Synthesis, bioevaluation and molecular docking study of new piperazine and amide linked dimeric 1,2,3-triazoles

Article abstract of DOI:10.1080/00397911.2019.1695275

In search of more potent new antitubercular agents, a library of novel piperazine tethered dimeric 1,2,3-triazoles were designed by assembling 1,2,3-triazoles and piperazine in a single molecular architectural framework. The titled compounds (3a–m) were synthesized by 1,3-dipolar cycloaddition of 1,4-di(prop-2-yn-1-yl)piperazine (1) and various azides (2a–m) using click chemistry approach with good yields. All the synthesized compounds (3a–m) have been screened for their in vitro antitubercular, antifungal and antioxidant activities against their respective strains. Among them, 3b, 3d, and 3i have revealed promising antitubercular activity against Mycobacterium tuberculosis (Mtb) H37Rv with MIC 12.5 μg/mL. Molecular docking results provided well-clustered solutions to the mode of binding for these molecules into the active site of Mtb enoyl reductase (InhA). In addition to this, most of synthesized compounds were found to have potential antifungal as well as antioxidant activity.

Full text of DOI:10.1080/00397911.2019.1695275

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis, bioevaluation and molecular docking
study of new piperazine and amide linked dimeric
1,2,3-triazoles
Tejshri R. Deshmukh, Smita P. Khare, Vagolu S. Krishna, Dharmarajan Sriram,
Jaiprakash N. Sangshetti, Vijay M. Khedkar & Bapurao B. Shingate
To cite this article: Tejshri R. Deshmukh, Smita P. Khare, Vagolu S. Krishna, Dharmarajan
Sriram, Jaiprakash N. Sangshetti, Vijay M. Khedkar & Bapurao B. Shingate (2019): Synthesis,
bioevaluation and molecular docking study of new piperazine and amide linked dimeric 1,2,3-
triazoles, Synthetic Communications, DOI: 10.1080/00397911.2019.1695275
To link to this article: https://doi.org/10.1080/00397911.2019.1695275
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https://doi.org/10.1080/00397911.2019.1695275
Synthesis, bioevaluation and molecular docking study of
new piperazine and amide linked dimeric 1,2,3-triazoles
a
a
b
b
Tejshri R. Deshmukh , Smita P. Khare , Vagolu S. Krishna , Dharmarajan Sriram ,
c
d
a
Jaiprakash N. Sangshetti , Vijay M. Khedkar , and Bapurao B. Shingate
a
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra,
b
India; Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad,
Telangana, India; Department of Pharmaceutical Chemistry, Y. B. Chavan College of Pharmacy,
Aurangabad, Maharashtra, India; Department of Pharmaceutical Chemistry, Shri Vile Parle Kelavani
c
d
Mandal’s Institute of Pharmacy, Dhule, Maharashtra, India
ABSTRACT
ARTICLE HISTORY
In search of more potent new antitubercular agents, a library of
novel piperazine tethered dimeric 1,2,3-triazoles were designed by
assembling 1,2,3-triazoles and piperazine in a single molecular archi-
tectural framework. The titled compounds (3a–m) were synthesized
by 1,3-dipolar cycloaddition of 1,4-di(prop-2-yn-1-yl)piperazine (1)
and various azides (2a–m) using click chemistry approach with good
yields. All the synthesized compounds (3a–m) have been screened
for their in vitro antitubercular, antifungal and antioxidant activities
against their respective strains. Among them, 3b, 3d, and 3i have
revealed promising antitubercular activity against Mycobacterium
tuberculosis (Mtb) H37Rv with MIC 12.5 mg/mL. Molecular docking
results provided well-clustered solutions to the mode of binding for
these molecules into the active site of Mtb enoyl reductase (InhA). In
addition to this, most of synthesized compounds were found to
have potential antifungal as well as antioxidant activity.
Received 7 June 2019
KEYWORDS
Antifungal activity;
antioxidant activity;
antitubercular activity;
dimeric 1,2,3-triazoles;
molecular docking study
GRAPHICAL ABSTRACT
CONTACT Bapurao B. Shingate
bapushingate@gmail.com
Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad, Maharashtra, 431 004, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
T. R. DESHMUKH ET AL.
Introduction
Tuberculosis (TB) is infectious lung disease caused by pathogenic bacterium
[
1]
Mycobacterium tuberculosis (Mtb). Near about one-third of the world’s population is
infected by Mtb from which only India and China altogether contributes to almost 40%
[
2]
of total new TB cases. According to the World Health Organization (WHO), over
[
3]
10.4 million new TB cases with 1.4 million TB related deaths have been reported.
Although there are several new therapeutic leads in different stages of clinical trials,
[
4]
Bedaquiline is the only new anti-TB drug approved in last half-century by FDA.
Hence, there is an urgent need to develop newer chemical entities with promising anti-
TB activity to kill TB completely with less side effects in shorter time period.
Immune-compromised individuals like organ transplant recipients as well as the
[
5]
patients of TB, cancer, AIDS, and leukemia are vulnerable to fungal infections. The
co-infection of Mtb with opportunistic pulmonary fungal pathogen causes infection in
[
6]
the lungs. Most of TB patients with HIV infection are usually infected by the fungal
[
7]
pathogen. It was also observed that the risk of fungal infections was at higher per-
[
8]
centage in the patients with MDR-TB. Many physicians fail to diagnose the fungal
co-infection with TB because it is hindered by TB and also it does not show any clinical
[
9]
sign of existence. In such cases, the fate of patients may lead to death even after TB
was cured completely. Hence, there is a need for such promising anti-TB drugs that
kills fungal pathogens too.
Intake of high doses of anti-TB drugs over a long period of time in the body causes
pulmonary tissue inflammation in TB patients. It is occurred due to the oxidative stress
developed by the free radicals burst from activated macrophages and various anti-TB
[
10]
drugs.
In such conditions antioxidants used to prevent the formation of free radicals
or scavenge the generation of reactive oxygen species (ROS) which inhibits the pulmon-
[
11]
ary inflammation.
Therefore, if the antitubercular drugs demonstrate antioxidant
activity as well then it is possible to avoid the pulmonary tissue inflammation in
TB patients.
Nowadays, the 1,2,3-triazoles are being highlighted by many researchers as showing
excellent biological as well as physical properties. Among the various triazoles, the
1
,4-disubstituted-1,2,3-triazole derivatives have been found to be promising drug core
[
12]
moiety.
It is easy to synthesize by Cu (I)-catalyzed 1,3-dipolar cycloaddition of azide
[
13]
and alkyne by using Sharpless and Meldal’s greener approach of click chemistry.
The
1
,2,3-triazoles are found as a bioisoster of amide bond due to which it can easily bind
[
14]
with a high affinity to many biological targets.
shown various biological activities like antitubercular,
antifungal,
and anticoccidiostats.
Piperazine bearing molecules have displayed a wide range of biological activities
The 1,2,3-triazole scaffolds have
[
15]
[16]
[17]
anti-HIV,
anticonvulsant,
antibacterial,
[
18]
[19]
[20]
[21]
[22]
[23]
antimalarial,
antiviral,
anticancer,
antioxidant
[
24]
[
25]
[26]
[27]
such as anticancer,
antitubercular
and antifungal.
Recently, the piperazine
[
28]
incorporated 1,2,3-triazole derivatives were reported and displays various activities.
Literature survey revealed that dimeric 1,2,3-triazoles, piperazine clubbed with 1,2,3-
triazole and 1,2,3-triazole with amide linker scaffolds displayed enhanced antituber-
[
29–32]
cular
activity and representative structures are shown in Figure 1.

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Figure 1. Antitubercular agents bearing 1,2,3-triazole, amide linker, dimeric triazole and pipera-
zine scaffolds.
Most of the receptors in human body have shown to possess two binding sites as
they possess symmetrical structures and show better binding affinity with dimeric drugs
as compared to monomers. Beddell and coworkers described the use of hemoglobin as
a drug-receptor model to explain that symmetrical receptors interact with drugs or hor-
[
33]
mone molecules, having symmetrical features.
Literature reveals that dimeric com-
[
34]
pounds show better bioactivities than monomers.
Therefore, to enhance the
bioactivity, most researchers are taking interest in the synthesis and bioevaluation of
dimeric compounds.
By considering the therapeutic significance of the above and in continuation of our
[
35–45]
earlier work on chemistry and biology of 1,2,3-triazole based compounds
herein,
we would like to report the synthesis of novel dimeric 1,2,3-triazoles with piperazine
scaffold and their antitubercular, antifungal and antioxidant activity evaluations. In add-
ition to this, we have also performed molecular docking study for newly synthe-
sized compounds.
Results and discussion
Chemistry
The designed scaffold was originated from molecular hybridization of pharmacophoric
[
31,46]
fragments of antitubercular agents
as shown in Figure 2. The design of newly syn-
thesized piperazine and amide linked dimeric 1,2,3-triazoles was broadly divided into
four segments. Substituted 1,2,3-triazolyl acetamide is a bioactive fragment from I-A09
and its analogs derived from the respective appended aromatic/cyclic/aliphatic groups as
variant unit contributes as most active pharmacophoric unit in the designed strategy. In
addition to this, the piperazinyl fragment from rifampicin also helps to enhance the
pharmacophoric property. The lipophilicity control in the designed strategy could be
accomplished with the substitutional variant unit of respective aromatic/cyclic/aliphatic
moieties. The main backbone of the design was the two 1,2,3-triazolyl units situated in
symmetrical manner and may exhibit drug-like properties.

4
T. R. DESHMUKH ET AL.
Figure 2. Design strategy for the synthesis of piperazine and amide linked dimeric 1,2,3-triazoles.
Scheme 1. Synthesis of piperazine and amide linked dimeric 1,2,3-triazoles (3a–m).
The synthetic route of new piperazine and amide linked dimeric 1,2,3-triazoles
(3a–m) is depicted in Scheme 1. We have freshly synthesized various azides and dia-
lkyne as a starting material for the synthesis of target compounds. The synthesis of one
of the starting compounds, 1,4-di(prop-2-yn-1-yl)piperazine (1) is described in
Scheme 2. In first step, piperazine was allowed to react with propargyl bromide in the
presence of NaH as a base in N,N-dimethylformamide (DMF) at room temperature to
[
47]
obtain key intermediate 1,4-di(prop-2-yn-1-yl)piperazine (1) in a good yield.
Various substituted azides (2a–m) were freshly prepared by reported procedure
[
48]
as
shown in Scheme 3. These azides (2a–m) were obtained from corresponding amines
when reacts with chloroacetyl chloride in presence of triethylamine as a base using
ꢀ
chloroform as a solvent at 0 C gives corresponding substituted chloroacetyl amide
intermediates. These intermediates on further reaction with sodium azide in DMF:H O
2
ꢀ
(
3:1) at 100 C resulted in the corresponding azides (2a–m) in good yields.
After the synthesis of all the starting materials, the targeted compounds (3a–m) were
synthesized by 1,3-dipolar cycloaddition of 1,4-di(prop-2-yn-1-yl)piperazine (1) with
freshly prepared azides (2a–m) in presence of catalytic amount of CuSO .5H O and
4
2

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5
Scheme 2. Synthetic route for azides (2a–m) from respective amines.
Scheme 3. Synthesis of 1,4-di(prop-2-yn-1-yl)piperazine (1).
sodium ascorbate as a source of copper (I) in t-BuOH/H O (1:2) for 8 h at room tem-
2
perature in good to excellent yields (Scheme 1).
1
All the newly synthesized compounds have been characterized using physical data, H
1
3
1
NMR, C NMR, and HRMS spectral analysis. One of the representative H NMR spec-
trum of compound (3d), displays peaks, at d 4.79, 5.52, 8.70, and 10.46 ppm as a single,
due to the O–CH , N–CH , triazolyl–H, and amido N–H, respectively. The presence of
2
2
13
two characteristic carbon signals is observed at d 21.7 and 175.0 ppm in C NMR spec-
trum of (3d) owing to the signals of methylene groups of piperazine and amide group,
respectively. The HRMS spectrum further strengthens the structure assigned to (3d) as
þ
it displays M þ H ion peak at m/z 515.2636 for the molecular formula C H N O
26
31 10 2
þ
and equivalent to the calculated M þ H ion peak at 515.2632.
Biological assay
In vitro antitubercular activity
These piperazine tethered dimeric 1,2,3-triazoles (3a–m) were tested for their in vitro
antitubercular activity against M. tuberculosis H37Rv (ATCC 27294) by using microplate

6
T. R. DESHMUKH ET AL.
[
49]
Almar Blue assay (MABA)
for the determination of MIC in triplicates. The MIC val-
ues (mg/mL) of compounds (3a–m) have been compared with standard drugs (rifampi-
cin, isoniazid, ethambutol, and ciprofloxacin) and the results are given in Table 1.
It has been observed that the dimeric triazoles were displayed good to moderate anti-
tubercular activity with MIC values ranging from 12.5 to 25 mg/mL. Among the newly
synthesized compounds, 3b, 3d, and 3i were exhibited good antitubercular activity with
MIC value 12.5 mg/mL. Further, the compounds 3a and 3m were also showed moderate
antitubercular activity against Mtb with MIC value 25 mg/mL. The remaining com-
pounds of the series having MIC values >25 mg/mL, that are considered to be inactive
against Mtb. It was observed that inhibition depends upon substituent group attached
to triazole ring. The compounds 3b, 3d, and 3i with substituent group R containing
phenyl ring with H, 3-CH and 3-Cl groups respectively, that might be one of the rea-
3
sons for better antitubercular activity as compared to other compounds of the series.
Whereas, the compounds 3a and 3m with substituent group R bearing dimethyl and 4-
NO group respectively, exhibits moderate antitubercular activity.
2
Lipophilicity is an important physicochemical property which may lead to improve
[
50]
therapeutic success and quality of drug.
In the discovery of any drug, the assessment
of lipophilicity is based on LogP/CLogP values. Therefore, to study the correlation of
antitubercular activity of synthesized compounds with lipophilicity parameters like LogP
and CLogP were calculated using ChemBiodraw ultra 12.0 software and the results are
displayed in Table 1. Compounds may show better lipophilicity when value of LogP ꢁ 5.
It was found that all synthesized compounds having values of LogP and CLogP are in
acceptable range. Hence, all the compounds show excellent lipophilic property which
helps to accelerate the rate of therapeutic success.
In vitro antifungal activity
All these newly synthesized compounds (3a–m) were also screened for their in vitro
antifungal activity against five human pathogenic fungal strains. The obtained screening
results were summarized in Table 2.
According to this, most of the synthesized compounds were shown good to excellent
antifungal activity against the tested strains. The compound 3g was found to be most
potent antifungal agent against all the tested strains as compared to standard drug
miconazole. It shows excellent activity against C. albicans and Aspargillus niger with
MIC 12.5 mg/mL and proved as two-fold more potent antifungal agent than standard
miconazole. In this case, the presence of 4-OCH group may influence the activity. The
3
compound 3 l was also displayed more potent or equipotent activity as compared to
miconazole. Out of five tested fungal stains, this compound was found to be active
against four strains. The presence of 3-NO group on compound 3l may influence
2
the activity.
The compounds 3e, 3h, and 3m possess good antifungal activity against at least two
fungal stains whereas compounds 3d, 3e, and 3k also show equipotent antifungal activ-
ity against only one of the tested stains. All these compounds show either more potent
or equipotent antifungal activity in comparison with miconazole, which might be due to
presence of variant groups in the molecular framework. Results show that the active

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Table 1. In vitro antitubercular evaluation of compounds (3a–m) against M. tuberculosis H37Rv.
a
b
Entry
Structures
MIC (mg/mL)
LogP
CLogP
3
a
25
ꢂ1.63
ꢂ1.8236
3
b
12.5
>25
12.5
1.23
2.2
1.0272
3
c
0.7252
2.0252
3
d
2.2
3
e
f
>25
>25
2.2
2.0252
1.178
3
0.97
3
g
>25
0.97
1.178
3
3
h
i
>25
2.34
2.34
1.2684
2.9684
12.5
(continued)

8
T. R. DESHMUKH ET AL.
Table 1. Continued.
Entry
a
b
Structures
MIC (mg/mL)
>25
LogP
CLogP
3
j
2.34
2.9684
3
3
k
l
>25
>25
–
–
0.6972
1.6172
3
m
25
–
1.6172
Isoniazid
0.1
0.2
1.56
1.56
–
–
–
–
–
–
–
–
Rifampicin
Ethambutol
Ciprofloxacin
a and b calculated using ChemBioDraw Ultra 12.0.
Table 2. In vitro antifungal and antioxidant activity of synthesized compounds (3a–m).
(MIC) in mg/mL against fungal strains
Compounds
CA
FO
AF
AN
CN
25
IC50 (mg/mL) antioxidant activity
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
25
75
150
50
50
37.5
50
75
50
150
25
25
100
150
37.5
50
25
25
100
50
100
25
175
100
175
75
39.74 ± 0.95
11.17 ± 0.89
31.04 ± 0.24
11.34 ± 0.45
10.12 ± 0.25
12.85 ± 0.27
38.62 ± 0.31
41.37 ± 0.08
10.64 ± 0.29
24.54 ± 0.20
25.09 ± 0.77
13.98 ± 0.44
11.17 ± 0.35
NT
62.5
ꢃ
25
25
25
50
100
ꢃ
100
12.5
37.5
75
125
25
25
62.5
25
175
12.5
37.5
150
125
50
12.5
25
12.5
62.5
25
12.5
37.5
12.5
ꢃ
150
ꢃ
j
k
l
175
62.5
25
100
25
m
25
25
NT
50
25
NT
Miconazole
BHT
NT
NT
NT
16.47 ± 0.18
CA: Candida albicans (NCIM 3471); FO: Fusarium oxysporum (NCIM 1332); AF: Aspergillus flavus (NCIM 539); AN:
Aspergillus niger (NCIM 1196); CN: Cryptococcus neoformans (NCIM 576); NT: not tested;
ꢃ
No activity up to 200 mg/mL; BHT: butylated hydroxy toluene.

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9
compounds will serve as an important scaffold for further designing and development
of new antifungal agents in future.
Antioxidant activity
Generally, due to intake of higher doses of antitubercular drugs by the patient of tuber-
culosis over a long period of time leads to develop oxidative stress which may result in
[
10]
[11]
pulmonary tissue inflammation.
DPPH radical scavenging activity
is the most
commonly used method for screening antioxidant activities of the various natural as
well as synthetic antioxidants. The IC50 of BHT (butylated hydroxyl toluene) used for
comparison and the results were summarized in Table 2. It was observed that most of
the synthesized compounds show excellent antioxidant activity with promising lower
IC50 values in comparison with standard antioxidant agent, BHT. The compounds 3e
and 3i were displayed excellent radical scavenging activity with IC50 10.12 and 10.64 mg/
mL, respectively and found as most potent antioxidant agents. Both these compounds
3
e and 3i were also found to be more potent than standard antioxidant agent, BHT. In
addition to this, the compounds 3b, 3d, and 3m were also displayed excellent radical
scavenging activity with IC50 values ranges 11.17–11.34 mg/mL and found to be more
potent than BHT. According to Table 2, the compounds 3f and 3 l also acts as better
antioxidant agents than BHT, as both having IC50 values 12.85 and 13.98 mg/mL,
respectively. Whereas, remaining compounds were observed as less potent than BHT.
Computational study
Molecular docking study
Promising level of anti-tubercular activity produced by the piperazine tethered dimeric
1,2,3-triazoles (compounds 3b, 3d, and 3i) prompted us to perform molecular docking
studies to identify their potential biological target and elucidate the plausible mechanism
by which these compounds inhibit the pathogen. It was performed using with Glide
[
51]
(Grid-Based Ligand Docking With Energetics) program.
Among the array of crucial
targets, mycobacterial enoyl reductase (InhA) enzyme has recently drawn significant
attention of medicinal chemists as a potential target to combat the pathogen. In add-
ition, several reports have demonstrated the potential of the triazole scaffold to inhibit
[
52]
mycobacterial enoyl reductase (InhA).
The enoyl-ACP (CoA) reductase (FabI/ENR/
InhA) plays a crucial role in the fatty acids elongation cycle contributing to mycolic
acid biosynthesis through the mycobacterial type II fatty acid biosynthesis pathway. Its
inhibition is shown in the fast-growing model organism Mycobacterium smegmatis to
[
53]
inhibit mycolic acid synthesis and induce cell lysis.
Therefore, impaired action of
InhA leads to the loss of cell integrity and consequently to cell death. These reports
served as the basis for selecting enoyl-ACP reductase as the target to investigate the
binding mode of the compounds and to gain an insight into the ligand-protein
interactions.
The theoretical predictions from the molecular docking study showed that all the five
compounds (3b, 3d, and 3i) could successfully dock into the active site of Mtb enoyl
reductase (InhA) with varying degree of affinities. Their complexation with the receptor

1
0
T. R. DESHMUKH ET AL.
was stabilized by formation of several bonded and non-bonded interactions. A detailed
per-residue interaction analysis between these molecules and the residue forming the
active site of the enzyme was carried out to identify the most significantly interacting
residues and the type of thermodynamic elements governing their binding to the target.
The intermolecular interaction energy values (Glidescore, Glide energy) along with per-
residue interactions obtained from the docking calculation are summarized in Table 3.
The lowest energy docked conformation (Fig. 3) of 3b was found to be tightly bound
to the active site of InhA at the same co-ordinates as the co-crystallized native ligand
with the central piperazine nucleus engaging in a significant van der Waals interactions
with Lys165 (ꢂ1.997 kcal/mol), Ala191 ꢂ1.020 kcal/mol), Met161 (ꢂ2.482 kcal/mol),
Asp148 (ꢂ2.05 kcal/mol), Met147 (ꢂ2.539 kcal/mol), Ile21 (ꢂ2.497 kcal/mol) and Ile16
(
ꢂ1.245 kcal/mol) residues; the triazole pharmacophores showed van der Waals interac-
tions with Ile194 (ꢂ1.831 kcal/mol), Pro193 (ꢂ2.576 kcal/mol), Tyr158 (ꢂ3.441 kcal/
mol), Met103 (ꢂ2.03 kcal/mol), Ser94 (ꢂ3.076 kcal/mol), Ala22 (ꢂ2.076 kcal/mol), Ser20
(ꢂ2.469 kcal/mol).
Similarly the N-phenylacetamide groups flanking the piperazine nucleus also showed
favorable van der Waals interactions via Leu218 (ꢂ2.664 kcal/mol), Ile215 (ꢂ2.582 kcal/
mol), Met199 (ꢂ3.424 kcal/mol), Ala157 (ꢂ2.164 kcal/mol), Met155 (ꢂ2.393 kcal/mol),
Phe149 (ꢂ2.83kcal/mol), Gly96 (ꢂ2.277 kcal/mol), Ile95 (ꢂ2.506 kcal/mol), Phe41
(
ꢂ2.933 kcal/mol), Ile15 (ꢂ2.537 kcal/mol) and Gly14 (ꢂ2.91kcal/mol) residues of active
site. On the other hand, Arg195 (ꢂ1.235 kcal/mol), Gly192 (ꢂ2.817 kcal/mol), Glu169
(
ꢂ2.300 kcal/mol) and Ser20 (ꢂ2.356 kcal/mol) residue interacted electrostatically with tri-
azole pharmacophore while Asp148 (ꢂ2.759 kcal/mol) got engaged in similar type of contact
with piperazine scaffold.
The enhanced binding affinity of 3b has also attributed to two prominent hydrogen-
bonding interaction observed first between Gly14 residue and the amine group substi-
tuted (–NH–) linker of the N-phenylacetamide group with a bonding distance of 2.12 Å
while second H-bond was observed between the Lys165 residue and piperazine nitrogen
with a bonding distance of 2.61 Å. Furthermore, a close p–p stacking interactions
observed between the triazole ring and Tyr158 residue (1.907 Å) contributed signifi-
cantly to the stability of 3b within the active site of InhA. These type of hydrogen
bonding and the p–p stacking interactions “anchor” the ligand into the active site of
the enzyme facilitating the steric and electrostatic interactions.
A similar binding mode and network of interactions was observed for 3d and 3i (Figs.
4
and 5) as well. The per-residue ligand interaction analysis suggests that steric comple-
mentarity with the active site residues of InhA governed the mechanical interlocking of
these molecules reflected in the relatively higher contribution of favorable van der Waals
interactions over the other components contributing to the binding affinity
(In Figs. 3–5, the green lines on right side signify p–p stacking interactions while the
pink lines represent the hydrogen bonding interactions.)
In silico ADME prediction
we have also predicted in silico ADME properties of newly synthesized piperazine teth-
ered dimeric 1,2,3-triazoles (3a–m). The results of ADME predictions were summarized

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11

1
2
T. R. DESHMUKH ET AL.
Figure 3. Binding mode of 3b into the active site of Mtb InhA.
Figure 4. Binding mode of 3d into the active site of Mtb InhA.
Figure 5. Binding mode of 3i into the active site of Mtb InhA.
in Table 4. In this study, we have calculated molecular volume (MV), molecular weight
(MW), logarithm of partition coefficient (mi LogP), number of hydrogen bond accept-
ors (n-ON), number of hydrogen bonds donors (n-OHNH), topological polar surface

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Table 4. Pharmacokinetic parameters for in silico ADME prediction.
Lipinski
i
Drug likeness
model score
a
b
2
c
d
e
f
g
h
Entry % ABS
TPSA (A ) n-RO TB
MV
MW
miLog n–ON
n–OH NH
violations
Rule
–
–
–
8
–
<500
ꢁ5
<10
12
12
12
12
12
14
14
12
12
12
18
18
18
<5
0
2
2
2
2
2
2
2
2
2
2
2
ꢁ1
–
3
3
3
3
3
3
3
3
3
3
3
3
3
a
a
b
c
d
e
f
g
h
i
71.56
65.49
65.49
65.49
65.49
59.12
59.12
65.49
65.49
65.49
33.87
33.87
33.87
108.53
126.11
126.11
126.11
126.11
144.58
144.58
126.11
126.11
126.11
217.76
217.76
217.76
388.48 418.50 ꢂ2.84
1
0.21
1.05
1.25
0.83
1.26
0.85
1.38
1.46
0.94
1.97
0.43
0.24
0.55
10
10
10
10
12
12
10
10
10
12
12
12
464.29 514.58
497.41 542.64
497.41 542.64
497.41 542.64
515.38 574.64
515.38 574.64
491.36 583.47
491.36 583.47
491.36 583.47
510.96 604.58
510.96 604.58
510.96 604.58
0.95
1.75
1.80
1.84
1.01
1.06
2.21
2.25
2.30
0.77
0.82
0.86
2
2
2
2
2
2
2
2
2
2
2
2
j
k
l
m
2
Percentage absorption.
b
topographical polar surface area.
c
number of rotatable bonds.
d
e
molecular volume.
molecular weight.
lipophilicity.
f
g
h
i
no. of hydrogen bond acceptors.
no. of hydrogen bond acceptors.
number of violations.
[
54]
area (TPSA), number of rotatable bonds (n-ROTB) and Lipinski’s rule of five
of all
the newly synthesized compounds using Molinspiration online property calculation
[
55]
toolkit.
Absorption (% ABS) of all the derivatives of the series was calculated by
using following formula.
[
56]
%
ABS ¼ 109 ꢂ ð0:345 ꢄ TPSAÞ
Drug-likeness model score (a collective property of physico-chemical properties,
pharmacokinetics and pharmacodynamics of a compound is represented by a numerical
[
57]
value) of each and every compound was computed by MolSoft software.
A molecule
is considered to develop an orally active drug if the drug violates only one of the
Lipinski’s rule of five having following four valid criteria’s: miLogP (octanol-water
partition coefficient) ꢁ5, molecular weight ꢁ500, number of hydrogen bond acceptors
ꢁ
10 and number of hydrogen bond donors ꢁ5.
It was observed that all the synthesized compounds exhibited moderate to good %
ABS ranging from 33.87 to 71.56%. A molecule is considered to develop an orally active
drug if the drug violates only one of the Lipinski’s rule of five. From the Table 4, it was
observed that most of the property predictions were found in an acceptable range and
possess average to good potential to develop an orally active drug molecules.
Conclusion
In conclusion, new piperazine tethered dimeric 1,2,3-triazoles (3a–m) were synthesized
and evaluated against Mtb H37Rv strain. The compounds 3 b, 3d and 3i have displayed
significant antitubercular activity with MIC value 12.5 mg/mL. Furthermore, antifungal
activity of the newly synthesized compounds were also evaluated against five human

1
4
T. R. DESHMUKH ET AL.
pathogenic fungal strains. Among the series, compounds 3g and 3l were displayed
excellent antifungal activity as compared to standard drug. In addition to this, all the
compounds were also examined for antioxidant activity and DPPH radical scavenging
assay revealed that the compounds 3b, 3d, 3e, 3i, and 3m possess more potent antioxi-
dant activity than BHT. Piperazine tethered dimeric 1,2,3-triazoles offers an attractive
lead series for the discovery of novel antitubercular, antifungal and antioxidant agents.
Furthermore, molecular docking investigation for the most active compounds into
the active site of InhA provided well-clustered solutions to the mode of binding into
the active site of mycobacterial InhA. The computational results correlated with the
observed experimental values in good agreement suggesting that these molecules could
serve as pertinent starting point for further optimization and development as InhA
target specific antitubercular agents.
Experimental
Materials and methods
All the chemicals were of laboratory grade, purchased from commercial suppliers
Spectrochem, Avra, Alfa Aesar and Sigma Aldrich and were used without further purifi-
cation. Purity and completion of reaction time of all synthesized compounds were
monitored by thin layer chromatography (TLC) using silica gel 60-F254 precoated on
aluminum sheets as an adsorbent, Merck, Germany and visualization was accomplished
by iodine/ultraviolet light. Melting points of all the synthesized compounds were deter-
1
mined in an open capillary tube method and are uncorrected. H NMR spectra were
recorded on a Brukar DRX-400 and 400 MHz NMR spectrometer using tetramethylsi-
lane (TMS) as an internal standard and chemical shifts are in d(ppm). The splitting pat-
tern abbreviations are designed as singlet (s); doublet (d); double doublet (dd); triplet
1
3
(
t); quartet (q) and multiplet (m). C NMR spectra were recorded on a Brukar DRX-75
and 100 MHz NMR in DMSO-d . High-resolution mass spectra (HRMS) were obtained
6
using HRMS-ESI-Q-Time of flight LC/MS instrument.
General procedure for the synthesis of piperazine incorporated dimeric 1,2,3-
triazoles (3a–m)
In a round bottom flask 1,4-di(prop-2-yn-1-yl)piperazine 1 (0.01 mol) and the newly
synthesized azides 2a–m (0.02 mol) were allowed to react in the presence of aqueous
solution of CuSO .5H O and sodium ascorbate t-BuOH/H O (1:2) at room temperature
4
2
2
for 8 h. The same experimental procedure of click reaction we have used in our earlier
[
58,59]
research work.
The progress of the reaction was monitored by TLC using ethyl
acetate: hexane (3:7) as a solvent system. After completion of the reaction, the reaction
mixture was poured on crushed ice. The obtained solid products (3a–m) were filtered,
dried and crystallised in ethanol-DMF.
0
0
Synthesis of 2,2 -(4,4 -(piperazine-1,4-diylbis(methylene))bis(1H-1,2,3-triazole-4,1-
diyl))bis (N-phenylacetamide) (3b)
The compound (3b) was obtained by Cu (I)-catalyzed 1,3-dipolar cycloaddition reaction
between 1,4-di(prop-2-yn-1-yl)piperazine (1) and azide (2b) as dark greenish solid;

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15
ꢀ
1
Yield: 94%; Mp: >270 C; H NMR (400 MHz, DMSO-d , d ppm) 2.95 (s, 4H, pipera-
6
H
zinyl-H), 3.02 (s, 4H, piperazinyl-H), 4.78 (s, 4H, piperazinyl N–CH ), 5.38 (s, 4H, tria-
2
zolyl N–CH ), 7.14–7.63 (m, 10H, Ar–H), 8.68 (s, 2H, triazolyl–H), 10.58 (s, 2H, amido
2
1
3
N–H); C NMR (100 MHz, DMSO-d , d ppm) 24.5, 70.2, 72.8, 116.9, 119.3, 133.1,
6
C
þ
1
33.5, 135.1, 138.5, 162.0; HRMS (ESI) calcd. for C H N O M þ H : 515.2632;
26
31 10 2
found 515.2636.
Acknowledgments
One of the author T.R.D. is very much grateful to Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad for the award of University Scholars Fellowship. Authors are also thank-
ful to the Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad-431 004, India for providing laboratory facility. We are also grateful to Schrodinger
Inc. for GLIDE software to perform the molecular docking studies.
Disclosure statement
The authors declare no competing interest.
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