1,2,3-
1
3
7
.06-7.13 (m, 3H, Ar–H), 8.03 (s, 1H, triazole-H).
C
triazole (5h) Green solid, yield: 79 %; m.p.116–118 °C;
-
20 % EtOAc in hexane, R = 0.23; IR (KBr, cm ); 2,969,
1
NMR (100 MHz, DMSO-d ): d 15.6, 16.1, 18.9, 24.2, 26.7,
6
f
5
1
0.1, 72.4, 112.8, 117.5, 121.2, 123.4, 123.9, 127.3, 131.3,
?
36.9, 158.2. ESI–MS: 326 [M ? H] ; Anal. Calcd. For
2,924, 2,871, 2,852, 1,619, 1,064, 1,491, 1,142, 1,052,
1
1,028. H NMR (400 MHz, DMSO-d ): d 1.56 (s, 3H,
6
C H N O: C, 73.81; H, 8.36; N, 12.91 %. Found: C,
3
CH ), 1.67 (s, 3H, CH ), 1.78 (s, 3H, CH ), 2.15 (m, 4H,
3
2
0
27
3
3
7
3.69; H, 8.51; N, 12.79 %.
CH ), 3.20 (s, 3H, OCH ), 4.80 (s, 2H, CH ), 4.91 (d,
2 3 2
J = 7.10 Hz, 2H, CH ), 5.06 (m, 1H, CH), 5.37 (t,
2
4
-((4-Chlorophenoxy)methyl)-1-(3,7-dimethylocta-2,6-die-
1
J = 7.64 Hz, 1H, CH), 7.95 (s, 1H, triazole-H). C NMR
3
nyl)-1H-1,2,3-triazole (5e) Dark green solid, yield: 75 %;
m.p.103–106 °C; 20 % EtOAc in hexane, R = 0.26; IR
(
100 MHz, DMSO-d ): d 16.7, 18.2, 25.1, 26.9, 48.7, 59.3,
6
f
7
2
9
0.4, 117.8, 122.9, 123.5, 131.6, 136.2, 141.8. ESI–MS:
?
50 [M ? H] ; Anal. Calcd. For C H N O: C, 67.43; H,
-
KBr, cm ); 3,078, 2,967, 2,925, 2,873, 2,849, 1,633,
1
(
1
,608, 1,498, 1,140, 1,049, 1,038, 725. H NMR
14 23 3
1
.30; N, 16.85 %. Found: C, 67.54; H, 9.41; N, 16.78 %.
(
400 MHz, DMSO-d ): d 1.59 (s, 3H, CH ), 1.68 (s, 3H,
6
3
CH ), 1.77 (s, 3H, CH ), 2.11 (m, 4H, CH ), 4.95 (d,
3
(1-(3,7-Dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4-yl)
3
2
J = 7.52 Hz, 2H, CH ), 5.03 (m, 1H, CH), 5.11 (s, 1H,
2
methyl propionate (5i) Dark green solid, yield: 74 %;
m.p.116–118 °C; 20 % EtOAc in hexane, R = 0.22; IR
CH ), 5.42 (t, J = 8.0 Hz, 1H, CH), 7.02 (d, J = 9.0 Hz,
2
f
-
(KBr, cm ); 2,972, 2,918, 2,869, 2,854, 1,725, 1,638,
1
2
H, Ar–H), 7.32 (d, J = 9.0 Hz, 2H, Ar–H), 8.02 (s, 1H,
1
3
1
1,609, 1,496, 1,137, 1,054, 1,025. H NMR (400 MHz,
triazole-H). C NMR (100 MHz, DMSO-d ): d 15.4, 19.1,
6
2
4.7, 26.3, 49.5, 71.8, 116.5, 117.3, 123.5, 123.9, 126.1,
?
31.4, 132.6, 142.8, 157.2. ESI–MS: 346.5 [M ? H] ;
DMSO-d ): d 1.02 (t, J = 6.0 Hz, 3H, CH ), 1.54 (s, 3H,
CH ), 1.68 (s, 3H, CH ), 1.75 (s, 3H, CH ), 2.11 (m, 4H,
3 3 3
6
3
1
Anal. Calcd. For C H ClN O: C, 65.98; H, 6.99; N,
1
CH ), 2.32 (q, J = 6.0 Hz, 2H, CH ), 4.95 (d, J = 7.0 Hz,
2 2
9
24
3
1
2.15 %. Found: C, 65.73; H, 7.31; N, 11.98 %.
2H, CH ), 5.05 (s, 2H, CH ), 5.14 (m, 1H, CH), 5.40 (t,
2 2
1
J = 8 Hz, 1H, CH), 8.01 (s, 1H, triazole-H). C NMR
3
4
-((2-Chlorophenoxy) methyl)-1-(3,7-dimethylocta-2,6-
(
100 MHz, DMSO-d ): d 9.8, 17.1, 18.3, 24.6, 26.2, 27.4,
6
dienyl)-1H-1,2,3-triazole (5f) Dark green solid, yield:
5
0.2, 61.7, 117.1, 122.5, 123.8, 131.6, 136.2, 142.7, 173.9.
7
0
1
0 %; m.p.140–142 °C; 20 % EtOAc in hexane, R =
f
?
ESI–MS: 292 [M ? H] ; Anal. Calcd. For C H N O :
-1
.26; IR (KBr, cm ); 3,075, 2,970, 2,923, 2,871, 2,850,
16 25 3 2
C, 65.95; H, 8.65; N, 14.42 %. Found: C, 65.83; H, 8.77;
N, 14.28 %.
1
,632, 1,605, 1,494, 1,140, 1,050, 1,036, 724. H NMR
(
400 MHz, DMSO-d ): d 1.57 (s, 3H, CH ), 1.66 (s, 3H,
6
3
CH ), 1.76 (s, 3H, CH ), 2.12 (m, 4H, CH ), 4.92 (d,
3
1-(3,7-Dimethylocta-2,6-dienyl)-4-((tetrahydro-2H-pyran-
2-yloxy)methyl)-1H-1,2,3-triazole (5j) Dark green solid,
yield: 66 %; m.p.96–98 °C; 20 % EtOAc in hexane,
3
2
J = 7.5 Hz, 2H, CH ), 5.02 (m, 1H), 5.15 (s, 2H, CH), 5.41
2
(
t, J = 8.0 Hz, 1H, CH), 6.66–6.75 (m, 2H, Ar–H),
.01–7.05 (m, 1H, Ar–H), 7.33 (bs, 1H, Ar–H), 8.00 (s, 1H,
-
1
7
R = 0.26; IR (KBr, cm ); 2,969, 2,921, 2,873, 2,849,
f
1
3
1
1,629, 1,604, 1,493, 1,141, 1,047, 1,032. H NMR
triazole-H). C NMR (100 MHz, DMSO-d ): d 16.4, 18.4,
6
2
1
3
6
1
4.2, 26.7, 49.8, 71.2, 112.1, 118.5, 122.9, 123.2, 123.5,
(400 MHz, DMSO-d ): d 1.56 (s, 3H, CH ), 1.63 (s, 3H,
6
3
23.8, 127.3, 131.8, 132.5, 136.1, 142.6, 154.9. ESI–MS:
?
46.5 [M ? H] ; Anal. Calcd. For C H ClN O: C,
CH ), 1.71-1.75 (m, 4H, Ar–H), 1.78-1.83 (m, 5H, CH ,
3
3
Ar–H), 2.15 (m, 4H, CH ), 3.67–3.71 (t, J = 10 Hz, 2H,
2
1
9
24
3
5.98; H, 6.99; N, 12.15 %. Found: C, 66.80; H, 7.28; N,
1.90 %.
Ar–H), 4.88 (d, J = 7.28 Hz, 2H, CH ), 5.08 (m, 1H, CH),
2
5.31 (t, J = 8.43 Hz, 1H, Ar–H), 5.42 (t, J = 7.68 Hz, 1H,
1
CH), 7.68 (s, 1H, triazole-H). C NMR (100 MHz,
3
(1-(3,7-Dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4yl)meth-
DMSO-d ): d 16.2, 18.5, 20.4, 23.9, 25.6, 26.1, 30.5, 38.7,
6
anol (5g) Dark green solid, yield: 82 %; m.p.152–154 °C;
4
9.2, 62.6, 63.1, 115.0, 118.3, 123.4, 123.9, 132.0, 136.3,
?
42.8. ESI–MS: 300 [M ? H] ; Anal. Calcd. For
-
0 % EtOAc in hexane, R = 0.32; IR (KBr, cm ); 3,460,
1
2
2
1
3
f
1
,967, 2,925, 2,875, 2,853, 1,628, 1,597, 1,496, 1,128,
1
C H FN : C, 72.21; H, 7.41; N, 14.04 %. Found: C,
18 22
3
,056, 1,023. H NMR (400 MHz, DMSO-d ): d 1.58 (s,
6
72.32; H, 7.31; N, 14.17 %.
H, CH ), 1.66 (s, 3H, CH ), 1.76 (s, 3H, CH ), 2.12 (m, 4H,
3
3
3
CH ), 2.96 (bs, 1H, OH), 4.48 (s, 2H, CH ), 4.94 (d,
2
2-(1-(3,7-Dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4-yl)
2
J = 7.33 Hz, 2H, CH ), 5.04 (m, 1H, CH), 5.41 (t,
2
ethanol (5k) Dark green solid, yield: 80 %; m.p.115–
117 °C; 20 % EtOAc in hexane, R = 0.22; IR (KBr,
1
3
J = 7.59 Hz, 1H, CH), 7.68 (s, 1H, triazole-H). C NMR
f
-
cm ); 3,440, 2,971, 2,927, 2,867, 2,852, 1,642, 1,612,
1
(
100 MHz, DMSO-d ): d 16.1, 18.7, 24.5, 26.8, 50.4, 53.7,
6
1
1,503, 1,138, 1,050, 1,023. H NMR (400 MHz, DMSO-
1
17.4, 122.5, 123.8, 132.1, 136.7, 141.9. ESI–MS: 236
?
M ? H] ; Anal. Calcd. For C H N O: C, 66.35; H, 8.99;
[
d ): d 1.55 (s, 3H, CH ), 1.67 (s, 3H, CH ), 1.76 (s, 3H,
1
3
21
3
6
3
3
N, 17.86 %. Found: C, 66.53; H, 8.86; N, 18.02 %.
CH ), 2.10 (m, 4H, CH ), 2.69 (t, J = 6.3 Hz, 2H, CH ),
2
3
2
123

Med Chem Res
3
.51 (bs, 1H, OH), 3.55 (t, J = 6.81, 2H, CH ), 4.94 (d,
2
1-(3,7-Dimethylocta-2,6-dienyl)-4-(phenoxymethyl)-1H-1,2,3-
J = 7.46 Hz, 2H, CH ), 5.01 (m, 1H, CH), 5.40 (t,
2
triazole (5o) Dark green solid, yield: 72 %; m.p.
145–147 °C; 20 % EtOAc in hexane, R = 0.30; IR (KBr,
1
J = 8.06 Hz, 1H, CH), 7.72 (s, 1H, triazole-H). C NMR
3
f
-
1
cm ); 3,078, 2,967, 2,918, 2,873, 2,857, 1,626, 1,621,
(
100 MHz, DMSO-d ): d 16.5, 18.3, 24.4, 26.7, 29.2, 49.5,
6
1
1,510, 1,150, 1,048, 1,032. H NMR (400 MHz, DMSO-
6
1.5, 118.2, 123.9, 131.1, 132.3, 136.8. ESI–MS: 250
?
M ? H] ; Anal. Calcd. For C H N O: C,67.43; H, 9.30;
[
d ): d 1.58 (s, 3H, CH ), 1.66 (s, 3H, CH ), 1.79 (s, 3H,
1
4
23
3
6
3
3
N, 16.85 %. Found: C, 67.58; H, 9.41; N, 16.78 %.
-(Bromomethyl)-1-(3,7-dimethylocta-2,6-dienyl)-1H-1,2,3-
triazole (5l) Dark green solid, yield: 81 %; m.p.105–
06 °C; 20 % EtOAc in hexane, R = 0.28; IR (KBr,
CH ), 2.17 (m, 4H, CH ), 4.92 (d, J = 7.28 Hz, 2H, CH ),
3 2 2
5.01 (m, 1H, CH), 5.12 (s, 2H, CH ), 5.35 (t, J = 8.14 Hz,
2
4
1
H, CH), 6.92–7.08 (m, 3H, Ar–H), 7.26–7.31 (m, 2H, Ar–
1
3
H), 8.04 (s, 1H, triazole-H). C NMR (100 MHz, DMSO-
1
f
d6): d 16.1, 18.6, 24.3, 26.9, 49.8, 72.5, 114.3, 117.8, 120.5,
-
1
cm ); 2,968, 2,924, 2,871, 2,847, 1,634, 1,607, 1,491,
1
3
8
22.7, 123.4, 129.7, 131.8, 136.8, 142.0, 159.5. ESI–MS:
?
12 [M ? H] ; Anal. Calcd. For C H N O: C, 73.28; H,
1
1
,130, 1,021, 660. H NMR (400 MHz, DMSO-d ): d 1.58
6
1
9 25 3
(
s, 3H, CH ), 1.66 (s, 3H, CH ), 1.78 (s, 3H, CH ), 2.13 (m,
3 3 3
.09; N, 13.49 %. Found: C, 73.43; H, 8.27; N, 13.38 %.
4
H, CH ), 3.73 (s, 2H, CH ), 4.92 (d, J = 7.24 Hz, 2H,
2 2
CH ), 5.04 (m, 1H, CH), 5.38 (t, J = 7.62 Hz, 1H, CH),
2
1-(3,7-Dimethylocta-2,6-dienyl)-4-phenyl-1H-1,2,3-triazole
1
.65 (s, 1H, triazole-H). C NMR (100 MHz, DMSO-d6):
3
7
(5p) Dark green solid, yield: 78 %; m.p.175–180 °C;
-
20 % EtOAc in hexane, R = 0.30; IR (KBr, cm ); 3,074,
1
d 15.8, 18.6, 24.3, 26.2, 27.5, 49.0, 117.6, 123.2, 124.1,
f
?
30.7, 132.3, 136.7. ESI–MS: 299 [M ? H] ; Anal. Calcd.
1
2,974, 2,928, 2,871, 2,846, 1,619, 1,615, 1,498, 1,142,
1
For C H BrN : C, 52.36; H, 6.76; N, 14.09 %. Found: C,
20
1,027. H NMR (400 MHz, DMSO-d ): d 1.57 (s, 3H,
1
3
3
6
5
2.24; H, 6.88; N, 14.20 %.
CH ), 1.68 (s, 3H, CH ), 1.75 (s, 3H, CH ), 2.15 (m, 4H,
3
3
3
CH ), 4.93 (d, J = 7.31 Hz, 2H, CH ), 5.03 (m, 1H, CH),
2
2
1
1
6
-(3,7-Dimethylocta-2,6-dienyl)-4-((2-nitrophenoxy)methyl)-
H-1,2,3-triazole (5m) Reddish dark green solid, yield:
9 %; m.p. 142–144 °C; 20 % EtOAc in hexane,
5
7
.41 (t, J = 8.0 Hz, 1H, CH), 7.31–7.36 (m, 3H, Ar–H),
1
3
.75–7.77 (m, 2H, Ar–H), 8.06 (s, 1H, triazole-H).
C
NMR (100 MHz, DMSO-d ): d 16.4, 18.3, 24.8, 26.1, 50.2,
-
1
6
R = 0.28; IR (KBr, cm ); 3,056, 2,965, 2,926, 2,872,
f
1
18.4, 120.8, 123.7, 127.3, 128.5, 129.1, 130.6, 131.9,
?
35.8, 147.5. ESI–MS: 282 [M ? H] ; Anal. Calcd. For
2
1
,848, 1,628, 1,611, 1,497, 1,552, 1,348, 1,147, 1,054,
1
,027. H NMR (400 MHz, DMSO-d ): d 1.58 (s, 3H,
1
6
C H N : C, 76.83; H, 8.24; N, 14.93 %. Found: C, 76.72;
18 23 3
CH ), 1.66 (s, 3H, CH ), 1.76 (s, 3H, CH ), 2.12 (m, 4H,
3
3
3
H, 8.39; N, 14.81 %.
CH ), 4.95 (d, J = 7.35 Hz, 2H, CH ), 5.06 (m, 1H, CH),
2
2
5
.34 (s, 2H, CH ), 5.43 (t, J = 7.71 Hz, 1H, CH), 7.06-
2
2-(1-(3,7-Dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4-yl)pyri-
7
.11 (m, 1H, Ar–H), 7.23-7.26 (m, 1H, Ar–H), 7.51-7.58
dine (5q) Dark green solid, yield: 66 %; m.p.191–
193 °C; 20 % EtOAc in hexane, R = 0.28; IR (KBr,
1
m, 2H, Ar–H), 7.84 (s, 1H, triazole-H). C NMR
3
(
(
f
-
cm ); 3,063, 2,970, 2,925, 2,873, 2,851, 1,628, 1,614,
1
100 MHz, DMSO-d ): d 16.3, 18.4, 24.6, 26.9, 50.4, 70.8,
6
1
1
1
14.7, 117.5, 122.2, 122.8, 124.2, 128.4, 132.5, 132.9,
?
36.8, 140.8, 142.5, 154.5. ESI–MS: 357 [M ? H] ; Anal.
1,611, 1,148, 1,032. H NMR (400 MHz, DMSO-d ): d
6
1.59 (s, 3H, CH ), 1.68 (s, 3H, CH ), 1.77 (s, 3H, CH ),
3
3
3
Calcd. For C H N O : C, 64.03; H, 6.79; N, 15.72 %.
3
2.12 (m, 4H, CH ), 4.91 (d, J = 7.36 Hz, 2H, CH ), 5.06
2 2
1
9
24
4
Found: C, 63.89; H, 6.64; N, 15.56 %.
(m, 1H, CH), 5.40 (t, J = 7.81 Hz, 1H, CH), 7.30–7.35 (m,
H, Ar–H), 7.84–7.89 (m, 1H, Ar–H), 7.97–8.00 (m, 1H,
Ar–H), 8.03 (s, 1H, triazole-H), 8.50–8.57 (m, 1H, Ar–H).
1
1
1
-(3,7-Dimethylocta-2,6-dienyl)-4-((4-nitrophenoxy)methyl)-
H-1,2,3-triazole (5n) Dark green solid, yield: 74 %;
1
3
C NMR (100 MHz, DMSO-d ): d 16.3, 18.1, 24.5, 26.4,
6
m.p.189–191 °C; 20 % EtOAc in hexane, R = 0.28; IR
f
4
1
9.5, 117.9, 123.2, 124.6, 130.3, 131.4, 132.4, 136.7,
?
37.5, 149.8, 155.4. ESI–MS: 283 [M ? H] ; Anal. Calcd.
-
KBr, cm ); 3,054, 2,970, 2,925, 2,868, 2,850, 1,631,
1
(
1
,613, 1,497, 1,550, 1,345, 1,147, 1,050, 1,030. H NMR
1
For C H N : C, 72.31; H, 7.85; N, 19.84 %. Found: C,
17 22 3
(
400 MHz, DMSO-d ): d 1.57 (s, 3H, CH ), 1.68 (s, 3H,
6
3
72.43; H, 7.71; N, 20.72 %.
CH ), 1.78 (s, 3H, CH ), 2.13 (m, 4H, CH ), 4.90 (d,
3
3
2
J = 7.34 Hz, 2H, CH ), 5.03 (m, 1H, CH), 5.26 (s, 2H,
2
3-(1-(3,7-Dimethylocta-2,6-dienyl)-1H-1,2,3-triazole-4-yl)
CH ), 5.40 (t, J = 7.62 Hz, 1H, CH), 7.04 (d, J = 9.0 Hz,
2
pyridine (5r) Dark green solid, yield: 62 %; m.p.
183–185 °C; 20 % EtOAc in hexane, R = 0.28; IR (KBr,
2
2
2
1
H, Ar–H), 7.36 (s, 1H, triazole-H), 8.20 (d, J = 9.13 Hz,
1
f
3
-1
cm ); 3,065, 2,968, 2,923, 2,871, 2,848, 1,631, 1,614,
H, Ar–H). C NMR (100 MHz, DMSO-d ): d 16.5, 19.1,
6
1
1,615, 1,494, 1,153, 1,034. H NMR (400 MHz, DMSO-
4.2, 26.5, 48.8, 71.5, 114.9, 118.2, 123.4, 123.8, 126.3,
32.5, 136.4, 140.2, 142.7, 164.1. ESI–MS: 357
?
M ? H] ; Anal. Calcd. For C H N O : C, 64.03; H,
d ): d 1.58 (s, 3H, CH ), 1.65 (s, 3H, CH ), 1.79 (s, 3H,
6
3
3
[
CH ), 2.14 (m, 4H, CH ), 4.94 (d, J = 7.19 Hz, 2H, CH ),
3 2 2
1
9
24
4
3
6
.79; N, 15.72 %. Found: C, 63.92; H, 6.63; N, 15.59 %.
5.04 (m, 1H, CH), 5.41 (t, J = 7.65 Hz, 1H, CH),
1
23

Med Chem Res
7
8
.36–7.40 (m, 1H, Ar–H), 7.59 (s, 1H, triazole-H),
.11–8.15 (m, 1H, Ar–H), 8.59–8.61 (m, 1H, Ar–H), 8.94
the sterility of the plates. Overnight-grown cultures
(100 lL) of B. cereus MTCC 430, S. aureus MTCC 3160,
E. coli MTCC 1610 and P. aeruginosa MTCC 2295 were
inoculated into the agar surface and spread with the help of
spreader. Whatman no. 1 filter-paper disks (approximate
6 mm in diameter) were dipped in solution of different
synthesized compounds. The concentration of the com-
pounds was 0.2 mg/mL of DMSO. The paper disks were
then gently placed on the agar using sterile forceps. The
plates were inverted and incubated at 37 °C for 18–24 h.
The appearance of clear zone of growth inhibition sur-
rounding the disk was measured using antibiotic zone
measurement scale (Hi-media) and tabulated. All the tests
were performed in triplicate, and the average was taken as
the final reading. The standard antibiotic, ciprofloxacin,
was used as the positive control, whereas DMSO alone as
the negative control for all the selected bacteria.
1
3
(
bs, 1H, Ar–H). C NMR (100 MHz, DMSO-d ): d 15.9,
6
1
1
8.2, 24.1, 25.8, 50.1, 117.5, 121.4, 123.6, 124.3, 131.8,
33.0, 134.1, 136.5, 145.8, 147.5. ESI–MS: 283
?
M ? H] ; Anal. Calcd. For C H N : C, 72.31; H, 7.85;
[
1
7 22 4
N, 19.84 %. Found: C, 72.45; H, 7.68; N, 20.71 %.
4
-(Cyclohexaloxy)-1-(3,7-dimethylocta-2,6-dienyl)-1H-1,2,3-
triazole (5s) Green solid, yield: 69 %; m.p.156–158 °C;
-
0 % EtOAc in hexane, R = 0.32; IR (KBr, cm ); 2,965,
1
2
2
1
2
f
,926, 2,870, 2,854, 1,624, 1,609, 1,497, 1,140, 1,050,
1
,030. H NMR (400 MHz, DMSO-d ): d 1.51–1.55 (m,
6
H, Ar–H), 1.58–1.63 (m, 7H, CH , Ar–H), 1.66 (s, 3H,
3
CH ), 1.75 (s, 3H, CH ), 1.98-2.02 (m, 4H, Ar–H), 2.15 (m,
3
3
4
H, CH ), 3.89–3.93 (m, 4H, Ar–H), 4.93 (d, J = 7.20 Hz,
2
2
H, CH ), 5.06 (m, 1H, CH), 5.45 (t, J = 7.63 Hz, 1H,
2
1
CH), 7.73 (s, 1H, triazole-H). C NMR (100 MHz,
3
DMSO-d ): d 16.2, 18.7, 24.2, 24.9, 26.3, 34.5, 39.4, 49.5,
6
Antioxidant activity
7
3
9
8.1, 117.6, 123.0, 130.9, 132.4, 133.9, 136.3. ESI–MS:
?
04 [M ? H] ; Anal. Calcd. For C H N O: C, 71.25; H,
1
8 29 3
Experimental study was started by dissolving DPPH
.63; N, 13.85 %. Found: C, 70.58; H, 9.12; N, 14.05 %.
(0.004 g) in MeOH (100 mL) to obtain a concentration of
1
00 lM. Serial dilutions were carried out with stock
Antibacterial activity
solutions (150 lM) of the compounds in methanol to
obtain final concentrations of 1, 2, 4, 8, 12, 16, 20, 24,
All newly synthesized 1-4 disubstituted triazole com-
pounds 5a–s were screened in vitro for their antibacterial
activity against two Gram-negative and two Gram-positive
bacterial strains. The above bacterial cultures, Bacillus
cereus MTCC 430, Staphylococcus aureus MTCC 3160,
Escherichia coli MTCC 1610 and Pseudomonas aerugin-
osa MTCC 2295 procured from Microbial Type Culture
Collection Centre, Institute of Microbial Technology,
Chandigarh, India, were used for the present study to
evaluate the antimicrobial activity of the synthesized
compounds. The antimicrobial activity of newly synthe-
sized compounds was evaluated according to the guidelines
of Clinical Laboratory Standards Institute (CLSI, 2007)
USA, using the agar disk diffusion method as well as liquid
broth assay.
3
0 lM in cuvette. Diluted solutions of the compound and
ascorbic acid (AA) (2 mL each) were mixed with metha-
nolic DPPH solution (1 mL, 100 lM) and allowed to stand
for 120 min for any reaction to occur. The absorbance was
recorded at 517 nm on Shimadzu PharmaSpec UV–Visible
spectrophotometer (Model-1700). The experiment was
performed in triplicate, and the average absorbance was
noted for each concentration. The IC50 value, which is the
concentration of the test compound that reduces 50 % of
the initial free radical concentration, was calculated in lM.
Ascorbic acid was used as reference standard, at the same
concentrations in methanol as were used for the tested
compounds.
Docking study on E.coli FabH enzyme
Kirby-Bauer agar diffusion method (Antibacterial
assay)
Docking procedures basically aim to identify the correct
conformation of ligands in the binding pocket of a protein
and to predict the affinity between the ligand and the protein
(Narsinghani et al., 2013). This has resulted in the best-fit
geometry of ligand-receptor complex with minimum energy
of interaction between ligand and receptor. The minimum
energy of interaction is represented by different scoring
functions, which allow screening of a set of compounds for
lead optimization. The affinity of ligand with the receptor has
been predicted with reasonable accuracy, yielding a relative
rank order of the docked compounds. In order to explore the
interactions of the synthesized compounds, binding
In Kirby-Bauer agar diffusion method, the Mueller–Hinton
agar (Hi-Media, India) was prepared according to the
manufacturer’s instructions; the media was sterilized at
1
21 °C for 15–20 min in autoclave and cooled to 50 °C in
heating water bath. Approximately 20–25 mL of the media
was poured on to the 90-mm sterile Petri plates, and it was
rotated in anticlockwise motion. It was then kept for
1
0–15 min at room temperature for solidification. Plates
were inverted and left for overnight in incubator to check
123

Med Chem Res
simulations by means of the Bio-Predicta module of VLife
MDS 3.5 suite (VLife ST, 2008) has been carried out. The
docking study was performed on experimental X-ray crystal
structure of the E.coli FabH protein (Protein Data Bank, PDB
entry 1HNJ) (Qiu et al., 2001; Zhang et al., 2014). The
computational work was performed on a HP Compaq PC
running on Intel Core i5 processor. The molecular structures
of the compounds in the data set were sketched using VLife
MDS (Molecular Design Suite) 3.5 software supplied by
VLife Sciences Technologies Pvt. Ltd., Pune, India. Energy
minimization was performed using the Merck Molecular
Force Field MMFF94 (Halgren, 1996) and Gasteiger–Mar-
sili (Gasteiger and Marsili, 1980) charges followed by AM-1
1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg Med Chem Lett
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(
Austin Model-1) Hamiltonian method available in MOPAC
˚
module with the convergence criterion 0.001 kcal/mol A.
All the optimized conformers were docked into active
binding site of E.coli FabH target protein (Protein Data
Bank, PDB entry 1HNJ, http://www.rcsb.org/pdb/home/
home.-do), which was considered as the reference to define
the active binding site in the present investigation (Qiu et al.,
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alkylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-ones and
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3
-alkyl-4-alkylamino-4,5-dihydro-1H-1,2,4-triazol-5-ones as
removed from the PDB file of E.coli FabH protein during
docking study. The crystal structure was refined using VLife
Science’s MDS 3.5 software. The refinement of the crude
PDB structure of receptor was done by completing the
incomplete residues. The side chain hydrogen was then
added to the crystal structure, and their positions were opti-
mized up to the rms gradient 1 by aggregating other part of
receptor. The active site selection was done by choosing the
cavity having maximum hydrophobic and van der Waals
surface area. The docking simulation was done using GRIP
batch docking. In this, all generated conformers of one ligand
were put as one batch in GRIP docking wizard. Likewise, the
batches for all other ligands were put. All the confirmers
were virtually docked at the defined cavity of the receptor.
The parameters fixed for docking simulation were the fol-
lowing: number of placement: 30, rotation angle: 5°,
exhaustive method and scoring function: dock score.
Docking interaction of synthesized compounds is discussed
in the ‘‘Results and Discussion’’ section.
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for MMFF94. J Comput Chem 17:553–586
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Acknowledgments We are thankful to Defence Research and
Development Organization (DRDO), New Delhi, for providing
financial support for the research project (ERIP/ER/1103024/M/01/
1476). We thank VLife Science Technologies Pvt. Ltd for providing
the software for the study.
Ji D, Lu JR, Lu BW, Xin CW, Mu JB, Li JF, Peng CY, Bao XR
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