Indian Journal of Chemistry
Vol. 50B, July 2011, pp. 941-945
Note
Synthesis, characterization and antimicrobial
activity of some 3-(2-(1H-benzo[d]imidazol-
2-yl)phenyl)-2-arylthiazolidin-4-ones
N C Desai*, Nayan Bhatt, Mukesh Kumar & Atul
Makwana
Medicinal Chemistry Division, University Department of
Chemistry, Bhavnagar University, Bhavnagar 364 002, India
E-mail: dnisheeth@rediffmail.com
Received 12 March 2009; accepted (revised) 4 May 2011
As a part of systematic investigation of synthesis, characteriza-
tion and biological activities, several new 3-(2-(1H-benzo-
[d]imidazol-2-yl)phenyl)-2-arylthiazolidin-4-ones 3a-l, have been
synthesized from Schiff bases of benzimidazoles 2a-l, which have
been prepared by condensation of different aldehydes with 2-(1H-
benzo[d]imidazol-2-yl)benzenamine 1. Compound 1 was obtained
by the reaction of 2-aminobenzoic acid and benzene-1,2-diamine.
All the synthesized compounds have been evaluated for their
antibacterial and antifungal activities against Escherichia coli,
Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus
pyogenes, Candida albicans, Asperigillus niger and Asperigillus
clavatus.
Keywords: 2-Aminobenzoic acid, benzene-1,2-diamine,
benzimidazole, thiazolidinone, antibacterial activity,
antifungal activity
During the past decades, compounds bearing
heterocyclic nuclei have received much attention due
to their chemotherapeutic value in the development of
novel antimicrobials1. Heterocyclic moieties like
benzimidazole and 4-thiazolidinone are well known
for their biological activities such as antifungal2,
anthelmentic3, anti-HIV4, antihistaminic5-7, anti-
ulcer8,9, cardiotonic10, antihypertensive11,12 and neuro-
leptic13, antibacterial, antifungal, diuretic, tuber-
culostatic, anticancer, anticonvulsant, anti-inflam-
matory, analgesic14-19, etc. Many reports have
revealed that the substitution at 1, 2 and 5 position of
benzimidazole is very important for enhancing
pharmacological activities20,21. 2-(Substituted phenyl)
benzimidazoles showed various types of biological
activities such as antibacterial22, antiviral23, anti-
tumoral24,25, and anti-inflammatory26. Therefore, in
the present paper, 4-thiazolidinone ring system was
introduced on 2nd position of benzimidazole. The
present scaffold 3 is a part of the synthesis of new
chemical entities which act as antimicrobial agents.
Certain strains of bacteria have developed resistance
against currently available antimicrobial agents27. The
present paper is in continuation of the previous
work28-33 to synthesize novel bio-active heterocyclic
compounds. Herein is reported the synthesis of
bioactive molecules bearing benzimidazole as well as
4-thiazolidinone moieties in one framework of
heterocycles. A series of 3-(2-(1H-benzo[d]imidazol-
2-yl)phenyl)-2-arylthiazolidin-4-ones 3a-l, were
synthesized and screened for their antimicrobial
activity.
The titled compounds 3a-l were synthesized in
three steps. The first step involves condensation of 2-
aminobenzoic acid with benzene-1,2-diamine to give
2-(1H-benzo[d]imidazol-2-yl)benzenamine 1. It was
then condensed with different aldehydes to yield
Schiff bases 2a-l. Finally treatment of compound 2a-l
with thioglycolic acid yielded 3-(2-(1H-benzo-
[d]imidazol-2-yl)phenyl)-2-arylthiazolidin-4-ones 3a-
l (Scheme I).
The characterization of newly synthesized
compounds of the series was carried out by IR, NMR
and mass spectral data. The spectral data are reported
in Table I. All compounds of the series were screened
against E. coli, S. aureus, P. aeruginosa, S. pyogenes,
C. albicans, A. niger and A. clavatus. Results of
biological activities are reported in Table II.
Biological activity
Antibacterial activity. Antibacterial activity was
tested by broth dilution method34,35. The strains used
for the activity were procured from Institute of
Microbial Technology, Chandigarh. The compounds
3a-l were screened for their antibacterial activity
against E. coli, S. aureus, P. aeruginosa and S.
pyogenes at concentrations of 1000, 500, 250, 125, 50
µg/mL respectively (Table II).
Antifungal activity. The same compounds were
tested for antifungal activity against C. albicans, A.
niger and A. clavatus at concentrations of 1000, 500
and 250 µg/mL respectively (Table II). The results
are recorded in the form of primary and secondary
screening. Each synthesized drug was diluted
obtaining 1000 µ g/mL concentration, as a stock
solution.
942 INDIAN J. CHEM., SEC B, JULY 2011
Scheme I
The synthesized compounds found to be active in
this primary screening were further tested in a second
set of dilution against all microorganisms. Secondary
screening: The compounds found active in primary
screening were similarly diluted to obtain 100, 50,
µg/mL concentrations. The lowest concentration which
showed no growth after spot subculture was considered
as MBC/MFC for each drug. The highest dilution
showing at least 99% inhibition was taken as
MBC/MFC. The result of this test is affected by the
size of the inoculum. The test mixture contained 108
organisms/mL. The standard drug used in the present
study was Gentamycin for evaluating antibacterial
activity which showed 0.05, 0.25, 0.5 and 1 µg/mL
MBC against E. coli, P. aeruginosa, S. aureus and S.
pyogenes respectively. K. Nystatin was used as the
standard drug for antifungal activity which showed 100
µg/mL MFC against fungi. Compound 3e was found to
be moderately active against E. coli and P. aeruginosa
as compared to standard drug Gentamycin due to the
presence of methyl group at the third position of phenyl
ring. 3a and 3f were found to be moderately active on
C. albicans as compared to standard drug K. Nystatin
due to the presence of fluorine and methyl group at the
fourth position of phenyl ring.
Experimental Section
Melting points were obtained in open capillaries
and are uncorrected. Homogeneity of compounds
were monitored on silica gel G coated TLC plates and
finally on TLC [aluminium sheet backed silica gel G
60 (E. Merck)]. The spots were visualized by keeping
the plates in iodine vapour. IR spectra were recorded
on Shimadzu-8300 FTIR instrument (KBr). 1H NMR
were recorded on Bruker Avance 300 MHz using
DMSO-d6 and mass spectra were recorded on
Shimadzu LC-MS 2010 spectrometer. Benzimida-
zoles and thiazolidinones were prepared by known
methods36,37.
2-(1H-benzo[d]imidazol-2-yl)benzeneamine, 1.
In a round bottom flask, a mixture of benzene-1,2-
diamine (0.01 mole), 2-aminobenzoic acid (0.01
mole) and polyphosphoric acid (PPA) (15 mL) were
heated at 160ºC in an oil-bath for 3 hr. The reaction
mixture was cooled to RT and poured into ice cold
water (100 mL), and neutralized with aqueous
ammonia. The separated solid was filtered, washed
with water and dried to obtain the desired product.
The crude product was purified by dissolving in 10%
HCl and reprecipitated by the addition of aqueous
ammonia. The product was purified by recrystal-
lization from ethyl acetate. m.p. 178ºC, yield 68%.
Anal. Found: C, 74.52; N, 20.15. Calcd for C13H11N3:
C, 74.62; N, 20.08%. IR (KBr): 3480 (N-H stretching,
secondary amine), 3350 and 3480 (N-H stretching,
primary amine), 3050, (C-H stretching, aromatic
ring), 1580, 1465 (C=C stretching, aromatic ring),
740-760 cm-1(C-H stretching, o-disubstituted benzene
 NOTES 943

Table I — Physical characterization data of 3-(2-(1H-benzo[d]imidazol-2-yl)phenyl)-2-arylthiazolidin-4-ones 3a-l

1
Compd -R Mol. Formula m.p. Yield Calcd % (Found) H NMR (DMSO-d6) (δ, ppm)
°C (%) C N

3a -4-F C22H16FN3OS 216 68 67.85 10.79 12.7 (s, 1H, -N-H,), 6.6-7.7 (m, 12H, Ar-H), 6.2 (s, 1H,
(67.32 10.35) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-)
3b -4-OH C22H17N3O2S 210 64 68.81 10.47 12.5 (s, 1H, -N-H), 9.4 (s, 1H, Ar-OH), 6.8-7.8 (m, 12H,
(68.72 10.49) Ar-H), 6.3 (s, 1H, >C-H), 3.9 (s, 2H, -N-CO-CH2-S-)
3c -2,4-(Cl)2 C22H15Cl2N3OS 188 48 60.80 09.25 12.6 (s, 1H, -N-H), 6.8-7.9 (m, 11H, Ar-H), 6.5 (s, 1H,
(60.32 09.52) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-)
3d -2-CH3 C23H19N3OS 200 58 72.15 10.52 12.7 (s, 1H, -N-H), 6.8-8.0 (m, 12H, Ar-H), 6.3 (s, 1H,
(72.13 10.58) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-), 2.4 (s, 3H, Ar-CH3)
3e -3-CH3 C23H19N3OS 255 60 72.15 10.52 12.7 (s, 1H, -N-H), 6.5-7.8 (m, 12H, Ar-H), 6.5 (s, 1H,
(72.19 10.54) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-), 2.3 (s, 3H, Ar-CH3)
3f -4-CH3 C23H19N3OS 215 64 72.15 10.52 12.5 (s, 1H, -N-H), 6.8-7.7 (m, 12H, Ar-H), 6.4 (s, 1H,
(72.11 10.59) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-), 2.1 (s, 3H, Ar-CH3)
3g -2-OCH3 C23H19N3O2S 245 56 69.37 10.11 12.8 (s, 1H, -N-H), 6.6-7.8 (m, 12H, Ar-H), 6.3 (s, 1H,
(69.23 10.25) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-), 3.5 (s, 3H, Ar-OCH3)
3h -2,5- C24H21N3O3S 226 52 67.40 09.43 12.6 (s, 1H, -N-H), 6.8-8.1 (m, 11H, Ar-H), 6.4 (s, 1H,
(OCH3)2 (67.23 09.53) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-), 3.4 (s, 6H, Ar-OCH3)
3i -3,4,5- C25H23N3O4S 186 63 65.67 08.84 12.7 (s, 1H, -N-H), 6.5-8.0 (m, 10H, Ar-H), 6.4 (s, 1H,
(OCH3)3 (65.23 08.63) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-), 3.5 (s, 9H, Ar-OCH3)
3j -2-NO2 C22H16N4O3S 232 64 64.17 13.01 12.6 (s, 1H, -N-H), 6.6-7.9 (m, 12H, Ar-H), 6.5 (s, 1H,
(64.18 12.94) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-)
3k -3-NO2 C22H16N4O3S 230 58 64.17 13.01 12.8 (s, 1H, -N-H), 6.8-8.0 (m, 12H, Ar-H), 6.2 (s, 1H,
(64.11 12.99) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-)
3l -4-NO2 C22H16N4O3S 196 50 64.17 13.01 12.7 (s, 1H, -N-H), 6.6-7.8 (m, 12H, Ar-H), 6.3 (s, 1H,
(64.05 13.09) >C-H), 3.9 (s, 2H, -N-CO-CH2-S-)

ring); 1H NMR (DMSO-d6): δ 12.8 (s, 1H, N-H,
secondary amine), 6.5-7.7 (m, 8H, Ar-H), 5.8 (s, 2H, -
NH2); LC-MS: m/z 209 [M+·].
2-(1H-benzo[d]imidazol-2-yl)-N-(4-fluorobenzyl-
idene)benzeneamine, 2a. In a round bottom flask, 2-
(1H-benzo[d]imidazol-2-yl)benzenamine (0.01 mole)
was taken in 1:4-dioxane (20 mL) and 4-
fluorobenzaldehyde (0.01 mole) was added. To this
mixture, a pinch of anhydrous zinc chloride was
added and refluxed for about 5 hr. The solution was
poured onto crushed ice. The product was filtered,
washed with cold water, dried and purified by
recrystallization from methanol. m.p. 243ºC, yield
72%. Anal. Found: C, 76.22; N, 13.25. Calcd for
C20H14FN3: C, 76.18; N, 13.33%. IR (KBr): 3480 (N-
H stretching, secondary amine), 3050 (C-H stretching,
aromatic ring), 1570, 1465 (C=C, C=N stretching,
aromatic ring), 740-760 cm-1 (C-H stretching,
o-disubstituted benzene ring); 1H NMR (DMSO-d6): δ
12.7 (s, 1H, -NH, secondary amine), 7.2-7.8 (m, 12H,
Ar-H), 8.1 (s, 1H, >CH); LC-MS: m/z 315.2 [M+·].
Other compounds of this series 2b-l were prepared
by following the same procedure.
3-(2-(1H-benzo[d]imidazol-2-yl)phenyl)-2-(4-fluo-
rophenyl)thiazolidin-4-one, 3a. In a round bottom
flask, 2-(1H-benzo[d]imidazol-2-yl)-N-(4-fluoroben-
zylidene) benzenamine (0.01 mole) in 1:4-dioxane (20
mL) and thioglycolic acid (0.01 mole) were taken. The
mixture was refluxed in an oil-bath for about 8 hr. The
reaction mixture was cooled and neutralized with
saturated aqueous solution of NaHCO3. The product
obtained was purified by recrystallization from ethanol
(95%). m.p. 216ºC, yield 68%. Anal. Found: C, 67.32;
N, 10.35. Calcd for C22H16FN3OS: C, 67.85; N,
10.79%. IR (KBr): 3480 (N-H stretching, secondary
amine), 3050 (C-H stretching, aromatic ring), 1670
(C=O stretching, thiazolidine ring), 1570, 1465 (C=C,
C=N stretching, aromatic ring), 740-760 cm-1 (C-H
stretching, o-disubstituted benzene); 1H NMR (DMSO-
d6): δ 12.7 (s, 1H, -N-H, secondary amine), 6.6-7.7 (m,
12H, Ar-H), 6.2 (s, 1H, >C-H), 3.9 (s, 2H, -CH2,
thiazolidine ring); LC-MS: m/z 389.2 [M+·].
944 INDIAN J. CHEM., SEC B, JULY 2011

Table II — Antimicrobial activity of the synthesized compounds 3a-l

Minimal bactericidal concentration Minimal fungicidal concentration

(MBC) in µg/mL (MFC) in µg/mL
E. coli P. aeruginosa S. aureus S. pyogenes C. albicans A. niger A. clavatus
Compd -R
MTCC 443 MTCC 1688 MTCC 96 MTCC 442 MTCC 227 MTCC 282 MTCC 1323
3a -4-F 250 250 500 250 250 500 1000
3b -4-OH 500 500 250 500 500 1000 1000
3c -2,4-(Cl)2 250 250 500 500 500 1000 1000
3d -2-CH3 100 500 1000 1000 250 500 1000
3e -3-CH3 62.5 125 200 250 500 1000 1000
3f -4-CH3 100 125 500 500 250 500 1000
3g -2-OCH3 250 250 500 500 500 1000 1000
3h -2,5-(OCH3)2 500 250 500 250 500 1000 1000
3i -3,4,5-(OCH3)3 100 125 250 500 500 1000 1000
3j -2-NO2 250 250 500 500 >1000 >1000 >1000
3k -3-NO2 500 250 100 125 >1000 >1000 >1000
3l -4-NO2 500 250 100 125 >1000 >1000 >1000

Other compounds of this series 3b-l were prepared
by following the same procedure and their physical
data are recorded in Table I.
Acknowledgement
The authors are thankful to the authorities of
Bhavnagar University, and Xavier Research
Foundation, St. Xavier’s College, Ahmedabad for
providing the research facilities.
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