Synthesis and antibacterial activity of a series of 2-trifluoromethylbenzimidazole-thiazolidinone derivatives

Article abstract of DOI:10.1002/jhet.3777

A series of 2-phenyl-3-(2-(trifluoromethyl)-1H-benzoimidazol-6-yl)thiazolidin-4-one derivatives were synthesized from p-nitro-o-phenylenediamine in a three-step reaction. Their structures were elucidated by NMR and mass spectral data. The synthesized comp

Full text of DOI:10.1002/jhet.3777

Received: 7 November 2018
DOI: 10.1002/jhet.3777
Revised: 13 September 2019
Accepted: 22 September 2019
A R T I C L E
Synthesis and antibacterial activity of a series of 2‐
trifluoromethylbenzimidazole‐thiazolidinone derivatives
Adele Cheddie | Suhas A. Shintre | Aishwarya Bantho | Chunderika Mocktar |
Neil A. Koorbanally
School of Chemistry and Physics and
Abstract
School of Health Sciences, University of
KwaZulu‐Natal, Durban, South Africa
A series of 2‐phenyl‐3‐(2‐(trifluoromethyl)‐1H‐benzoimidazol‐6‐yl)thiazolidin‐
‐one derivatives were synthesized from p‐nitro‐o‐phenylenediamine in a
4
Correspondence
three‐step reaction. Their structures were elucidated by NMR and mass spec-
tral data. The synthesized compounds showed excellent antibacterial activity
ranging from 3‐fold, to greater than 100‐fold higher than the standard antibi-
otics, ciprofloxacin and levofloxacin. Compounds 3d (2′‐Br), 3j (4′‐Br), and 3l
Neil A. Koorbanally, School of Chemistry
and Physics; School of Health Sciences,
University of KwaZulu‐Natal, Private Bag
X54001, Durban 4000, South Africa.
Email: koorbanally@ukzn.ac.za
(
4′‐NO ) displayed a broad spectrum of activity against the strains tested
2
Funding information
(
0.14–38.33 μM). The brominated derivatives 3d and 3j showed excellent activ-
National Research Foundation, South
Africa; Incentive Funding for Rated
Researchers, Grant/Award Number:
ity against the Gram‐positive bacterial strains (MBC between 0.12 and
5.46 μM), while the nitro derivative 3l showed excellent activity against all
3
1
14817; Competitive Grant for Rated
Researchers, Grant/Award Number:
18534; University of KwaZulu‐Natal
four Gram‐negative strains tested (MBC between 0.15 and 9.58 μM).
1
1
| INTRODUCTION
such as albendazole and tiabendazole (anthelmintic),
pantoprazol and omeprazole (proton pump inhibitors),
Bacterial infections are a significant health threat and
responsible for the majority of hospital‐acquired infec-
tions, leading to extensive mortality and high burden on
healthcare systems. New virulent forms of bacteria have
emerged, with different levels of resistance to current
therapeutic treatments, such as methicillin‐resistant
bendamustine
fuberidazole
(antihypertensive).
(anticancer),
carbendazim
and telmisartan
and
(antimicrobials),
[
6]
Thiazolidinones are derivatives of thiazoles contain-
ing nitrogen, sulfur, and a carbonyl group. They are
considered as privileged scaffolds in medicinal chemis-
try because of their various biological activities such as
[1]
Staphylococcus aureus (MRSA),
multidrug‐resistant
extended‐spectrum β‐
lactamase (ESBL)‐producing Enterobacteriaceae, and
[2]
[7,8]
[9]
[10,11]
tuberculosis
(MDR‐TB),
antimicrobial,
antiinflammatory,
antihypertensive,
anticancer,
and antidiabetic
[
12]
[13]
anti‐HIV,
[3]
[14]
Escherichia coli. There is an urgent need for new and
more effective drug development against both drug‐
resistant and drug‐sensitive pathogens.
activities.
Hybrid molecules have recently been developed as
new antimycobacterial agents
[
15]
and are obtained by
Recently, much attention has focused on the develop-
ment of heterocyclic scaffolds for the discovery of new
the amalgamation of two or more different
pharmacophores. Hybrid molecules have also demon-
strated good bioactivity as antimicrobial agents.
[4,5]
[16–18]
drugs.
Benzimidazoles are five‐membered aromatic
heterocyclic compounds containing two nitrogen atoms.
They are structural isosteres of nucleotides and used
extensively in medicinal chemistry with the core moiety
being present in a number of well‐established drugs
The promising activity exhibited by these molecules
prompted us to explore new conjugates by combining
benzimidazole and thiazolidinones to search for possible
hybrid molecules with antimicrobial activity.
J Heterocyclic Chem. 2019;1–9.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
CHEDDIE ET AL.
Microwave‐assisted synthesis has recently been shown
benzimidazole‐thiazolidinones 3a‐l were synthesized as
racemic mixtures in yields of 75%–83%.
to have a number of advantages over conventional
methods for organic reactions. It has been shown to
reduce the duration of the reactions and improve the
Although forming thiazolidines with primary amines,
aldehydes, and thioglycolic acid is common, conven-
tional methods use harsh solvents such as DMF, diox-
[19]
quality and yields of the products.
It has been popu-
[24,26]
larly used for the synthesis of benzimidazole derivatives
ane, and toluene with long reaction times (16 h),
whereas microwave methods use toluene as the solvent
[20–23]
with different solvents and catalysts.
Although the
[
23]
benzimidazole core has been synthesized using micro-
wave irradiation, there have been relatively few reports
on the thiazolidinone moiety being synthesized under
with shorter reaction times (5–10 min).
We have suc-
cessfully synthesized the thiazolidinones from benzimid-
azole precursors using the eco‐friendly ethanol as
solvent under microwave irradiation. This is a simple,
attractive, and greener method for preparing
benzimidazole‐thiazolidinone hybrid molecules. The
products were purified to >95% purity, monitored by
[23–25]
microwave conditions.
In the present investigation, the benzimidazole‐
thiazolidinone hybrid molecules were synthesized using
microwave synthesis and the antimicrobial activity of
the compounds was determined.
1
the integration of their H NMR spectra.
The structures of the synthesized compounds were
established by NMR spectroscopy and High Resolution
Mass Spectrometry (HRMS). HRMS was particularly
important because the benzimidazole carbon resonances
2
2
| RESULTS AND DISCUSSION
.1 | Chemistry
13
were not observed in the C NMR spectra because of
the degenerated tautomerism of the NH proton, resulting
in the resonances becoming magnetically equivalent
because of the rapid proton exchange between N1 and
An appropriate synthetic strategy was selected for the syn-
thesis of benzimidazole‐thiazolidinone hybrids 3a‐l
[
27]
(Figure 1). We have successfully synthesized 12 new deriv-
N3.
This is also responsible for the broadening of the
atives using microwave‐assisted irradiation in the final
step. The 2‐trifluoromethyl benzimidazoles 2 were pre-
pared from 4‐nitro‐1,2‐phenyldiamine and trifluoroacetic
acid. The nitro group was then reduced to the amine by cat-
alytic (Pd/C) hydrogenation and thiazolidinones were
formed using a one‐pot technique by employing the
Knoevenagel condensation of the amino group (of the
H‐4, H‐6, and H‐7 resonances, which should have
appeared as a doublet (J ~ 2 Hz), double doublet (J ~ 8
and 2 Hz), and doublet (J ~ 8 Hz), respectively, but
appeared as broadened singlets for H‐4 and H‐7. H‐6
appeared as a doublet (not a double doublet) in many
instances and only in the case of 3l, the para nitro deriv-
ative, it did appear with its correct splitting pattern, a
double doublet. Compound 3l was, therefore, used to
benzimidazole),
substituted
benzaldehydes,
and
1
thioglycolic acid under microwave conditions. The final
fully interpret the H NMR spectra.
1
The H NMR spectrum of 3l contained four resonances
in the aromatic region of the spectrum between δ 7.30
and 8.10. The aromatic proton resonances of the para‐
substituted phenyl ring were present at δ 7.68 (H‐2b/6b)
and the H‐3b/5b doublet appeared at δ 8.07. For the benz-
imidazole ring, the H‐4 resonance coincided with H‐2b/
6b at δ 7.68. The H‐7 resonance appeared as a doublet
at δ 7.61 and H‐6 as a doublet of doublets at δ 7.33. These
resonances had coupling constants in keeping with their
position on the benzimidazole ring, with JH6,
=
8.8 Hz for ortho coupling and JH6,H4 = 1.9 Hz for
H7
meta coupling. These chemical shifts for the aromatic
protons of the benzimidazole ring are consistent with
[
27]
those reported in Nieto et al..
In the thiazolidine ring, the H‐2a proton was present at
δ 6.64 and the diastereotopic protons H‐5ai and H‐5aii as
a double doublet and doublet, respectively were present at
δ 4.07 and δ 3.92 with JH5ai,H5aii = 15.8 Hz and JH5ai,
=
1.5 Hz. These coupling constants were clearly seen,
even though the resonances coincided with the solvent
FIGURE
1
Synthesis
of
substituted
2‐phenyl‐3‐(2‐
H2a
(
trifluoromethyl)‐1H‐benzimidazol‐6‐yl)thiazolidin‐4‐ones

CHEDDIE ET AL.
3
peak. However, inother compounds, H‐5ai andH‐5aii were
separated from the solvent peak and were clearly observed.
The large coupling constant of 15.8 Hz for JH5ai,H5aii is typi-
cal of geminal protons adjacent to the pi system of the car-
bonyl group. This is in keeping with J values cited in Singh
In the N‐3 methylated 2‐nitro derivative, the benzimid-
azole resonances appeared as a doublet for H‐7 at δ 7.74
(J = 8.8 Hz), a double doublet for H‐6 at δ 7.15 (J = 8.8,
1.8 Hz), and a singlet for H‐4 at δ 7.65. The N‐methyl reso-
nance was present as a singlet at δ 3.87. The thiazolidinone
resonances of H‐2a and the two geminal protons of H‐5a
appeared at δ 6.90 as a singlet for H‐2a and δ 3.92 and
3.81, two doublets with a coupling constant of 16.0 Hz.
The 2‐nitrophenyl proton resonances were present at δ
8.03 (d, J = 8.1 Hz, H‐3b), 7.44 (t, J = 7.5 Hz, H‐4b), and δ
7.59–7.62 (2H, m, H‐5b, H‐6b). The carbon resonances of
the benzimidazole ring was now present at δ 106.7 (C‐4),
120.1 (C‐6), and 122.3 (C‐7) for the protonated resonances
and δ 134.9 (C‐5), 136.1 (C‐8), and 139.5 (C‐9) for the sin-
glet resonances. The C‐2 and CF3 carbon resonances
appeared as quartets at δ 142.2 (J = 38.3 Hz, C‐2) and δ
118.8 (J = 269.8 Hz). The thiazolidinone carbon resonances
were present at δ 171.8 (C‐4a, C=O), 60.9 (C‐2a, methine),
and 32.7 (C‐5a, methylene). The 2‐nitrophenyl carbon res-
onances appeared at δ 147.1 and 136.2 for the singlet car-
bons, C‐1b and C‐2b, and 134.3, 129.5, 126.9, and 125.9
for the protonated aromatic resonances C‐6b, C‐4b, C‐5b,
and C‐3b, respectively. The N‐methyl carbon resonance
occurred at δ 31.0. The N‐1 methylated 2‐nitro derivative
was elucidated in a similar manner. The two isomers were
differentiated by NOESY data. The N‐3 methylated com-
pound showed a NOESY correlation to the H‐4 doublet at
δ 7.64, while the N‐1 methylated compound showed a
NOESY correlation to the H‐7 doublet at δ 7.41.
[28]
et al., which quotes values of 17–18 Hz for geminal cou-
pling in thiazolidinones.
As mentioned previously, because of the degenerate
tautomerism of the NH proton, the benzimidazole carbon
13
resonances C‐4 to C‐9 were not observed in the C NMR
spectra, however, C‐2 and the CF carbon resonances
3
were present in almost all compounds. These occurred
as two quartets, at δ 141.9 (J = 40.0 Hz) and δ 119.1
(
J = 271.6 Hz) in 3l. The three thiazolidinone carbon res-
onances were present at δ 171.5 (C‐4a), 63.5 (C‐2a), and
3.2 (C‐5a). The nitrophenyl carbon resonances were
present at δ 147.9 (C‐1b), 129.0 (C‐2b/6b), 124.3 (C‐3b/
3
5
b), and 133.9 (C‐4b).
To investigate the absence of the carbon resonances in
the benzimidazole ring, we methylated one of the com-
pounds, the 2‐nitro derivative 3f, using methyl iodide as
a methylating agent. Since there are two nitrogen atoms
present in the benzimidazole scaffold, a mixture of the
two methylated compounds was observed upon methyla-
tion; the two methylated compounds were purified and
1
13
their H and C NMR data were obtained. As expected,
the carbon resonances of the benzimidazole ring were
now observed in both isomers, the N‐1 and N‐3 methyl-
ated compounds.
TABLE 1 Minimum bactericidal concentration (MBC in μM) of compounds 3a‐l
Gram –ve
Gram +ve
No.
R
S.t.
K.p.
E.c.
0.66
P.a.
S.a.
MRSA
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
H
–
–
–
–
–
–
–
0.66
0.16
0.16
35.46
9.07
4.79
0.15
0.16
0.30
0.27
0.12
38.33
94.3
21.6
–
2‐F
0.32
5.28
0.14
0.14
0.15
0.15
0.32
0.61
0.14
0.25
0.15
11.8
21.6
–
0.16
–
2‐Cl
2‐Br
2‐CF
0.65
0.54
–
0.16
0.27
0.28
–
–
17.73
–
3
2‐NO
2
0.15
4.79
79.71
–
–
g
2‐OCH
4‐F
3
–
–
–
h
–
0.16
0.61
0.55
–
–
i
j
4‐Cl
–
0.61
0.27
–
–
4‐Br
17.73
–
35.46
–
k
l
4‐CF
3
4‐NO
2
0.15
2.95
21.6
0.15
2.95
0.34
9.58
>250
188.6
86.5
Cip
Lev
188.6
345.0
Note. S.t. = S. typhimurium, K.p. = K. pneumonia, E.c. = E. coli, P.a. = P. aeruginosa, S.a. = S. aureus, Cip = Ciprofloxacin, Lev = Levofloxacin.

4
CHEDDIE ET AL.
2
.2 | Antimicrobial
2‐F (3b) and 4‐F (3h) compounds were very similar, as were
the 2‐Br (3d) and 4‐Br (3j) compounds, however, the 4‐Br
compound 3j was additionally active against S.
typhimurium, whereas the 2‐Br (3d) derivative was not.
Similar benzimidazoles with a phenyl group at C‐2,
instead of a trifluoromethyl group, also showed good
antimicrobial activity, comparable with that of ciprofloxa-
The synthesized compounds were evaluated for their
in vitro antibacterial activity against four Gram‐negative
bacteria, Pseudomonas aeruginosa, Klebsiella pneumonia,
Escherichia coli, and Salmonella typhimurium and two
Gram‐positive bacteria, Staphylococcus aureus and Staph-
ylococcus aureus Rosenbach (methicillin‐resistant S.
aureus (MRSA)). These are causative agents for urinary
tract, gastrointestinal, and nosocomial infections as well
as pneumonia and bronchitis.
[
29]
cin and 2,3‐disubstituted thiazolidinone‐benzimidazole
hybrids with a methylthio group instead of the
trifluromethyl group at C‐2 and a thiazolidinone group
attached to a thiosemicarbazone at N‐1, showed a broad‐
[16]
Overall, the compounds demonstrated excellent activity
spectrum antibacterial activity, similar to ampicillin.
(
Table 1), when compared with the known antibiotics, cip-
2‐Mercaptobenzimidazole‐4‐phenylthiazolidinone deriva-
tives, with a thiol group at C‐2 instead of a trifluoromethyl
group showed up to four‐fold better activity against strain‐
rofloxacin and levofloxacin (Figure 2). The Gram‐negative
K. pneumonia and Gram‐positive S. aureus were most sus-
ceptible to all the synthesized derivatives with MBC values
of between 0.14–5.28 μM and 0.12–38.33 μM, respectively.
Several compounds were approximately 80‐fold more
active than ciprofloxacin and 140‐fold more active than
levofloxacin against K. pneumonia while being approxi-
mately 600‐fold more active than ciprofloxacin and 140‐
fold more active than levofloxacin against S. aureus. Com-
pounds 3d, 3j, and 3l, containing bromine and nitro
groups, displayed broad‐range activity against all test
strains. The 2‐Br (3d) and 4‐Br (3j) derivatives showed
excellent activity, higher than that of ciprofloxacin, against
both the Gram‐positive strains (S. aureus = 94.3 μM and
[
26]
specific bacteria than that of ciprofloxacin.
Our results
have shown better activity to those previously reported,
with a broader spectrum, and have further shown the
potential of the trifluoromethyl group to be a useful moiety
to tag onto C‐2 of benzimidazoles to produce small mole-
cules with good antibacterial activity.
3
| CONCLUSION
A series of new benzimidazole‐thiazolidinone hybrids
were synthesized by a simple and attractive method using
4‐nitro‐1,2‐phenyldiamine, trifluoroacetic acid, thiog-
MRSA = 188.6 μM). The 4‐NO (3l) derivative showed
2
lycolic acid, and a series of benzaldehydes. Microwave syn-
thesis using ethanol as the solvent was successfully
employed to synthesize the thiazolidinones in the final step
with good yields in a more eco‐friendly method. This is a
rapid method of adding a thiazolidinone moiety to a core
structure with a free amino group, providing an avenue
to increase its bioactivity. The synthesized compounds
showed excellent antibacterial activity against a series of
Gram‐positive and Gram‐negative bacterial strains.
Among them, the bromo and nitro derivatives 3d, 3j, and
excellent activity against the Gram‐negative strains with
MBC values of 0.15 μM against S. typhimurium, K. pneu-
monia, and E. coli and 9.58 μM against P. aeruginosa.
The activity of the compounds was enhanced by the
substitution on the phenyl ring of the thiazolidine. Com-
pound 3a, with an unsubstituted phenyl ring, was only
active against E. coli and S. aureus and lower than other
compounds with substituents on the phenyl ring. It did
not seem to make too much of a difference whether the
substituents were at the 2‐ or the 4‐ position, however,
slightly better activity was seen in substituents at the 4‐
3
l showed a broad spectrum of activity, being active against
all of the strains tested with MBC values between 0.14 and
8.33 μM. These compounds are good hits that can be
position. For example, the 2‐NO derivative 3f, had lower
2
3
activity than that of the 4‐NO derivative 3l, against E.
2
developed into lead compounds for new antibiotics.
coli and was not active against P. aeruginosa. However,
it was more active than the 4‐NO derivative 3l, against
2
S. aureus. The activities of the 2‐Cl (3c) and 4‐Cl (3i), and
4 | EXPERIMENTAL
4.1 | General
All reagents and chemicals were purchased from Sigma
Aldrich (Germany) and used without purification. Reac-
tions were monitored using thin layer chromatography
(
silica gel 60‐F254 aluminum‐coated plates) and visualized
FIGURE 2 Structures of the standard antibiotics levofloxacin
under UV light. Column chromatography was carried out
and ciprofloxacin
using silica gel (60–120 mesh) as the stationary phase and

CHEDDIE ET AL.
5
varying ratios of organic solvents as the mobile phase. Melt-
ing points were obtained using a Stuart Smart Scientific
melting point instrument and were uncorrected. Micro-
wave reactions were performed using a CEM Discover,
Explorer‐12 Hybrid microwave. H, C, and 2D NMR anal-
ysis was acquired on a Bruker Avance 400 MHz spectrome-
ter using tetramethylsilane (TMS) as the internal standard.
Note: C‐4, C‐6, and C‐7 for all compounds were not
present in the C NMR spectra because of the degenerate
tautomerism of the NH proton, resulting in the reso-
nances becoming magnetically equivalent because of
13
1
13
[27]
rapid proton exchange between N1 and N3.
This is
1
also responsible for the broadening of the H resonances
for H‐4, H‐6, and H‐7 resulting in the theoretical splitting
patterns being absent. HRMS confirmed the structures of
all compounds.
Chemical shifts were reported in ppm in DMSO‐d (δ 2.50
6
1
13
1
for H and 39.51 for C NMR) or CD OD (δ 3.35 for H
3
13
and49.15for CNMR). Couplingconstants(J)arereported
in hertz (Hz). High resolution mass spectrometry (HRMS)
wasrecordedwithaBrukermicroTOF‐QIIESIinstrument.
All column chromatography was performed using silica gel
4
.2.2 | 2‐Phenyl‐3‐(2‐(trifluoromethyl)‐1H‐
benzimidazol‐5‐yl)thiazolidin‐4‐one (3a)
(60–120 mesh).
Cream solid; 82% yield; mp 117°C–118°C; IR (KBr)
−
1
1
υmax:1631 cm (C=O); H NMR (DMSO‐d , 400 MHz)
6
δ 13.99 (1H, s, H‐NH), 7.70 (1H, bs, H‐4), 7.60 (1H, bs,
H‐7), 7.41 (2H, d, J = 7.5 Hz, H‐2b/6b), 7.32 (1H, bs, H‐
4
4
.2 | Synthesis
6), 7.25 (2H, t, J = 7.5 Hz, H‐3b/5b), 7.20 (1H, t,
.2.1 | General procedure for the synthesis
J = 7.5 Hz, H‐4b), 6.55 (1H, s, H‐2a), 4.05 (1H, d,
of 2‐phenyl‐3‐(2‐(trifluoromethyl)‐1H‐
benzo[d]imidazol‐6‐yl)thiazolidin‐4‐ones
1
3
J = 15.6 Hz, 5ai), 3.92 (1H, d, J = 15.6 Hz, 5aii);
C
NMR (DMSO‐d , 100 MHz)δ 170.7 (C‐4a), 140.9 (q,
6
J = 39.1 Hz, C‐2), 139.9 (C‐1b), 128.6 (C‐3b/5b), 128.5
4
‐Nitro‐1,2‐phenyldiamine (1.00 g, 0.65 mol) was stirred
at room temperature in trifluoroacetic acid (10 mL) for
h. The reaction was monitored to completion by TLC,
after which, the trifluoroacetic acid was evaporated under
pressure. The crude 6‐nitro‐2‐
(
C‐4b), 127.2 (C‐2b/6b), 118.9 (q, J = 270.7, CF ), 64.0
3
(
C‐2a), 32.7 (C‐5a); HR‐ESI(−)‐MS. Anal. Calcd. for
2
C H N OF S [M‐H]: 362.0575. Found 362.0583.
17
11
3
3
trifluoromethylbenzimidazole was dissolved in ethyl ace-
tate (15 mL), basified with sodium hydrogen carbonate
4
.2.3 | 2‐(2‐Fluorophenyl)‐3‐(2‐
(
trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
(pH 8.5), and partitioned with water (15 mL). The organic
thiazolidin‐4‐one (3b)
layer was evaporated under reduced pressure to yield 6‐
nitro‐2‐trifluoromethyl‐benzimidazole 1 as a pale white
solid (86% yield). Pd/C (10%) was then added to 1 (0.5 g,
Cream solid; 81% yield; mp 200°C–202°C; IR (KBr)
υmax:1631 cm (C=O); H NMR (DMSO‐d , 400 MHz) δ
−1
1
6
2
.2 mmol) dissolved in methanol and the mixture was
7
(
.69 (2H, bs, H‐4,7), 7.49 (1H, t, J = 8.0 Hz, H‐6b), 7.35
1H, d, J = 8.0 Hz, H‐6), 7.26 (1H, m, H‐4b), 7.10 (2H, m,
H‐3b/5b), 6.74 (1H, s, H‐2a), 4.03 (1H, d, J = 15.6 Hz, H‐
stirred at room temperature for 4 h under hydrogen
atmosphere. On completion, the Pd was filtered off under
vacuum using celite 545 and the filtrate reduced under
pressure and purified by column chromatography using
ethyl acetate and hexane (30:70) to yield 2‐
trifluoromethylbenzimidazol‐6‐amine 2 as a brown solid
13
5ai), 3.93 (1H, d, J = 15.6 Hz, H‐5aii); C NMR (DMSO‐
d6, 100 MHz)δ 170.6 (C‐4a), 159.9 (d, J = 245.8 Hz, C‐2b),
1
1
41.2 (q, J = 39.3 Hz, C‐2), 130.8 (d, J = 8.5 Hz, C‐4b),
29.3 (d, J = 2.7 Hz, C‐6b), 126.9 (d, J = 10.8, 1b), 124.9
(70% yield).
(
(
d, J = 3.2 Hz, C‐5b), 118.9 (q, J = 271.7 Hz, CF ), 115.9
d, J = 20.8 Hz, C‐3b), 58.9 (d, J = 2.9 Hz, C‐2a), 32.8 (C‐
3
Compound 2 (0.2 g, 1.0 mmol) and substituted benzal-
dehydes (1.5 mmol) were dissolved in ethanol (3 mL) and
thioglycolic acid (0.2 mL, 3.0 mmol) and glacial acetic
acid (3–5 drops) was added dropwise to the mixture.
The mixture then underwent microwave irradiation for
5a); HR‐ESI(−)‐MS. Anal. Calcd. for C H N OF S [M‐
17
10
3
4
H]: 380.0481. Found 380.0484.
3
0 min at 110°C. The reaction was then basified using
4.2.4 | 2‐(2‐Chlorophenyl)‐3‐(2‐
sodium bicarbonate until just alkaline and extracted with
ethyl acetate. The organic layer was dried over anhydrous
sodium sulfate and evaporated under reduced pressure.
The residue was purified by column chromatography on
silica gel (hexane:ethyl acetate, 7:3) to yield cream solids
(trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
thiazolidin‐4‐one (3c)
Cream solid; 76% yield; mp 162°C–163°C; IR (KBr)
−
1
1
υmax:1630 cm (C=O); H NMR (DMSO‐d , 400 MHz) δ
6
3
a‐l in yields between 75% and 83%.
14.02 (NH), 7.82 (1H, bs, H‐4), 7.72 (1H, bs, H‐7), 7.59

6
CHEDDIE ET AL.
(
6
1H, bs, H‐3b), 7.43 (1H, bs, H‐6), 7.36 (1H, d, J = 7.8 Hz, H‐
b), 7.29–7.21 (2H, m, H‐4b, H‐5b), 6.87 (1H, s, H‐2a), 4.03
1H, d, J = 15.5 Hz, H‐5ai), 3.94 (1H, d, J = 15.5 Hz, H‐5aii);
J = 8.0, 1.2 Hz, H‐6b), 7.83 (1H, bs, H‐4), 7.71 (1H, dt,
J = 8.0, 1.2 Hz, H‐5b), 7.64 (1H, d, J = 8.8 Hz, H‐7),
7.50 (1H, dd, J = 8.8, 1.5 Hz, H‐6), 7.47 (1H, dt, J = 8.0,
1.2 Hz, H‐4b), 6.85 (1H, s, H‐2a), 4.05 (1H, dd, J = 15.8,
(
1
3
C NMR (DMSO‐d , 100 MHz)δ 170.8 (C‐4a), 141.5 (q,
6
1
3
J = 38.9 Hz, C‐2), 136.7 (C‐2b), 131.6 (C‐1b), 130.0* (2C,
C‐3b, 5b), 127.7* (2C, C‐4b, C‐6b), 118.8 (q, J = 270.7 Hz,
1.5 Hz, H‐5ai), 3.88 (1H, d, J = 15.8 Hz, H‐5aii);
C
NMR (DMSO‐d , 100 MHz)δ 171.0 (C‐4a), 147.2 (C‐2b),
6
CF ), 61.9 (C‐2a), 32.62 (C‐5a); * assignments may be
141.1 (q, J = 39.3 Hz, C‐2), 135.2 (C‐1b), 134.4 (C‐5b),
129.5 (C‐4b), 128.1 (C‐6b), 124.8 (C‐3b), 59.6 (C‐2a), 31.9
(C‐5a); HR‐ESI(−)‐MS. Anal. Calcd. for C H N O F S
3
interchanged; HR‐ESI(−)‐MS. Anal. Calcd. for
C H N OF SCl [M‐H]: 396.0185. Found 396.0174.
17
10
3
3
17 10 4 3 3
[M‐H]: 407.0426. Found 407.0420.
4
.2.5 | 2‐(2‐Bromophenyl)‐3‐(2‐
(
trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
4.2.8 | 2‐(2‐Methoxyphenyl)‐3‐(2‐
thiazolidin‐4‐one (3d)
(trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
thiazolidin‐4‐one (3g)
Cream solid; 81% yield; mp 191°C–192°C; IR (KBr) υmax:
−
1
1
1
679 cm (C=O); H NMR (DMSO‐d , 400 MHz) δ 7.75
Cream solid; 75% yield; mp 170°C–172°C; IR (KBr) υmax:
−
6
1
1
(
(
1H, bs, H‐4), 7.65 (1H, bs, H‐6b), 7.59 (1H, bs, H‐7), 7.53
1H, d, J = 7.8 Hz, H‐3b), 7.42 (1H, d, J = 8.4 Hz, H‐6),
1676 cm (C=O); H NMR (CD OD, 400 MHz) δ 7.97
3
(1H, d, J = 7.4 Hz, H‐6), 7.63 (1H, d, J = 8.6 Hz, H‐3b),
7.20 (1H, dt, J = 8.0, 1.5 Hz, H‐5b), 7.02–6.96 (3H, m, H‐
4b, H‐4, H‐7), 6.78 (1H, d, J = 8.0 Hz, H‐6b), 6.24 (1H, bs,
H‐2a), 3.40 (1H, d, J = 16.0 Hz, H‐5ai), 3.38 (3H, s,
7
1
1
.32 (1H, t, J = 7.8 Hz, H‐5b), 7.15 (1H, dt, J = 7.8,
.6 Hz, H‐4b), 6.79 (1H, s, H‐2a), 4.02 (1H, dd, J = 15.6,
.3 Hz, H‐5ai), 3.93 (1H, d, J = 15.6 Hz, H‐5aii); C NMR
13
13
(DMSO‐d , 100 MHz)δ 170.9 (C‐4a), 141.3 (q, J = 39.4 Hz,
OCH ), 2.81 (1H, d, J = 16.0 Hz, H‐5aii); C NMR
6
3
C‐2), 140.9 (C‐2b), 130.3 (C‐3b), 128.3 (2C, C‐5b, C‐6b),
(CD OD‐d , 100 MHz) δ 173.8 (C‐4a), 158.4 (C‐2b), 130.4
3
4
1
21.7 (C‐1b), 118.8 (q, J = 270.1 Hz, CF ), 63.5 (C‐2a),
(C‐3b), 129.6 (C‐5b), 121.0 (C‐4b), 111.6 (C‐6b), 55.6
3
3
1.3 (C‐5a); HR‐ESI(−)‐MS. Anal. Calcd. for
(OCH ), 31.9 (C‐5a); HR‐ESI(−)‐MS. Anal. Calcd. for
3
C H N OF SBr [M‐H]: 439.9680. Found 439.9683.
C H N O F S [M‐H]: 392.0681. Found 392.0674.
18 13 3 2 3
17
10
3
3
4
.2.6 | 3‐(2‐(trifluoromethyl)‐1H‐
4.2.9 | 2‐(4‐Fluorophenyl)‐3‐(2‐
(trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
thiazolidin‐4‐one (3h)
benzimidazol‐5‐yl)‐2‐(2‐(trifluoromethyl)
phenyl)thiazolidin‐4‐one (3e)
Cream solid; 79% yield; mp 194°C–196°C; IR (KBr) υmax:
Cream solid; 83% yield; mp 212°C–213°C; IR (KBr) υmax:
−
1
1
−1
1
1
667 cm (C=O); H NMR (DMSO‐d , 400 MHz) δ 7.96
1632 cm (C=O); H NMR (DMSO‐d , 400 MHz) δ 7.62
6
6
(
1H, d, J = 7.8 Hz, H‐6b), 7.71 (1H, bs, H‐4), 7.65 (2H,
(2H, bs, H‐4, H‐7), 7.47 (2H, dd, J = 8.8, 5.4 Hz, H‐2b/
6b), 7.29 (1H, d, J = 8.6 Hz, H‐6), 7.07 (2H, t,
J = 8.8 Hz, H‐3b/5b), 6.55 (1H, s, H‐2a), 4.04 (1H, d,
m, H‐4b, H‐6), 7.57 (1H, d, J = 7.8 Hz, H‐3b), 7.40 (2H,
m, H‐5b, H‐7), 6.74 (1H, s, H‐2a), 4.07 (1H, d,
J = 15.5 Hz, H‐5ai), 3.95 (1H, d, J = 15.5 Hz, H‐5aii);
J = 15.6 Hz, H‐5ai), 3.92 (1H, d, J = 15.6 Hz, H‐5aii);
1
3
13
C NMR (DMSO‐d , 100 MHz)δ 171.0 (C‐4a), 141.6 (q,
C NMR (DMSO‐d , 100 MHz)δ 170.7 (C‐4a), 162.1 (d,
6
6
J = 39.5 Hz, C‐2), 138.4 (C‐1b), 133.5 (C‐4b), 129.2 (C‐
b), 129.0 (C‐6b), 125.6 (q, J = 45.6 Hz, C‐2b), 125.4 (q,
J = 5.7 Hz, C‐3b), 118.8 (q, J = 270.3 Hz, CF ), 59.8 (C‐
J = 243.7 Hz, C‐4b), 141.1 (q, J = 39.9, C‐2), 136.1 (d,
J = 2.8 Hz, C‐1b), 129.5 (d, J = 9.2 Hz, C‐2b/6b), 118.8
5
(q, J = 271.2 Hz, CF ), 115.5 (d, J = 21.1 Hz, C‐3b/5b),
3
3
2
a), 32.6 (C‐5a); HR‐ESI(−)‐MS. Anal. Calcd. for
63.4 (C‐2a), 32.8 (C‐5a); HR‐ESI(−)‐MS. Anal. Calcd. for
C H N OF S [M‐H]: 380.0481. Found 380.0484.
C H N OF S [M‐H]: 430.0449. Found 430.0445.
18
10
3
6
17 10
3
4
4
.2.7 | 2‐(2‐Nitrophenyl)‐3‐(2‐
4.2.10 | 2‐(4‐Chlorophenyl)‐3‐(2‐
(trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
thiazolidin‐4‐one (3i)
(trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
thiazolidin‐4‐one (3f)
Cream solid; 76% yield; mp 149°C–150°C; IR (KBr)
Cream solid; 78% yield; mp 188°C–190°C; IR (KBr) υmax:
−
1
1
−1
1
υmax:1667 cm (C=O); H NMR (DMSO‐d , 400 MHz)
1656 cm (C=O); H NMR (DMSO‐d , 400 MHz) δ
6
6
δ 7.94 (1H, dd, J = 8.0, 1.2 Hz, H‐3b), 7.88 (1H, dd,
14.00 (1H, bs, NH), 7.71 (1H, bs, H‐4), 7.58 (1H, bs, H‐

CHEDDIE ET AL.
7
7
7
), 7.46 (2H, d, J = 8.4 Hz, H‐2b/6b), 7.31 (1H, bs, H‐6*),
.30 (2H, d, J = 8.4 Hz, 3b/5b*), 6.58 (1H, s, H‐2a), 4.06
(2H, d, J = 8.8 Hz, H‐3b/5b), 7.68 (3H, d, J = 8.8, H‐2b/
6b, H‐4*), 7.61 (1H, d, J = 8.8 Hz, H‐7), 7.33 (1H, dd,
J = 8.8, 1.9 Hz, H‐6), 6.64 (1H, s, H‐2a), 4.07 (1H, dd,
J = 15.8, 1.5 Hz, H‐5ai), 3.92 (1H, d, J = 15.8 Hz, H‐
(1H, d, J = 15.7 Hz, H‐5ai), 3.93 (1H, d, J = 15.7 Hz, H‐
13
5
1
1
aii); C NMR (DMSO‐d , 100 MHz) δ 170.5 (C‐4a),
6
13
41.2 (q, J = 39.8 Hz, C‐2), 139.0 (C‐1b), 132.9 (C‐4b),
29.2 (C‐2b/6b), 128.6 (C‐3b/5b), 118.8 (q, J = 270.2 Hz,
5aii); C NMR (DMSO‐d , 100 MHz) δ 171.5 (C‐4a),
6
147.9 (C‐1b), 141.9 (q, J = 40.0 Hz, C‐2), 133.9 (C‐4b),
129.0 (C‐2b/6b), 124.3 (C‐3b/5b), 119.1 (q, J = 271.6 Hz,
CF ), 63.1 (C‐2a), 32.7 (C‐5a); *overlapping resonances;
3
HR‐ESI(−)‐MS. Anal. Calcd. for C H N OF SCl [M‐
CF ), 63.5 (C‐2a), 33.2 (C‐5a); *H‐4 overlaps with H‐2b/
17
10
3
3
3
H]: 396.0185. Found 396.0179.
6b; HR‐ESI(−)‐MS. Anal. Calcd. for C H N O F S [M‐
17
10 4 3 3
H]: 407.0426. Found 407.0431.
4
.2.11 | 2‐(4‐Bromophenyl)‐3‐(2‐
(trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
4
3
.2.14 | Methylation of 2‐(2‐nitrophenyl)‐
‐(2‐(trifluoromethyl)‐1H‐benzimidazol‐5‐
thiazolidin‐4‐one (3j)
Cream solid; 83% yield; mp 200°C–201°C; IR (KBr)
yl)thiazolidin‐4‐one (3f)
−
1
1
υmax:1634 cm (C=O); H NMR (DMSO‐d , 400 MHz)
6
2‐(2‐Nitrophenyl)‐3‐(2‐(trifluoromethyl)‐1H‐benzimida-
δ 7.64 (2H, bs, H‐4, H‐7), 7.45 (2H, d, J = 8.5 Hz, H‐
zol‐5‐yl)thiazolidin‐4‐one 3f (142 mg, 0.336 mmol) and
potassium carbonate (193 mg, 1.40 mmol) were added to
dimethylformamide (5 mL) and stirred at room tempera-
ture for 45 min. Thereafter, iodomethane (0.2 mL) in
dimethylformamide (0.5 mL) was added dropwise to the
reaction mixture, which was stirred at room temperature
for 15 h. The reaction mixture was poured into an ice
slurry, where a white precipitate formed. The precipitate
was filtered, washed with water, and air dried to afford a
mixture of the N‐1 and N‐3 methylated compounds in
3
b/5b), 7.40 (2H, d, J = 8.5 Hz, H‐2b/6b), 7.31 (1H, d,
J = 8.8 Hz, H‐6), 6.56 (1H, s, H‐2a), 4.06 (1H, dd,
J = 15.7, 1.4 Hz, H‐5ai), 3.93 (1H, d, J = 15.7 Hz, H‐
13
5
1
5
aii); C NMR (DMSO‐d , 100 MHz) δ 170.6 (C‐4a),
6
41.2 (q, J = 39.5 Hz, C‐2), 139.5 (C‐1b), 131.5 (C‐3b/
b), 129.5 (C‐2b/6b), 121.6 (C‐4b), 118.8 (q,
J = 271.2 Hz, C‐CF ), 63.2 (C‐2a), 37.7 (C‐5a); HR‐
ESI(−)‐MS. Anal. Calcd. for C H N OF SBr [M‐H]:
3
17
10
3
3
4
39.9680. Found 439.9682.
72% yield. They were separated by column chromatogra-
4
.2.12 | 3‐(2‐(Trifluoromethyl)‐1H‐
phy on silica gel (hexane:ethyl acetate, 8:2) to yield pure
cream solids of N‐1 methyl derivative (27 mg) and N‐3
methyl derivative (9 mg) in yields of 19% and 6%, respec-
tively. An amount of 55 mg (39%) remained as a mixture
of the two N‐methylated derivatives.
benzimidazol‐5‐yl)‐2‐(4‐(trifluoromethyl)
phenyl)thiazolidin‐4‐one (3k)
Cream solid; 82% yield; mp 183°C–184°C; IR (KBr) υmax:
−
1
1
1
637 cm (C=O); H NMR (DMSO‐d , 400 MHz) δ 7.71
6
(1H, s, H‐4), 7.67 (3H, d, J = 8.3 Hz, H‐2b/6b, H‐7*),
7
.61 (2H, d, J = 8.3 Hz, H‐3b/5b), 7.35 (1H, d,
4
(
.2.15 | N‐1 methylated derivative of 3f: 3‐
1‐methyl‐2‐(trifluoromethyl)‐1H‐benzo[d]
imidazol‐5‐yl)‐2‐(2‐nitrophenyl)thiazolidin‐
‐one
J = 8.7 Hz, H‐6), 6.68 (1H, s, H‐2a), 4.10 (1H, d,
J = 15.6 Hz, H‐5ai), 3.95 (1H, d, J = 15.6 Hz, H‐5aii);
13
C NMR (DMSO‐d , 100 MHz) δ 170.8 (C‐4a), 144.9 (C‐
6
4
1
b), 141.4 (q, J = 40.0 Hz, C‐2), 128.9 (q, J = 31.3 Hz,
C‐4b), 128.0 (C‐2b/6b), 125.7 (d, J = 3.7 Hz, C‐3b/5b),
24.7 (q, J = 270.4 Hz, PhCF ), 118.8 (q, J = 270.4 Hz,
1
Cream solid; H NMR (CDCl , 600 MHz) δ 8.03 (1H, d,
3
1
3
J = 8.1 Hz, H‐3b), 7.74 (1H, d, J = 8.8 Hz, H‐7), 7.65 (d,
J = 1.8 Hz, H‐4), 7.59–7.62 (2H, m, H‐5b, H‐6b), 7.44
1H, t, J = 7.5 Hz, H‐4b), 7.15 (1H, dd, J = 8.8, 1.8 Hz,
H‐6), 6.90 (1H, s, H‐2a), 3.92 (1H, d, J = 16.0 Hz, H‐
ai), 3.87 (3H, s, N‐CH ), 3.81 (1H, d, J = 16.0 Hz, H‐
5aii); C NMR (CDCl , 150 MHz) δ 171.8 (C‐4), 147.1
(C‐1b), 142.2 (q, J = 38.3 Hz, C‐2), 139.5 (C‐9), 136.2 (C‐
2b), 136.1 (C‐8), 134.9 (C‐5), 134.3 (C‐6b), 129.5 (C‐4b),
CF ), 63.2 (C‐2a), 32.7 (C‐5a); *H‐7 is underneath the H‐
3
2
b/6b resonance; HR‐ESI(−)‐MS. Anal. Calcd. for
(
C H N OF S [M‐H]: 430.0449. Found 430.0448.
18
10
3
6
5
3
13
4
.2.13 | 2‐(4‐Nitrophenyl)‐3‐(2‐
3
(trifluoromethyl)‐1H‐benzimidazol‐5‐yl)
thiazolidin‐4‐one (3l)
1
26.9 (C‐5b), 125.9 (C‐3b), 122.3 (C‐7), 120.0 (C‐6), 118.8
Cream solid; 78% yield; mp 153°C–154°C; IR (KBr) υmax:
(q, J = 269.8 Hz, CF ), 106.7 (C‐4), 60.9 (C‐2a), 32.7 (C‐
5a), 31.0 (N‐CH3).
3
−
1
1
1
671 cm (C=O); H NMR (DMSO‐d , 400 MHz) δ 8.07
6

8
CHEDDIE ET AL.
4
.2.16 | N‐3 methylated derivative of 3f: 3‐
control. The lowest concentration that inhibited the
growth of bacteria was taken to be the MBC value. The
assay was performed in triplicate and an average of the
readings was taken.
(
1‐methyl‐2‐(trifluoromethyl)‐1H‐benzo[d]
imidazol‐6‐yl)‐2‐(2‐nitrophenyl)thiazolidin‐
‐one
4
1
Cream solid; H NMR (CDCl , 600 MHz) δ 8.04 (1H, d,
3
ACKNOWLEDGMENTS
J = 8.2 Hz, H‐3b), 7.62–7.63 (2H, m*, H‐5b, H‐6b), 7.60
(
1H, d, J = 1.8 Hz, H‐4), 7.56 (1H, dd, J = 8.9, 1.8 Hz,
The authors thank the University of KwaZulu‐Natal for
funding the project and Ms Caryl Janse van Rensburg
for assistance with HRMS. NK thanks the National
Research Foundation, South Africa for a Competitive
Grant for Rated Researchers (Grant No. 118534) and
Incentive Funding for Rated Researchers (Grant No.
114817).
H‐6), 7.44 (1H, m, H‐4b), 7.41 (1H, d, J = 8.9 Hz, H‐7),
6
1
J = 16.1 Hz, H‐5aii); C NMR (CDCl , 150 MHz) δ
1
.78 (1H, d, J = 1.0 Hz, H‐2a), 3.92 (1H, dd, J = 16.1,
.0 Hz, H‐5ai), 3.88 (3H, s, N‐CH ), 3.80 (1H, d,
3
13
3
71.9 (C‐4a), 146.9 (C‐1b), 141.0 (C‐5), 136.4 (C‐8), 134.4
(C‐5b), 133.6 (C‐9), 129.4 (C‐4b), 126.9 (C‐6b), 125.9 (C‐
3
3
b), 122.8 (C‐6), 117.9 (C‐4), 111.0 (C‐7), 61.2 (C‐2a),
2.4 (C‐5a), 31.0 (N‐CH ). *This resonance appears as a
3
ORCID
doublet but two separate resonances, H‐5b and H‐6, over-
lap in this region. The C‐2 and CF resonances were not
Neil A. Koorbanally
https://orcid.org/0000-0002-6214-
3
detected.
4021
4.3 | Antibacterial assays
REFERENCES AND NOTES
[
[
[
1] A. Hassoun, P. K. Linden, B. Friedman, Crit. Care 2017, 21,
11.
The antibacterial activity of the synthesized compounds
was tested against two Gram‐positive bacteria, Staphylo-
coccus aureus ATCC 25923 and Staphylococcus aureus
Rosenbach ATCC BAA‐1683 (methicillin‐resistant S.
aureus), and four Gram‐negative bacteria, Pseudomonas
aeruginosa ATCC 27853, Klebsiella pneumonia ATCC
2
2] M. A. S. Almahdawi, A. A. Mankh, M. M. Kdban, World J.
Pharm. Pharm. Sci. 2018, 7, 197.
3] G. Mulisa, L. G. Selassie, W. Tilaye, G. Jarso, T. Shiferew, A.
Zewdu, W. Abebe, F. Belachew, T. J. Sewunet, Emerg. Infect.
Dis. 2016, 1, 1000102.
3
1488, Escherichia coli ATCC 25922, and Salmonella
[
[
[
4] A. P. Taylor, R. P. Robinson, Y. M. Fobian, D. C. Blakemore, L.
H. Jones, O. Fadeyi, Org. Biomol. Chem. 2016, 14, 6611.
typhimurium ATCC 14026.
Sterilized Mueller‐Hinton agar plates were lawn inocu-
lated with different bacterial strains. Stock solutions of
each test compound (1 mg mL in DMSO) were pre-
pared and 5 μL of each compound was placed onto the
plates and incubated at 37°C for 24 h, after which, the
compounds that inhibited bacterial growth were further
tested using the minimum bactericidal concentration
5] I. B. Campbell, J. F. Mcdonald, P. A. Procopiou, Drug Discov.
Today 2018, 23, 219.
−
1
6] W. Akhtar, M. F. Khan, G. Verma, M. Shaquiquzzaman, M. A.
Rizvi, S. H. Mehdi, M. Akhter, M. M. Alam, Eur. J. Med. Chem.
2017, 126, 705.
[
[
7] S. J. Gilani, K. Nagarajan, S. P. Dixit, M. Taleuzzaman, S. A.
Khan, Arabian J Chem 2016, 9, S1523.
(MBC) assay.
8] S. Carradori, B. Bizzarri, M. D'Ascenzio, C. De Monte, R.
Grande, D. Rivanera, A. Zicari, E. Mari, M. Sabatino, A.
Patsilinakos, R. Ragno, D. Secci, Eur. J. Med. Chem. 2017,
4
.4 | Minimum bactericidal concentration
140, 274.
assay
[9] K. R. A. Abdellatif, M. A. Abdelgawad, H. A. H. Elshemy, S. S.
R. Alsayed, Bioorg. Chem. 2016, 64, 1.
All compounds showing any activity in the initial disk
diffusion screening assay were tested for their antibacte-
rial activity by the MBC assay. They were dissolved in
DMSO and a two‐fold serial dilution was carried out to
[
[
[
10] P. Sharma, T. S. Reddy, D. Thummuri, K. R. Senwar, N. P.
Kumar, V. G. M. Naidu, S. K. Bhargava, N. Shankaraiah, Eur.
J. Med. Chem. 2016, 124, 608.
11] K. A. Szychowski, M. L. Leja, D. V. Kaminskyy, U. E. Binduga,
−
1
−1
give a range from 1000 μg mL
to 0.03 μg mL .
O. R. Pinyazhko, R. B. Lesyk, J. Gmiński, Chemico‐Biol Interact
Mueller‐Hinton agar plates lawn inoculated with the dif-
ferent bacterial strains were impregnated with 5 μL of
each concentration of compound and incubated for 24 h
at 37°C. Ciprofloxacin and levofloxacin were used as pos-
itive controls, while DMSO was used as a negative
2017, 262, 46.
12] R. Suryawanshi, S. Jadhav, N. Makwana, D. Desai, D.
Chaturbhuj, A. Sonawani, S. Idicula‐Thomas, V. Murugesan,
S. B. Katti, S. Tripathy, R. Paranjape, S. Kulkarni, Bioorg. Chem.
2017, 71, 211.

CHEDDIE ET AL.
9
[
[
13] C. M. Bhalgat, P. V. Darda, K. G. Bothara, S. V. Bhandari, J.
[26] R. Saini, S. R. Malladi, N. Dharavath, J. Heterocyclic Chem.
2018, 55, 1579.
Gandhi, B. Ramesh, Eur. J. Med. Chem. 2014, 76, 580.
14] M. J. Nanjan, M. Mohammed, B. R. P. Kumar, M. J. N.
[27] C. I. Nieto, P. Cabildo, M. A. García, R. M. Claramunt, I.
Chandresekar, Bioorg. Chem. 2018, 77, 548.
Alkorta, J. Elguero, Beilstein J. Org. Chem. 2014, 10, 1620.
[
[
15] Shaveta, S. Mishra, P. Singh, Eur. J. Med. Chem. 2016, 124, 500.
[28] S. P. Singh, S. S. Parmar, K. Raman, V. I. Stenberg, Chem. Rev.
1981, 81, 175.
16] A. M. Mahmoud, O. I. A. Salem, S. G. Abdel Moty, A. M. Abdel
Alim, Indian J. Pharm. Sci. 2013, 75, 545.
[29] A. K. Verma, R. Kumari, A. K. Singh, R. Maurya, M. C.
Sharma, World J. Pharm. Pharm. Sci. 2014, 3, 1417.
[
[
17] N. C. Desai, D. D. Pandya, K. A. Bhatt, G. M. Kotadiya, P.
Desai, Med. Chem. Res. 2014, 23, 3823.
18] L. R. Singh, S. R. Avula, S. Raj, A. Srivastava, G. R. Palnati, C.
SUPPORTING INFORMATION
K. M. Tripathi, M. Pasupuleti, K. V. Sashidhara, J. Antibiot.
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
2
017, 70, 954.
19] R. Dubbey, N. S. H. N. Moorthy, Chem. Pharm. Bull. 2007, 55,
15.
[
[
[
1
20] M. S. Khajavi, K. Rad‐Moghadam, H. Hazarkhani, Synth.
Commun. 1999, 29, 2617.
21] K. M. Hosamani, H. R. Seetharamareddy, R. S. Keri, M. S.
Hanamanthagouda, M. G. Moloney, J. Enzyme Inhib. Med.
Chem. 2009, 24, 1095.
How to cite this article: Cheddie A, Shintre SA,
Bantho A, Mocktar C, Koorbanally NA. Synthesis
and antibacterial activity of a series of 2‐
trifluoromethylbenzimidazole‐thiazolidinone
derivatives. J Heterocyclic Chem. 2019;1–9. https://
doi.org/10.1002/jhet.3777
[
[
22] N. Naeimi, N. Alishahi, J. Ind. Eng. Chem. 2014, 20, 2543.
23] P. Sharma, T. S. Reddy, N. P. Kumar, K. R. Senwar, S. K.
Bhargava, N. Shankaraiah, Eur. J. Med. Chem. 2017, 138, 234.
[
[
24] A. Dandia, R. Singh, S. Khaturia, C. Mérienne, G. Morgant, A.
Loupy, Bioorg. Med. Chem. 2006, 14, 2409.
25] S. Patil, S. M. Hipparagi, D. Meharoon, R. K. Sharma, S.
Dwivedi, Int J Res Pharm Sci 2011, 1, 77.