Synthesis, antitubercular evaluation and molecular docking studies of phthalimide bearing 1,2,3-triazoles

Article abstract of DOI:10.1080/00397911.2019.1614630

In a search for safer and potent antitubercular agents, here a library of newly substituted dioxoisoindolinylmethyl-triazolyl-N-phenylacetamide derivatives (5a–l) has been synthesized via click chemistry approach. All synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB). Among the screened compounds, 5d, 5e, 5h, and 5l showed good antitubercular activity. The compounds 5d and 5l have shown very effective antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB) with MIC 12.5 μg/mL. All the newly synthesized compounds were thoroughly characterized by ¹H NMR, ¹³C NMR, and HRMS spectral data. We further performed exploratory docking studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase to demonstrate the mechanism of antitubercular activity.

Full text of DOI:10.1080/00397911.2019.1614630

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, antitubercular evaluation and
molecular docking studies of phthalimide bearing
1,2,3-triazoles
Pramod S. Phatak, Rajubai D. Bakale, Sambhaji T. Dhumal, Lalita K.
Dahiwade, Prafulla B. Choudhari, Vagolu Siva Krishna, Dharmarajan Sriram
& Kishan P. Haval
To cite this article: Pramod S. Phatak, Rajubai D. Bakale, Sambhaji T. Dhumal, Lalita K.
Dahiwade, Prafulla B. Choudhari, Vagolu Siva Krishna, Dharmarajan Sriram & Kishan P. Haval
(2019): Synthesis, antitubercular evaluation and molecular docking studies of phthalimide bearing
1,2,3-triazoles, Synthetic Communications, DOI: 10.1080/00397911.2019.1614630
To link to this article: https://doi.org/10.1080/00397911.2019.1614630
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1614630
Synthesis, antitubercular evaluation and molecular docking
studies of phthalimide bearing 1,2,3-triazoles
Pramod S. Phataka, Rajubai D. Bakalea, Sambhaji T. Dhumalb, Lalita K. Dahiwadec,
Prafulla B. Choudharic, Vagolu Siva Krishnad, Dharmarajan Sriramd, and
Kishan P. Havala
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University Sub-Campus,Osmanabad,
b
MS, India; Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad,
c
MS, India; Department of Pharmaceutical Chemistry, Bharati Vidhyapeeth College of Pharmacy,
d
Kolhapur, MS, India; Department of Pharmacy, Birla Institute of Technology and Science-Pilani,
Hyderabad, India
ABSTRACT
ARTICLE HISTORY
Received 13 April 2019
In a search for safer and potent antitubercular agents, here a library
of newly substituted dioxoisoindolinylmethyl-triazolyl-N-phenylaceta-
mide derivatives (5a–l) has been synthesized via click chemistry
approach. All synthesized compounds were evaluated for their anti-
tubercular activity against Mycobacterium tuberculosis H37Rv (MTB).
Among the screened compounds, 5d, 5e, 5h, and 5l showed good
antitubercular activity. The compounds 5d and 5l have shown very
effective antitubercular activity against Mycobacterium tuberculosis
H37Rv (MTB) with MIC 12.5lg/mL. All the newly synthesized com-
pounds were thoroughly characterized by 1H NMR, 13C NMR, and
HRMS spectral data. We further performed exploratory docking stud-
ies on the crystal structure of Mycobacterium tuberculosis enoyl reduc-
tase to demonstrate the mechanism of antitubercular activity.
KEYWORDS
Antitubercular activity; click
chemistry; molecular
docking study; N-
phenylacetamide; phthali-
mide; 1,2,3-triazole
GRAPHICAL ABSTRACT
CONTACT Kishan P. Haval
havalkp@gmail.com
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University Sub-Campus, Osmanabad, 413501, MS, 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

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P. S. PHATAK ET AL.
Introduction
According to the World Health Organization (WHO) report on TB, the diseases,
namely tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis (MTB) is
one of the most deadliest infectious disease. As per Global Tuberculosis Report-2018, it
is the leading cause due to a single infectious agent and its percentage is above HIV/
AIDS.[1] Drug-Resistant TB is a major issue of public health. In 2017, WHO estimated
that about 558,000 people in the world having TB are resistant to first-line drug rifam-
picin (RR-TB) and 82% having multi-drug resistant TB (MDR-TB). Treatment for
drug-sensitive TB takes up to 2 months and for drug-resistant TB, it may take up to
24 months.[2] So, there is an urgent need to search for new drugs and their strategies
for effective treatment. Mycobacterium tuberculosis has a unique cell wall made up of
mycolic acids, which are highly lipophilic one. These mycolic acids are the major hurdle
for antimycobacterial drug action. Mycolic acids are synthesized in the Mycobacterium
via fatty acid biosynthesis process. Enoyl-ACP reductase is an important enzyme of the
type II fatty acid synthase (FAS-II) system in Mycobacterium. This enzyme has no
homologs in the mammalian system, so it deserves full credentials to act as an utilizable
antitubercular target.
The heterocyclic compounds containing phthalimide core are the biologically active spe-
cies which shows a-glucosidase inhibition,[3] antimalarial,[4] anti-inflammatory,[5] anti-
microbial, anti-oxidant, [6] and anti-angiogenic[7] activities. Phthalimide when coupled with
other heterocyclic groups like sulfonamide group, aminoquinoline, etc. also shows in vitro
antitubercular activities.[8–11] Azoles are the important class of nitrogen-containing hetero-
cycles that shows very good biological activities such as antifungal, antibacterial, antimalar-
ial, anti-inflammatory, and antitubercular.[12,13] Particularly, 1,2,3-triazole is an important
class of heterocyclic compounds, which has attracted increasing attention in medicinal
chemistry and drug discovery (Figure 1).[14–16] 1,2,3-Triazoles are synthesized by “Click
Chemistry” approach, which was firstly reported by Sharpless and research group.[17] 1,2,3-
Triazole derivatives are endowed with numerous therapeutic activities, such as antimicro-
bial,[18] acidic corrosion inhibitor for steel,[19] SGLT2 inhibitor,[20] histone deacetylase 1
inhibitor,[21] a-glucosidase inhibitor,[22] and antitubercular.[23]
Figure 1. Some representative examples of 1,2,3-triazoles having antitubercular activity.

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Results and discussions
Chemistry
Considering the urgent need for preparing a library of new antitubercular agents
and highly impressed by the antitubercular activities displayed by 1,2,3-triazoles, here
we thought worthwhile to design and synthesize newly substituted 1,2,3-triazoles
bearing phthalimide and acetyl phenoxy acetamide scaffolds in a single molecular
framework with the hope to obtain better antimycobacterial activity. Herein, we have
reported new dioxoisoindolinylmethyl-triazolyl-N-phenylacetamides (5a-l) via “Click
Chemistry” approach. All the synthesized derivatives were evaluated for their antitu-
bercular activity against Mycobacterium tuberculosis H37Rv and determined their
MIC (minimum inhibitory concentration) values. Molecular docking study and in sil-
ico ADME predictions of the synthesized compounds have been performed and
results are incorporated.
In the present study, we have reported the synthesis of substituted 2-(4-((1,3-dioxoi-
soindolin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-phenylacetamides (5a–l) starting from
phthalimide via click chemistry approach. Firstly, we performed the reaction of phthali-
mide (1) and propargyl bromide (2) in the presence of K2CO3 in DMF at room tem-
perature to obtain 2-(prop-2-ynyl)isoindoline-1,3-dione (3) (Scheme 1) with 90%
yield.[24–26] The structure of 2-(prop-2-ynyl)isoindoline-1,3-dione (3) was confirmed by
spectral data. Further, the reaction of compound 2-(prop-2-ynyl)isoindoline-1,3-dione
(3) and freshly prepared substituted N-phenyl acetamides (4a–l) were carried out in the
presence of CuSO4.5H2O and sodium ascorbate in PEG-400 at room temperature and
to furnish the corresponding substituted 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1H-
1,2,3-triazol-1-yl)-N-phenylacetamides (5a–l) with 75–90% yields (Scheme 2). The phys-
ical data of 1,2,3-triazoles is incorporated in Table 1.
Scheme 1. Synthesis of 2-(prop-2-ynyl)isoindoline-1,3-dione (3).
Scheme 2. Synthesis of substituted 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-
phenylacetamides (5a–l).

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P. S. PHATAK ET AL.
Table 1. Physical data and MIC values of substituted 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1H-1,2,3-
triazol-1-yl)-N-phenylacetamides (5a-l).
Entry
Compounds
M. P. (oC)
Yield (%)
90
MIC (lg/mL)
>25
5a
240–242
5b
5c
270–272
255–257
80
85
>25
>25
5d
270–272
80
12.5
5e
5f
290–291
205–207
240–243
85
90
75
25
>25
>25
5g
5h
5i
250–252
200–202
80
90
25
>25
5j
5k
5l
250–252
210–211
235–237
85
90
85
>25
>25
12.5
MIC values of isoniazid and rifampicin are 0.1 and 0.2 mg/mL, respectively. The bold values indicates the better MIC val-
ues of compounds 5d, 5e, 5h and 5l as comparative to other remaining compounds.
1
All the newly synthesized compounds have been characterized using their IR, H
NMR, 13CNMR, and HRMS spectral data. In IR spectrum of compound (5a), the char-
1
acteristic peak at 1540 cmꢀ1 indicates the presence of C¼N bond. The H NMR spec-
trum of compound (5a) displays a singlet at d 2.32 ppm due to the CH3 attached to the
aromatic ring. The characteristic peaks of two singlets at d 5.02 and 5.23 ppm confirms
the presence of two CH2 groups. The singlet at d 7.96 ppm confirms the presence of
1,2,3-triazole ring in compound (5a). The three characteristic peaks in the 13CNMR
spectrum of (5a) in the upfield region at d 28.26, 31.83, and 51.47 ppm confirm the
presence of one CH3 and two CH2 carbons, respectively. The signals observed at d
162.41 and 166.23 ppm clearly indicates the presence of two carbonyl groups of N-phe-
nylacetamide and phthalimide, respectively. The HRMS spectrum further strengthens
the structure assigned to 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-
N-(p-tolyl)acetamide (5a) as it displays [M þ H]þ ion peak at m/z 376.1410 for the
molecular formula C20H17N5O3.

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Antitubercular activity
The inoculum was prepared from fresh LJ medium re-suspended in 7H9-S medium
(7H9 broth, 0.1% casitone, 0.5% glycerol, supplemented oleic acid, albumin, dextrose,
and catalase [OADC]), adjusted to OD590 1.0, and diluted 1:20; 100 ml was used as an
inoculum. Each drug stock solution was thawed and diluted in 7H9-S at four-fold, the
final highest concentration tested. Serial two-fold dilutions of each drug were prepared
directly in a sterile 96-well microtiter plate using 100 ml 7H9-S. A growth control con-
taining no antibiotic and a sterile control was also prepared on each plate. Sterile water
was added to all perimeter wells to avoid evaporation during the incubation. The plate
was covered, sealed in plastic bags, and incubated at 37 ꢁC in a normal atmosphere.
After 7 days of incubation, 30 ml of Alamar blue solution was added to each well and
the plate was re-incubated overnight. A change in color from blue (oxidised state) to
pink (reduced) indicated the growth of bacteria and the MIC was defined as the lowest
concentration of drug that prevented this change in color.[27] The compounds 5d, 5e,
5h, and 5l showed notable antitubercular activity with MIC values 12.5, 25, 25, and
12.5 lg/mL, respectively (Table 1). It has been observed that the compounds having
4-bromo (5d) or 2-methyl (5l) substituents on aromatic ring are showing very good
antitubercular activities. Also, 3-nitro (5e) or 4-fluoro (5h) substituents are useful for
possessing antitubercular activities.
Docking analysis
Docking analysis was utilized to predict the mechanism of action of the designed
derivatives for antimycobacterial potential. All the molecules exhibited binding ener-
gies in the range of -92.69 to - 112.27 kcal/mol. Most active molecules (5d) exhibited
hydrogen bond interactions with TYR158 and MET199, showed aromatic interaction
with TYR158, hydrophobic interaction with MET199, TYR158 and Van der Waals
interactions with PHE97, MET98, MET103, GLY104, PHE149, PRO156, ALA157,
TYR158, MET161, ILE202, LEU207, ALA211, ILE215 (Figure 2). The compound (5l)
showed hydrogen bond interactions with TYR158 showed aromatic interaction with
TYR158 and PHE149 hydrophobic interaction with GLY96, PHE97, MET98,
MET161, MET199, and Vander Waals interactions with PHE97, MET98, MET103,
GLY104, PHE149, PRO156, ALA157, TYR158, MET161, ILE202, LEU207, ALA211,
ILE215 (Figure 3). The compound (5e) showed hydrogen bond interactions with
TYR158, GLY104, showed aromatic interaction with PHE149, TYR158 hydrophobic
interaction with PHE149, LYS165, PRO193, MET199, LEU218, and Van der Waals
interactions with GLY96, PHE97, MET98, MET103, GLY104, PHE149, PRO156,
ALA157, TYR158, MET161, ALA198, ILE202, LEU207, ALA211, and ILE215
(Figure 4). The compound (5h) showed hydrogen bond interactions with TYR158,
showed aromatic interaction with PHE149, TYR158 hydrophobic interaction with
PHE149, PRO193, and Van der Waals interactions with PHE97, MET98, MET103,
GLY104, PHE149, PRO156, ALA157, TYR158, MET161, ALA198, ILE202, LEU207,
ALA211, and ILE215 (Figure 5).

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P. S. PHATAK ET AL.
Figure 2. Binding mode of 5d into the active site of InhA predicted by molecular docking.
Figure 3. Binding mode of 5l into the active site of InhA predicted by molecular docking.

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Figure 4. Binding mode of 5e into the active site of InhA predicted by molecular docking.
Figure 5. Binding mode of 5h into the active site of InhA predicted by molecular docking.
ADME prediction
ADME prediction of all the synthesized molecules is predicted using Swiss ADME por-
tal. All the molecules showed excellent physicochemical parameters with low Lipinski
violation, which is desirable for the oral absorption of drug candidates (Table 2). All
synthesized derivatives showed good physicochemical properties, which are infusing the
ADME properties.

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P. S. PHATAK ET AL.
Table 2. Physicochemical property prediction of substituted 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-
1H-1,2,3-triazol-1-yl)-N-phenylacetamides (5a-l).
Entry
Mol. Wt.
Rotatable bonds
H-bond acceptors
H-bond donors
LOGP
Bioavai-lability Score
5a
5b
5c
5d
5e
5f
5g
5h
5i
375.38
395.80
361.35
440.25
406.35
391.38
395.80
379.34
391.38
395.80
391.38
375.38
6
6
6
6
7
7
6
6
7
6
7
6
5
5
5
5
7
6
5
6
6
5
6
5
1
1
1
1
1
1
1
1
1
1
1
1
2.35
2.22
2.06
2.60
1.55
2.51
2.62
2.17
2.58
2.28
2.39
2.36
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
5j
5k
5l
Conclusions
In conclusion, we have reported a series of newly substituted dioxoisoindolinylmethyl-
triazolyl-N-phenylacetamide derivatives by 1,3-dipolar cycloaddition of the alkyne (3)
and substituted phenyl acetamides (4a-l). Amongst the synthesized 1,2,3-triazoles, the
compounds 5d, 5e, 5h, and 5l have displayed notable antitubercular activity against
Mycobacterium tuberculosis H37Rv. Molecular docking study indicates that all the mole-
cules are binding to the enoylreductase of the Mycobacterium tuberculosis. We think the
results obtained herein will provide a strong platform for structure-based optimization
of these newly identified 1,4-disubstituted 1,2,3-triazole derivatives as antitubercu-
lar agents.
Experimental
The chemicals used were of laboratory grade. Melting points of all the synthesized com-
pounds were determined in open capillary tubes and are uncorrected. The IR spectra
(KBr pellets) were recorded on Bruker FT-IR spectrometer. 1H NMR spectra were
recorded on a Bruker DRX-300 MHz NMR spectrometer using tetramethylsilane (TMS)
as an internal standard and chemical shifts are in d (ppm). 13C NMR spectra were
recorded on a Bruker DRX-75 MHz NMR in CDCl3 þ DMSO-d6. High-resolution mass
spectra (HRMS) were obtained using the Agilent 6520 (Q-TOF) ESI-HRMS instrument.
The purity of the title and intermediate compounds was checked by thin-layer chroma-
tography (TLC).
Synthesis of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (3)
A mixture of phthalimide (3) (0.01 mol), propargyl bromide (0.01 mol), and K2CO3
(0.02 mol) was stirred in DMF at room temperature. The progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction mixture was poured
on crushed ice. The solid obtained was filtered, washed with water, and recrystallized
from ethanol.
1
Yield: 90%, M.P.: 151–153 ꢁC; White Solid. H NMR (300 MHz, CDCl3 þ DMSO-d6)
d ppm ¼ 3.17 (s, 1H), 4.43 (d, J ¼ 3 Hz, 2H), 7.78–7.83 (m, 2H), 7.85–7.90 (m, 2H).

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General procedure for the synthesis of 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1H-
1,2,3-triazol-1-yl)-N-phenylacetamides (5a-l)
2-(Prop-2-yn-1-yl)isoindoline-1,3-dione (3) (0.01 mol) and substituted N-phenylaceta-
mides (4a-l) (0.01 mol) were stirred in the presence of CuSO4.5H2O (20 mol%) and
sodium ascorbate (20 mol%) in PEG-400. The progress of the reactions was monitored
by TLC. After completion of reactions (5–6 h), the reaction mixtures were poured in ice
cold water. The products obtained were filtered, washed with water, and recrystallized
from ethanol.
2-(4-((1,3-Dioxoisoindolin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-(p-tolyl)acetamide
(5a): Yield: 90%, M.P.: 240–242 ꢁC; White Solid; IR (KBr) ꢀ cmꢀ1: 3270, 3147, 3052,
1
2333, 1692, 1667, 1540, 1396, 1335, 1091, 818, 711; H NMR (300 MHz, CDCl3 þ
DMSO-d6) d ppm ¼ 2.32 (s, 3H), 5.02 (s, 2H), 5.23 (s, 2H), 7.12 (d, J ¼ 9 Hz, 2H),
7.47(d, J ¼ 9 Hz, 2H), 7.74–7.78 (m, 2H), 7.83–7.87 (m, 2H), 7.96 (s, 1H), 10.01 (s, 1H) ;
13C NMR (75 MHz, CDCl3þ DMSO-d6) d ppm ¼ 28.26, 31.83, 51.47, 118.51, 122.11,
123.69, 128.08, 130.70, 132.18, 133.13, 134.53, 141.17, 162.41, 166.23; HRMS (ESI)þ
calcd. for C20H17N5O3 [M þ H]þ: 376.1365 and found 376.1410.
Docking analysis
Molecular docking analysis was performed to predict the possible mode of action of the
synthesized triazole derivatives. Crystal structure of Mycobacterium tuberculosis enoylre-
ductase (INHA) complexed with N-(3-chloro-2-methylphenyl)-1-cyclohexyl- 5-oxopyr-
rolidine-3-carboxamide (PDB ID: 4TZT) was enoylreductase downloaded from the free
protein database www.rcsb.org. Crystal structure of the download was refined via
removal of the water and addition of the hydrogen atoms so that native geometry of
the protein is achieved. Ligands were prepared in Vlife engine module and optimized
via the Merck molecular force field. Biopredicta module of the V life MDS 4.3 was uti-
lized for docking analysis.[28–32] ADME of the synthesized derivatives was predicted
[33–35]
from the free online server http://www.swissadme.ch.
Supporting material to this article containing spectral data, H and 13C NMR spec-
1
trums and docking images of synthesized compounds are available for the author-
ized users.
Acknowledgement
Authors are thankful to Professor R. A. Mane for his invaluable discussions and guidance.
Authors are also very much grateful to Birla Institute of Technology and Science-Pilani,
Hyderabad Campus for providing screening data of synthesized compounds.
Funding
One of the authors, PHATAK PRAMOD SHAHAJEE has received UGC Junior Research
Fellowship (JRF). The Sr. No. 2061410333 and Ref. No. 22/06/2014 (i) EU-V.

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P. S. PHATAK ET AL.
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