Syntheses and evaluation of 2,5-disubstituted 4-thiazolidinone analogues as antimicrobial agents

Article abstract of DOI:10.1007/s00044-011-9730-1

Two novel series of 4-thiazolidinone derivatives, bearing 2-nitrophenyl imino and 4-nitrophenyl imino groups at position-2 and substituted arylidene groups at position-5, have been synthesized and evaluated for antimicrobial activity against four bacteria

Full text of DOI:10.1007/s00044-011-9730-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2064–2071
DOI 10.1007/s00044-011-9730-1
ORIGINAL RESEARCH
Syntheses and evaluation of 2,5-disubstituted 4-thiazolidinone
analogues as antimicrobial agents
•
Pooja Chawla Ranjit Singh Shailendra K. Saraf
•
Received: 3 March 2011 / Accepted: 21 June 2011 / Published online: 10 July 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Two novel series of 4-thiazolidinone deriva-
tives, bearing 2-nitrophenyl imino and 4-nitrophenyl imino
groups at position-2 and substituted arylidene groups at
position-5, have been synthesized and evaluated for anti-
microbial activity against four bacterial and one fungal
strain. The success of the synthesis of compounds was
confirmed on the basis of spectral analysis. All the newly
synthesized compounds were obtained in high yields and
exhibited good antibacterial activity; however, the anti-
fungal potential was limited to a few agents.
explore broad spectrum antimicrobials (Chugh, 2008).
Structure–activity relationship between pharmacophore and
heterocyclic backbone also need to be emphasized. Novel
potent antimicrobial agents with different modes of action
have to be developed so as to avoid problems of cross
resistance (Williams, 1996; Khan et al., 2005). Researchers
across the world are synthesizing new drugs against patho-
genic microorganisms. The 4-thiazolidinones are well-
known heterocyclic compounds with tremendous structural
as well as pharmacological importance. The wonder nucleus
is well reputed for a spectrum of biological activities, such as
antimicrobial (Ronad et al., 2010; Omar et al., 2010; Mehta
et al., 2006; Sattigeri et al., 2005; Liu et al., 2000; Sharma
and Kumar, 2000), antitubercular (Kukukguzel et al., 2002),
anthelmintic (Choudhari et al., 1995), anti-inflammatory
(Goel et al., 1999), etc. Some researchers have reported that
2-arylimino-4-thiazolidinone derivatives possess diverse
pharmacological activities (Ottana et al., 2005, 2007, 2009;
Chavan and Rai, 2007; Vicini et al., 2008; Geronikaki et al.,
2008). Halogenated and nitro substituents can affect the
biological activity of the basic nucleus. Thus, an attempt was
made to synthesize 2-substituted arylimino-5-substituted
arylidene thiazolidine-4-one derivatives with 2-nitroimino
and 4-nitroimino groups at position-2 and substituted ary-
lidene groups at position-5 of 4-thiazolidinone, and evaluate
them against bacterial and fungal strains.
Keywords 4-Thiazolidinones ꢀ Arylidene ꢀ
Spectral analysis ꢀ Antimicrobial
Introduction
Diseases caused by microbial infections are very common
worldwide. In the past few decades, the development of
microbial resistance has led to an increase in the number and
severity of infections. Hence, there is a continuous need to
P. Chawla
Faculty of Pharmacy, Babu Banarasi Das National Institute
of Technology and Management, Sector 1, Dr. Akhilesh Das
Nagar, Faizabad Road, Chinhut, Lucknow 227105,
Uttar Pradesh, India
R. Singh
School of Pharmaceutical Sciences, Shobhit University,
Modipuram, Meerut 250010, Uttar Pradesh, India
Experimental section
General
S. K. Saraf (&)
Faculty of Pharmacy, Northern India Engineering College,
Sector 2, Dr. Akhilesh Das Nagar, Faizabad Road, Chinhut,
Lucknow 227105, Uttar Pradesh, India
e-mail: dirpharmniec@gmail.com
Synthetic starting material, reagents, and solvents were pro-
cured from Aldrich, Himedia and SD Fine Chemicals. The
reacting materials were used as received. Melting points were
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2-(2-Nitrophenylimino) thiazolidin-4-one (3)
determined using open capillary method and are uncorrected.
The kmax were recorded on Shimadzu 1700 UV–Visible
spectrophotometer. The infra red (IR) spectra were recorded
on Shimadzu 8400S FTIR spectrophotometer using KBr
Bright shining orange crystals; Reaction time 4 h; yield
68%; mp 161–164°C (from dioxane); Rf value 0.87 (Ethyl
acetate: Chloroform, 9:1); IR (KBr,cm-1) m: –C=O: 1731;
–NH stretch 3463; –NH– bend 1593; C=N 1639; C–N
1257; C–H stretch (aromatic) 3001; Ar–NO2 1342(Sym),
1514(Asym); C–H bend (aromatic ortho substituted) 765;
Mass: M?1 peak at 238.
1
pellet technique. HNMR spectra were recorded on Bruker
DRX-300 spectrophotometer using tetramethyl silane (TMS)
as internal standard and DMSO-d6 as solvent. Chemical shift
(d) values are reported in ppm. Splitting patterns were des-
ignated as follows: s(singlet), d(doublet); and m(multiplet).
High-Resolution Mass spectra were recorded on JEOL-Accu
TOF JMS-T100LC spectrometer. Progress of the reactions
was monitored by precoated TLC silica gel-G plates and spots
were detected in iodine chamber.
2-(4-Nitrophenylimino) thiazolidin-4-one (4)
Yellowish orange crystals; Reaction time 5 h; yield 70%;
mp 230–233°C (from dioxane); Rf value 0.72 (Ethyl ace-
tate: Chloroform, 9:1); IR (KBr,cm-1) m: –C=O: 1677;
–NH stretch 3260; –NH– bend 1510; C=N 1643; C–N
1245; C–H stretch (aromatic) 2968; Ar–NO2 1342(Sym),
1413(Asym); C–H bend (aromatic para substituted) 746;
Mass: M?1 peak at 238.
Synthesis of 2-chloro-N-(substituted phenyl) acetamide
(2a and 2b)
Ice cold chloroacetyl chloride (0.46 mol) was added
dropwise to substituted aniline (1a and 1b) (0.2 mol) under
anhydrous conditions till the addition was complete fol-
lowed by stirring at room temperature for 4 h. The semi-
solid residue was neutralized with sodium bicarbonate
solution. The contents were filtered off and washed thor-
oughly with cold water. The crude mass was air dried and
recrystallized from ethanol (Scheme 1).
General procedure for the synthesis of 2-(substituted
phenylimino)-5-(substituted arylidene)-4-
thiazolidinones (5a–5g; 6a–6g)
0.004 mol of 2-(substituted phenylimino) thiazolidin-4-one
(3 and 4) in 35 ml of acetic acid was stirred, followed by
buffering with 0.008 mol sodium acetate. Knoevenagel
reaction was carried out by addition of different aryl
aldehydes (0.006 mol) and refluxing for different time
periods till the completion of reaction. The reaction mix-
ture was cooled to room temperature, and the precipitated
solid was filtered, washed thoroughly with water, and
recrystallized from dioxane (Vicini et al., 2006).
Synthesis of 2-(substituted phenylimino) thiazolidin-4-
one (3 and 4)
A solution of 0.10 mol 2-chloro-N-(substituted phenyl) acet-
amide and 0.20 mol of ammonium thiocyanate was refluxed
in ethanol for 5 h and allowed to stand overnight. The pre-
cipitate was filtered, washed with water, and recrystallized
from 1,4-dioxane (Vicini et al., 2006).
Scheme 1 Synthetic route to
the title compounds 5a–5g and
6a–6g
O
ClCOCH2Cl
O
C
NH4SCN, EtOH,
reflux, 5-9hrs
HN
RT, 4hrs
NH2
N
NH
CH2Cl
S
R1
R1
3, 4
R1
2a, 2b
1a, 1b
R2C6H4CHO,
AcOH,AcONa
reflux, 4-5hrs
R1=4-NO2
R1=2-NO2
6a:R2=H
5a:R2=H
6b:R2=2-Cl
6c:R2=4-Cl
6d:R2=4-OH
6e:R2=2-NO2
6f: R2=3-NO2
5b:R2=2-Cl
5c:R2=4-Cl
5d:R2=4-OH
5e:R2=2-NO2
5f: R2=3-NO2
O
HN
N
S
R1
6g:R2=4-OH,3-OCH3
5g:R2=4-OH,3-OCH3
5 a-g
6 a-g
R2
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Med Chem Res (2012) 21:2064–2071
2-(2-Nitrophenylimino-5-arylidene-4-thiazolidinone) (5a)
–NH stretch 3338; –C–N 1276; C=N 1600; C–H stretch
(aromatic) 3026; C=C 1656; Ar–NO2 1342 (Sym), 1514
(Asym); Ar–OH 3326 (Broad band); C–H bend (aromatic
ortho) 765; C–H bend (aromatic para) 805; 1HNMR
(DMSO-d6, 300 MHz) (d, ppm): 12.34 (s, 1H, NH); 8.01
(d, 1H, H-3); 7.59 (s, 1H, CH); 7.81–7.67 (m, 3H, H-4, 5,
6); 7.37–7.19 (m, 2H, H-20 and 60); 7.17–6.85 (m, 2H, H-30
and 50); 10.18 (s, OH); HRMS calcd for C16H11N3O4S:
341.3412, found 342.0561.
Reaction time 4 h; yield 69%; Light Brown crystals; mp
238–240°C (from dioxane); Rf value: 0.69 (Toluene: Eth-
anol, 8:2); kmax 285 nm; IR(KBr,cm-1) m: C=O 1726;
–NH– stretch 3423; –NH-bend 1593; –C–N 1251; C=N
1643; C–H stretch (aromatic) 300; C=C 1633; Ar–NO2
1344 (Sym), 1519 (Asym); C–H bend (aromatic ortho)
761; 1HNMR (DMSO-d6, 300 MHz) (d, ppm): 12.74
(s, 1H, NH); 8.04 (d, 1H, J = 8.1 Hz, H-3); 7.51(s, 1H, CH);
7.73–7.64 (m, 2H, H-4 and 5); 7.30 (d, 1H, J = 7.5 Hz, H-6);
7.30-7.18 (m, 2H, H-20 and 60); 7.44–7.31 (m, 2H, H-30 and
50); 7.39 (m, 1H, J = 7.2 Hz, H-40); HRMS calcd for
C16H11N3O3S: 325.3418, found 326.0326.
2-(2-Nitrophenylimino)-5-(2-nitrobenzylidene)-4-
thiazolidinone (5e)
Reaction time 9 h; yield 60%; Light Brown crystals; mp
230–235°C (from dioxane); Rf value: 0.81 (Toluene: Eth-
anol 8:2); kmax 284 nm; IR (KBr,cm-1) m: –C=O 1726;
–NH stretch 3415; –C–N 1257; C=N 1600; C–H stretch
(aromatic) 3001; C=C 1643; Ar–NO2 1342 (Sym), 1514
(Asym); C–H bend (aromatic ortho) 763, 801; 1HNMR
(DMSO-d6, 300 MHz) (d, ppm): 12.88 (s, 1H, NH); 8.16
(d, 1H, J = 8.1 Hz H-3); 8.15–7.95 (m, 2H, H-4 and 5);
8.01 (d, 1H, J = 8.1 Hz, H-6); 7.92 (s, 1H, CH); 7.25
(d, 1H, J = 7.8 Hz, H-30); 7.71–7.61 (m, 2H, H-40 and 50);
7.79 (d, 1H, J = 7.5 Hz, H-60); HRMS calcd for
C16H10N4O5S: 370.3394, found 371.0268.
2-(2-Nitrophenylimino)-5-(2-chlorobenzylidene)-4-
thiazolidinone (5b)
Reaction time 9 h; yield 65%; Rust colored crystals; mp
242–247°C (from dioxane); Rf value: 0.69 (Toluene: Eth-
anol, 8:2); kmax 331 nm; IR (KBr,cm-1) m: –C=O 1720;
–NH stretch 3423; NH bend 1562; C=N 1658; –C–N 1253;
C=C 1643; Ar–NO2 1342 (Sym), 1517 (Asym); Ar–Cl
1041; C–H bend (aromatic ortho) 761, 779; 1HNMR
(DMSO-d6, 300 MHz) (d, ppm): 12.9 (s, 1H, NH); 8.04 (d,
1H, J = 8.1 Hz, H-3); 7.85 (s, 1H, CH); 7.72–7.60 (m, 2H,
H-4 and 5); 7.97 (d, 1H, J = 7.8 Hz, H-6); 7.28 (d, 1H,
J = 7.8 Hz, H-30); 7.61–7.46 (m, 2H, H-40 and 50); 7.17
(d, 1H, J = 7.5 Hz, H-60). HRMS calcd for C16H10ClN3
O3S: 359.7869, found 360.2831.
2-(2-Nitrophenylimino)-5-(3-nitrobenzylidene)-4-
thiazolidinone (5f)
Reaction time 9 h; yield 63%; Light Orange colored
powder crystals; mp 230–235°C (from dioxane); Rf
value: 0.71 (Toluene: Ethanol, 8:2); kmax 284 nm; IR
(KBr,cm-1) m: –C=O 1726; NH stretch 3452; –C–N
1253; C=N 1600; C–H stretch (aromatic) 3060; C=C
1665; Ar–NO2 1350 (Sym), 1519 (Asym); C–H bend
(aromatic ortho) 745, C–H bend (aromatic meta) 795,
821; 1HNMR (DMSO-d6, 300 MHz) (d, ppm): 12.91
(s, 1H, NH); 8.24 (d, 1H, J = 7.8 Hz, H-3); 7.78–7.73
(m, 2H, H-4 and 5); 8.05 (d, 1H, J = 7.5 Hz, H-6); 7.88
(s, 1H, CH); 8.39 (s, 1H, H-20); 7.93 (d, 1H, J = 7.5 Hz,
H-40); 7.42 (t, 1H, J = 7.8 Hz, H-50); 7.32 (d, 1H,
J = 7.5 Hz, H-60); HRMS calcd for C16H10N4O5S:
370.3394, found 371.2654.
2-(2-Nitrophenylimino)-5-(4-chlorobenzylidene)-4-
thiazolidinone (5c)
Reaction time 8 h; yield 69%; Buff colored powder; mp
205–210°C (from dioxane); Rf value: 0.84 (Toluene: Eth-
anol, 8:2); kmax 285 nm; IR (KBr,cm-1) m: –C=O 1722;
–NH stretch 3450; –C–N 1255; C–H stretch (aromatic)
2997; C=C 1643; Ar–NO2 1344 (Sym), 1519 (Asym);
Ar–Cl 1057; C–H bend (aromatic ortho) 757; C–H bend
(aromatic para) 800; 1HNMR (DMSO-d6, 300 MHz)
(d, ppm): 12.79 (s, 1H, NH); 8.04 (d, 1H, J = 8.1 Hz,
H-3); 7.54 (s, 1H, CH); 7.97–7.67 (m, 2H, J = 7.5 Hz, H-4
and 5); 7.97 (d, 1H, J = 8.1 Hz, H-6); 7.40–7.38 (m, 2H,
H-20 and 60); 7.35–7.16 (m, 2H, H-30 and 40); HRMS calcd
for C16H10ClN3O3S: 359.7869, found 360.0325.
2-(2-nitrophenylimino)-5-(4-hydroxy-3-
methoxybenzylidene)-4-thiazolidinone (5g)
2-(2-Nitrophenylimino)-5-(4-hydroxybenzylidene)-4-
thiazolidinone (5d)
Reaction time 10 h; yield 63%; mustard colored crystals;
mp 245–250°C (from dioxane); Rf value: 0.73 (Toluene:
Ethanol, 8:2); kmax 283 nm; IR (KBr,cm-1) m: –C=O 1726;
NH stretch 3452; –C–N 1253; C=N 1600; C–H stretch
(aromatic) 3060; C=C 1665; Ar–NO2 1342 (Sym), 1514
(Asym); Ar–OH 3452 (Broad band); C–H bend (aromatic
Reaction time 8.5 h; yield 72%; Brown colored crystals;
mp 210–215°C (from dioxane); Rf value: 0.67 (Toluene:
Ethanol, 8:2); kmax 280 nm; IR (KBr,cm-1) m: –C=O 1703;
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2067
ortho) 765; C–H bend (aromatic meta) 821 and 871, C–H
1
bend (aromatic para) 805; HNMR (DMSO-d6, 300 MHz)
H-20 and 60); 7.96–7.71 (d, 2H, H-30 and 50); HRMS calcd
for C16H10ClN3O3S: 359.7869, found 360.0356.
(d, ppm): 12.12 (s, 1H, NH); 7.83 (d, 1H, J = 3.9 Hz,
H-3); 8.30–8.01(m, 3H, H-4, 5 and 6); 7.25(s, 1H, CH);
6.93 (s, 1H, H-2); 7.43–7.39 (m, 2H, H-50 and 60); 9.85
(s, OH), 4.009 (s, 3H, OCH3); HRMS calcd for
C17H13N3O5S: 371.3672, found 372.1055.
2-(4-nitrophenylimino)-5-(4-hydroxybenzylidene)-4-
thiazolidinone (6d)
Reaction time 8 h; yield 72%; Light yellow crystals; mp
[320°C (from dioxane); Rf value: 0.70 (Toluene: Ethanol,
8:2); kmax 254 nm; IR (KBr,cm-1) m: –C=O 1665; NH
stretch 3272; –C–N 1244; C=N 1565; C–H stretch (aro-
matic) 3014; C=C 1631; Ar–NO2 1340 (Sym), 1517
(Asym); Ar–OH 3413 (Broad band); C–H bend (aromatic
para) 794 and 856; 1HNMR (DMSO-d6, 300 MHz)
(d, ppm): 12.34 (s, 1H, NH); 7.38 (s, 1H, H-2); 8.03–7.77
(m, 3H, H-3,5,6); 7.60(s, 1H, CH); 7.38–7.17 (m, 2H, H-20
and 60); 7.71–7.59 (m, 2H, H-30 and 50); 10.18 (s, OH);
HRMS calcd for C16H11N3O4S: 341.3412, found 342.0532.
2-(4-Nitrophenylimino-5-arylidene-4-thiazolidinone) (6a)
Reaction time 7 h; yield 72%; Light Brown crystals; mp
280–283°C (from dioxane); Rf value: 0.72 (Toluene: Eth-
anol, 8:2); kmax 285 nm; IR(KBr,cm-1) m: –C=O 1665;
–NH stretch 3269; –NH bend 1565; –C–N 1244; C=N
1631; C–H stretch (aromatic) 3016; C=C 1631; Ar–NO2
1342 (Sym), 1519 (Asym); C–H bend (aromatic para) 748;
1HNMR (DMSO-d6, 300 MHz): (d, ppm): 12.74 (s, 1H,
NH); 7.40 (d, 1H, J = 8.1 Hz, H-2); 7.95 (d, 1H,
J = 6.9 Hz, H-3); 7.45–7.40 (m, 2H, H-5 and 6); 7.51
(s, 1H, CH); 7.18–7.15 (m, 2H, H-20 and 60); 7.76–7.71
(m, 3H, H-40, 30 and 50); HRMS calcd for C16H11N3O3S:
325.3418, found 326.0695.
2-(4-nitrophenylimino)-5-(2-nitrobenzylidene)-4-
thiazolidinone (6e)
Reaction time 9 h; yield 60%; Light Brown crystals; mp
250–252°C (from dioxane); Rf value: 0.76 (Toluene:
Ethanol, 8:2); kmax 255 nm; IR (KBr,cm-1) m: –C=O
1677; NH– stretch 3278; –C–N 1244; C=N 1599; C–H
stretch (aromatic) 2983; C=C 1643; Ar–NO2 1385(Sym),
1510 (Asym); C–H bend (aromatic ortho) 745, C–H bend
(aromatic para) 800; 1HNMR (DMSO-d6, 300 MHz)
(d, ppm): 12.88 (s,1H, NH); 7.96 (s, 1H, H-2); 8.16 (d,
1H, J = 8.1 Hz, H-3); 7.80 (t, 1H, J = 7.2 Hz, H-5); 7.26
(d, 1H, J = 7.8 Hz, H-6); 7.92 (s, 1H, CH); 8.01 (d, 1H,
J = 8.01 Hz, H-30); 7.80 (t, 1H, J = 7.2 Hz, H-40);
7.69 (t, 1H, J = 7.8 Hz, H-50); 7.26 (d, 1H, J = 7.8 Hz,
H-60); HRMS calcd for C16H10N4O5S: 370.3394, found
371.0649.
2-(4-Nitrophenylimino)-5-(2-chlorobenzylidene)-4-
thiazolidinone (6b)
Reaction time 7 h; yield 65%; Light Rust (Coffee) colored
crystals; mp 250–255°C (from dioxane); Rf value: 0.69
(Toluene: Ethanol, 8:2); kmax 255 nm; IR (KBr,cm-1) m:
–C=O 1665; NH stretch 3270; –C–N 1244; C=N 1631;
C–H stretch (aromatic) 3014; C=C 1631; Ar–NO2 1342
(Sym), 1517 (Asym); Ar–Cl 1114; C–H bend (aromatic
ortho) 748, C–H bend (aromatic para) 794; 1HNMR
(DMSO-d6, 300 MHz) (d, ppm): 12.90, (s, 1H, NH); 7.46,
(s, 1H, H-2); 8.04 (d, 1H, J = 8.1 Hz, H-3); 7.72–7.96 (m,
2H, H-5 and 6); 7.86(s, 1H, CH); 7.71–7.29 (d, 2H, H-30
and 60); 7.43 (t, 2H, J = 9.6 Hz, H-40 and 50); HRMS calcd
for C16H10ClN3O3S: 359.7869, found 360.5326.
2-(4-Nitrophenylimino)-5-(3-nitrobenzylidene)-4-
thiazolidinone (6f)
2-(4-Nitrophenylimino)-5-(4-chlorobenzylidene)-4-
thiazolidinone (6c)
Reaction time 9 h; yield 63%; Light Brown (clay) colored
crystals; mp [310°C (from dioxane); Rf value: 0.80 (Tol-
uene: Ethanol, 8:2); kmax 255 nm; IR (KBr,cm-1) m: –C=O
1677; NH stretch 3278; –C–N 1242; C=N 1596; C–H
stretch (aromatic) 2945; C=C 1643; Ar–NO2 1344 (Sym),
1514 (Asym); C–H bend (aromatic para) 748, C–H bend
Reaction time 8 h; yield 69%; Light yellow crystals; mp
245–250°C (from dioxane); Rf value: 0.85 (Toluene: Eth-
anol, 8:2); kmax 254 nm; IR (KBr,cm-1) m: –C=O 1665;
–NH stretch 3274; –C–N 1244; C=N 1565; C–H stretch
(aromatic) 3018; C=C 1643; Ar–NO2 1344 (Sym), 1517
(Asym); Ar–Cl 1114; C–H bend (aromatic para) 817 and
854; 1HNMR (DMSO-d6, 300 MHz) (d, ppm): 12.79
(s, 1H, NH); 7.71 (s, 1H, H-2); 8.04 (d, 1H, J = 8.1 Hz,
H-3); 7.40 (t, 1H, J = 7.5 Hz, H-5); 7.30 (d, 1H,
J = 7.8 Hz, H-6); 7.54 (s, 1H, CH); 7.31–7.16 (m, 2H,
1
(aromatic meta) 808, 845; HNMR (DMSO-d6, 300 MHz)
(d, ppm): 12.91 (s, 1H, NH); 8.39 (s, 1H, H-2); 8.24 (d, 1H,
J = 7.8 Hz, H-3); 7.75 (t, 1H, J = 6.6 Hz, H-5); 7.32
(d, 1H, J = 7.5 Hz, H-6); 7.88 (s, 1H, CH); 8.39 (s, 1H,
H-20); 8.05 (d, 1H, J = 7.5 Hz, H-40); 7.42 (t, 1H,
J = 7.8 Hz, H-50); 7.93 (d, 1H, J = 7.5 Hz, H-60); HRMS
calcd for C16H10N4O5S: 370.3394, found 371.3654.
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Med Chem Res (2012) 21:2064–2071
2-(4-Nitrophenylimino)-5-(4-hydroxy-3-
methoxybenzylidene)-4-thiazolidinone (6g)
Microbiological studies
Antimicrobial assay of the synthesized compounds was
carried out using standard cup plate method (Indian Phar-
macopoeia 1996). Twenty-four-hour-old subcultures were
used. Bacillus subtilis and Staphylococcus aureus were used
as Gram positive bacterial strains whereas Escherichia coli
and Pseudomonas aeruginosa served as Gram negative
strains. One fungal strain viz. Candida albicans was chosen
for the activity. Ciprofloxacin and fluconazole (100 lg/ml)
were taken as standard drugs for antibacterial and antifungal
activities, respectively. Pure strains were procured from
Institute of Microbial Technology (IMTECH), Chandigarh,
India. The compounds were dissolved in 8% v/v dimethyl
sulfoxide and dilutions were made as 50, 100, 200, and
Reaction time 10 h; yield 63%; mustard colored crystals; mp
270–275°C (from dioxane); Rf value: 0.78 (Toluene: Etha-
nol, 8:2); kmax 254 nm; IR (KBr,cm-1) m: –C=O 1665; NH
stretch 3271; –C–N 1244; C=N 1565; C–H stretch (aromatic)
3016; C=C 1631; Ar–NO2 1340 (Sym), 1517 (Asym);
Ar–OH 3423 (Broad band); C–H bend (aromatic ortho) 745;
C–H bend (aromatic meta) 856 and 871, C–H bend (aromatic
para) 795; 1HNMR (DMSO-d6, 300 MHz) (d, ppm): 12.00
(s, 1H, NH); 7.48 (s, 1H, H-2); 7.40–6.91(m, 3H, H-3, 5 and
6); 7.82 (s, 1H, CH); 7.67 (s, 1H, H-20); 7.58 (m, 2H, H = 50
and 60); 9.85 (s, OH), 4.066 (s, 3H, OCH3); HRMS calcd for
C17H13N3O5S: 371.3672, found 372.3265.
Table 1 Antimicrobial activity
of the synthesised compounds
(5a–5g)
Compound code
Conc. (lg/ml)
Zone of Inhibition (mm) (n = 3)
Gram ?ve bacteria
Gram-ve bacteria
Fungus
CA
SA
BS
PA
EC
5a
5b
5c
5d
5e
5f
50
10
11
12
15
11
12
14
15
14
15
16
18
10
10
10
11
10
10
13
14
8
8
6
7
10
11
13
18
10
16
18
19
–
100
200
300
50
10
11
13
11
13
15
18
13
14
15
16
10
10
10
11
9
6
8
8
10
12
9
10
8
100
200
300
50
10
12
15
14
15
17
18
–
10
10
12
10
11
11
11
–
100
200
300
50
–
–
–
–
100
200
300
50
–
–
–
–
–
–
–
–
–
10
10
13
13
10
11
15
16
–
8
10
16
23
26
10
12
14
16
–
100
200
300
50
9
8
10
10
7
10
11
10
8
100
200
300
50
10
14
16
7
15
20
22
8
13
15
–
5g
100
200
300
100
100
–
8
8
–
–
–
8
10
12
27
–
–
–
–
8
–
–
–
Ciprofloxacin
16
–
18
–
15
–
–
Fluconazole
35
–
– no measurable zone of
inhibition
Control (8%v/v DMSO)
–
–
–
–
123

Med Chem Res (2012) 21:2064–2071
2069
Table 2 Antimicrobial activity
of the synthesised compounds
(6a–6g)
Compound code
Conc. (lg/ml)
Zone of Inhibition (mm) (n = 3)
Gram ?ve bacteria Gram -ve bacteria
Fungus
CA
SA
BS
PA
EC
6a
6b
6c
6d
6e
6f
50
12
13
14
16
15
16
17
19
13
14
15
17
11
12
13
15
11
15
16
17
11
15
16
17
14
15
16
17
19
–
11
12
13
15
13
14
15
17
15
16
17
18
11
12
14
15
11
12
13
15
11
12
13
15
11
12
14
15
22
–
10
10
11
13
13
14
16
17
11
12
13
14
10
11
11
12
10
11
12
12
10
11
12
12
14
15
15
17
28
–
11
12
13
15
13
14
15
16
15
16
16
18
11
12
13
15
11
11
12
12
11
11
12
12
11
12
12
13
18
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
35
–
100
200
300
50
100
200
300
50
100
200
300
50
100
200
300
50
100
200
300
50
100
200
300
50
6g
100
200
300
100
100
–
Ciprofloxacin
Fluconazole
– no measurable zone of
inhibition
Control (8%v/v DMSO)
–
–
–
–
300 lg/ml. An 8% v/v solution of dimethyl sulfoxide was
used as control. In all determinations, tests were performed
in triplicates, and the results were taken as mean of the three
findings. The diameters of the circular zones of inhibition
were measured and are reported in the Tables 1 and 2.
compounds is given in Scheme 1. The title compounds
were synthesized through a three-step reaction starting
from chloroacetylation of 2-nitro and 4-nitro aniline (1a
and 1b) to give 2-chloro-N-(substituted phenyl) acetamides
(2a and 2b). Intermediate acetamides were heterocyclized
with ammonium thiocyanate to yield 2-(substituted phe-
nylimino) thiazolidin-4-one (3 and 4). The title compounds
were obtained by condensing 3 and 4 with various aryl
aldehydes through Knoevenagel reaction. Compounds were
characterized by physicochemical and spectral techniques
Results and discussion
Synthesis
1
(UV, IR, HNMR and Mass).
In the present study, two series of 2,5-disubstituted
4-thiazolidinone (5a–5g and 6a–6g) derivatives were syn-
thesized in an attempt to find new candidates for antimi-
crobial activity. The synthetic pathway leading to the title
UV spectra of the synthesized compounds showed
characteristic K bands arising due to C=N chromophoric
group at 267–347 nm justifying the bathochromic shift
attributable to nitro and chloro groups. The peaks observed
123

2070
Med Chem Res (2012) 21:2064–2071
in IR spectra (cm-1) of lactam NH at 3200, 1550, C=O at
1670 and C=C at 1633 agreed with the structures. Syn-
thesized compounds can exist as potential E and Z geo-
metrical isomers; 5-exocyclic C=C was assigned Z
configuration on the basis of NMR spectra. The methine
proton deshielded by adjacent C=O was detected at
pronounced against Gram positive organisms than Gram
negative organisms. Some of the compounds among 2-nitro
imino series (5a–5g) showed activity against Candida
albicans. Thus, 4-thiazolidinone analogues exhibit prom-
ising antimicrobial activity which could lead to discovery
of some promising agents.
1
7.70–7.75 in HNMR spectra as observed for analogous
Acknowledgments The authors are thankful to Central Drug
Research Institute, Lucknow, India for the library facility and spectral
characterization.
arylidene 2,4 thiazolidinedione (Bruno et al., 2002). Owing
to less deshielding effect of 1-S, such protons resonate at a
lower chemical shift value and were assigned E configu-
ration (Momose et al., 1991). In 1HNMR spectra, NH
proton observed at 11.8–12.7 ppm shows substitution at
2nd position instead of 3rd position, which indicates a
lactam proton, since imine proton appears at much higher
field (Ispida et al., 1990). The presence of M??1 peaks
with 100% abundance in HRMS (high-resolution mass
spectrometry) further confirmed the synthesis and purity of
compounds.
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