Effect of chloro and fluoro groups on the antimicrobial activity of 2,5-disubstituted 4-thiazolidinones: A comparative study

Article abstract of DOI:10.1007/s00044-011-9864-1

The article reports the synthesis of a series comprising of twenty-one 2,5-disubstituted-4-thiazolidinone derivatives, bearing 3-chloro-4-fluorophenyl imino, 4-chlorophenyl imino and 3-chlorophenyl imino groups at position-2 and substituted arylidene grou

Full text of DOI:10.1007/s00044-011-9864-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3263–3271
DOI 10.1007/s00044-011-9864-1
ORIGINAL RESEARCH
Effect of chloro and fluoro groups on the antimicrobial activity
of 2,5-disubstituted 4-thiazolidinones: a comparative study
•
Pooja Chawla Ranjit Singh Shailendra K. Saraf
•
Received: 1 September 2011 / Accepted: 31 October 2011 / Published online: 16 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The article reports the synthesis of a series
comprising of twenty-one 2,5-disubstituted-4-thiazolidi-
none derivatives, bearing 3-chloro-4-fluorophenyl imino,
4-chlorophenyl imino and 3-chlorophenyl imino groups at
position-2 and substituted arylidene groups at position-5.
The title compounds were obtained in high yields through
Knoevenagel condensation and evaluated for antimicrobial
activity against B. subtilis, S. aureus, P. aeruginosa,
E. coli, and C. albicans. Success of the synthesis was
confirmed through spectral analysis. The newly synthe-
sized compounds exhibited promising antibacterial activity
but no antifungal activity. SAR studies revealed that the
presence of a fluoro group in addition to a chloro group had
a marked influence on the antibacterial activity.
Introduction
Medicinal chemistry involves the discovery of new
chemical entities for the treatment of disease and system-
atic study of SARs of these compounds. Such studies
provide the basis of development of better medicinal agents
from lead compounds (Fries, 2008). The nature of these
compounds is largely synthetic with some compounds
being natural or semi-synthetic. Among the synthetic
compounds, only a few qualify to be a ‘‘drug.’’ It is an
established fact that one drug out of three is a halogenated
derivative and halogens are found in drugs belonging to
practically all therapeutic classes (Wermuth, 2003). Halo-
gen groups impart different effects on physicochemical and
pharmacological activities of drugs.
Keywords 4-Thiazolidinones ꢀ Arylidene ꢀ
Spectral analysis ꢀ Imino ꢀ Knoevenagel condensation ꢀ
Antimicrobial
Antibiotics belong to one of the most prescribed classes
of drugs. However, their misuse and evolutionary pressures
have led to growing incidences of drug resistant pathogens
(Prescott, 2007). This coupled with a decreased pace of
discovery of anti-infective agents has aggravated the
problem. Thus, there is an urgent need to develop new
pharmacophores which not only offer a broad spectrum of
activity but also possess a different mechanism of action so
as to avoid cross resistance (Chugh, 2008; Williams, 1996).
Heterocyclic compounds present themselves as a group
with a plethora of varying biological activities. 4-thiazo-
lidinones are moieties which possess innumerable activities
like antimicrobial (Bondock, 2006, 2007; Bonde and
Gaikwad 2004; Kavitha et al., 2006; Ronad et al., 2010;
Omar et al., 2010; Vicini et al., 2008); anti-convulsant
(Shingalapur et al., 2010); anti-diabetic (Faidallah et al.,
2011); anti-HIV(Rawal et al., 2005, 2007); cardio-protec-
tive (Ozaki and Ohi, 1999); tumor necrosis factor-a antag-
onist activities (Voss et al., 2003); Ca2? channel blocker
(Kato et al., 1999; Hara et al., 1999) and the list is ever
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
e-mail: pvchawla@gmail.com
R. Singh
School of Pharmaceutical Sciences, Shobhit University,
Modipuram, Meerut 250010, Uttar Pradesh, India
e-mail: ranjitsps@gmail.com
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
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Med Chem Res (2012) 21:3263–3271
increasing. Various substitutions at this nucleus are possible
but greatest difference occurs after making changes at 2 and
5-positions. Compounds with 2-imino-5-arylidene substi-
tutions have been reported to possess various biological
activities like anti-inflammatory (Ottana et al., 2005);
antimicrobial (Chavan and Rai, 2007); anti-diabetic
(Maccari et al., 2011); and anti-arthritic (Ottana et al.,
2007). In continuation of the study (Chawla et al., 2011),
new substitutions on the imino groups at position-2 and the
arylidene ring at position-5 were explored and the synthe-
sized compounds were screened for antimicrobial activity.
(0.2 mol) under anhydrous conditions. The reaction mix-
ture was stirred at room temperature for 4 h. The residue
was neutralized with sodium bicarbonate solution. The
contents were filtered off and washed thoroughly with cold
water and re-crystallized from ethanol (Scheme 1).
Synthesis of 2-(substituted phenylimino) thiazolidin-4-
one (3, 4 and 5)
2-chloro-N-(substituted phenyl) acetamide (2a, 2b, and 2c)
(0.10 mol) was refluxed with ammonium thiocyanate
(0.20 mol) for 5–6 h using ethanol as solvent. The reaction
mixture was allowed to stand overnight. The contents were
filtered off, washed with water, and recrystallized from 1,4-
dioxane (Vicini et al., 2006).
Experimental section
General
2-(3-chloro-4-fluorophenylimino) thiazolidin-4-one (3)
The chemicals and solvents were purchased from Aldrich,
Himedia, and SD Fine Chemicals and were used as
received. Melting range were determined using open cap-
illary method and are uncorrected. kmax were determined
using Shimadzu 1700 UV–Visible spectrophotometer. The
infra red (IR) spectra were recorded using KBr pellet
technique on Shimadzu 8400S FTIR spectrophotometer.
1HNMR spectra were obtained on Bruker DRX-300 spec-
trophotometer using tetramethyl silane (TMS) as internal
standard and DMSO-d6 as solvent. Chemical shift (d)
values are reported in ppm. High resolution mass spectra
(HRMS) were recorded on JEOL-Accu TOF JMS-T100LC
spectrometer. Precoated TLC silica gel-G plates were used
for monitoring the progress of reactions.
Reaction time 5 h; yield 60%; mp 212–215°C (from
dioxane); Rf value 0.72 (Ethyl acetate:chloroform 9:1); IR
(KBr) (m cm-1): –C=O: 1701, –NH– stretch 3400, –NH–
bend 1641, C=N 1618, C–N 1248, C–H stretch (aromatic)
2922, C–H bend (aromatic para substituted) 860, C–H bend
(aromatic meta substituted) 650, 800, CH2 1438, Ar–Cl
1060, Ar–F 1191; Mass: M ? 1 peak at 245; calculated
C9H6ClFN2OS C 44.18, H 2.47, N 11.45.
2-(4-chlorophenylimino) thiazolidin-4-one (4)
Reaction time 5 h; yield 65%; mp 200–203°C (from
dioxane); Rf value: 0.81 (Ethyl acetate:Chloroform 9:1); IR
(KBr) (m cm-1): –C=O: 1733; –NH– stretch: 3413; –NH–
bend: 1598; C=N: 1637; C–N: 1257; C–H stretch (aro-
matic): 2921; C–H bend (aromatic para substituted): 862;
CH2: 1465 Ar–Cl: 1150; Mass: M ? 1 peak at 227; cal-
culated C9H7ClN2OS C 47.69, H 3.11, N 12.36.
Synthesis of 2-chloro-N-(substituted phenyl) acetamide
(2a, 2b and 2c)
Previously cooled chloro-acetyl chloride (0.46 mol) was
added drop-wise to various anilines (1a, 1b, and 1c)
Scheme 1 Synthetic route to
the title compounds 6a–g, 7a–g,
and 8a–g
O
ClCOCH2Cl
O
C
NH4SCN, EtOH,
reflux, 5-9hrs
HN
RT, 4hrs
NH2
N
NH
2a-c
CH2Cl
S
R1
R1
3, 4, 5
R1
1a-c
R2C6H4CHO,
AcOH,AcONa
reflux, 4-5hrs
R1=3-Cl
7a:
R1=3-Cl, 4-F
6a:R2=H
6b:
6c:R2=4-Cl
R1=4-Cl
R2=H
7a:
7b:
7c:
7d:
7e:
7f:
R2=H
7b:
7c:
7d:
7e:
7f:
R2=2-Cl
R2=4-Cl
R2=4-OH
R2=2-NO2
R2=3-NO2
R2=2-Cl
R2=4-Cl
R2=4-OH
R2=2-NO2
R2=3-NO2
R2=2-Cl
O
HN
6d:R2=4-OH
6e:R2=2-NO2
N
S
6f: R2=3-NO2
6g:
R1
7g:
7g:
R2=4-OH,3-OCH3
R2=4-OH,3-OCH3
R2=4-OH,3-OCH3
6 a-g
7 a-g
8 a-g
R2
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Med Chem Res (2012) 21:3263–3271
3265
J = 2.1, H-40); 7.156 (d, 1H, J = 4.8, H-60); 7.04 (m, 2H,
J = 5.4, H-30 and 50); 6.962 (s, 1H, H-2); HRMS calcd for :
C16H9Cl2FN2OS: 365.9797, found 366.9628.
2-(3-chlorophenylimino) thiazolidin-4-one (5)
Reaction time 5.5 h; yield 60%; mp 201–208°C (from
dioxane); Rf value: 0.74 (Ethyl acetate:Chloroform 9:1); IR
(KBr) (m cm-1): –C=O: 1701; –NH– stretch 3409; –NH–
bend 1573; –C–N 1247; C=N 1612; C–H stretch (aromatic)
3062; CH2: 1446 Ar–Cl 1095; C–H bend meta (aromatic)
775, 867; Mass: M ? 1 peak at 227; calculated
C9H7ClN2OS C 47.69, H 3.11, N 12.36.
2-(3-chloro-4-fluorophenylimino)-5-(4-chlorobenzylidene)-
4-thiazolidinone (6c)
Reaction time 5 h; yield 64%; Light brown crystals; mp
215–220°C (from dioxane); Rf value: 0.71 (Toluene:Etha-
nol, 8:2); kmax 347 nm; IR (KBr,cm-1) m: –C=O: 1690;
–NH– stretch: 3137; –NH– bend: 1587; –C–N: 1257; C–H
stretch (aromatic): 3053; C–H bend (aromatic para substi-
tuted): 879, 817; (aromatic meta substituted): 669, 786; C=C:
1654; Ar–F: 1257; Ar–Cl: 1100; 1HNMR (DMSO-d6,
300 MHz) (d, ppm): 12.1 (s, 1H, NH); 8.09 (d, 1H, J = 24,
H-5); 7.74 (s, 1H, CH); 7.66 (d, 2H, J = 8.7, H-30 and 50);
7.47 (d, 2H, J = 9.3, H-20 and 60); 7.29 (d, 1H, J = 5.0, H-5);
7.15 (d, 1H, J = 3.9, H-6); 6.962 (s, 1H, H-2).; HRMS calcd
for C16H9Cl2FN2OS: 365.9797, found 366.9652.
General procedure for the synthesis of 2-(substituted
phenylimino)-5-(substituted arylidene)-4-
thiazolidinones (6a–6g; 7a–7g and 8a–8g)
2-(substituted phenylimino) thiazolidin-4-one (3, 4 and 5)
(0.004 mol) was stirred in acetic acid (35 ml) in the pres-
ence of sodium acetate (0.008 mol). Different aryl alde-
hydes (0.006 mol) were added and the mixture was
refluxed for different time periods till the completion of
reaction through Knoevenagel reaction. Precipitates were
obtained after cooling the reaction mixture to room tem-
perature and subsequently filtered, washed thoroughly with
water. 1,4-dioxane was used as solvent for recrystallization
from (Vicini et al., 2006).
2-(3-chloro-4-fluorophenylimino)-5-(4-
hydroxybenzylidene)-4-thiazolidinone (6d)
Reaction time 6 h; yield 69%; Yellowish white crystals;
mp 210–213°C (from dioxane); Rf value: 0.73 (Toluene:
Ethanol, 8:2); kmax 267 nm; IR (KBr,cm-1) m: –C=O: 1703;
–NH– stretch: 3406; –NH– bend: 1585; –C–N: 1259; C–H
stretch (aromatic): 3055; C–H bend (aromatic para substi-
tuted): 819, 883; (aromatic meta substituted): 653, 744;
Ar–F: 1191; C=C: 1643; Ar–Cl: 1056; Ar-OH: 3500; C–O:
1220; 1HNMR (DMSO-d6, 300 MHz) (d, ppm): 11.8 (s, 1H,
NH); 8.0 (s, 1H, CH); 7.15 (d, 2H, J = 4.5, H-30 and 50);
6.95 (d, 2H, J = 3.6, H-20 and 60); 7.70 (m, 3H, H-2, 5 and
6); HRMS calcd for C16H10ClFN2O2S: 348.0136, found
349.0015.
2-(3-chloro-4-fluorophenylimino-5-arylidene-4-
thiazolidinone) (6a)
Reaction time 4 h; yield 62%; Light Brown crystals; mp
208–210°C (from dioxane); Rf value: 0.69 (Toluene:Ethanol,
8:2); kmax 278 nm; IR(KBr,cm-1) m: –C=O 1674; –NH–
stretch 3419; –NH-bend1550; –C–N1244; C=N 1630; stretch
(aromatic) 3001; C=C 1633; Ar–Cl 1050, Ar–F 1164; C–H
1
bend (aromatic ortho) 758; HNMR (DMSO-d6, 300 MHz)
(d, ppm): 12.3 (s, 1H, NH), 8.09 (d, 1H, J = 29.4 Hz, H-5),
7.85 (s, 1H, CH), 7.65 (d, 2H, J = 12.3 Hz, H-30and 50), 7.29
(d, 1H, J = 5.1 Hz, H-40), 7.15 (s, 1H, H-2), 7.07 (d, 2H,
J = 3.1 Hz, H-20and 60); HRMS calcd for C16H10ClFN2OS:
332.0186, found 333.0165.
2-(3-chloro-4-fluorophenylimino)-5-(2-nitrobenzylidene)-
4-thiazolidinone (6e)
Reaction time 5 h; yield 63%; Rust colored crystals; mp
189–191°C (from dioxane); Rf value: 0.66 (Toluene:Etha-
nol 8:2); kmax 267 nm; IR (KBr,cm-1) m: –C=O: 1703;
–NH– stretch: 3436; –NH– bend: 1585; C=N: 1614; –C–N:
1259; C–H stretch (aromatic): 3053; C–H bend (aromatic
ortho substituted): 750; C–H bend (aromatic meta substi-
tuted): 651, 786; C–H bend (aromatic para substituted):
819; C=C: 1643, Ar-NO2: 1346 (sym), 1504 (asym);
2-(3-chloro-4-fluorophenylimino)-5-(2-chlorobenzylidene)-
4-thiazolidinone (6b)
Reaction time 5 h; yield 67%; Off-white crystals; mp
195–200°C (from dioxane); Rf value: 0.69 (Toluene:Etha-
nol, 8:2); kmax 274 nm; IR(KBr,cm-1) m: C=O: 1703;
–NH– stretch: 3253; –NH– bend: 1587; C=N: 1616; –C–N:
1242; C–H stretch (aromatic): 3053; C–H bend (aromatic
meta substituted): 648, 759; C–H bend (aromatic para
substituted):819; C–H bend (aromatic ortho substituted):
750; C=C: 1643; Ar–Cl: 1100; Ar–F: 1242; 1HNMR
(DMSO-d6, 300 MHz) (d, ppm): 11.358 (s, 1H, NH); 8.31
(d, 1H, J = 14.1, H-5; 7.8 (s, 1H, CH); 7.269 (t, 1H,
1
Ar–Cl: 1056; Ar–F: 1191; HNMR (DMSO-d6, 300 MHz)
(d, ppm): 11.9 (s, 1H, NH); 8.268 (s, 1H, CH); 8.234 (d,
1H, J = 4.2, H-5); 7.249 (d, 1H, J = 6.6, H-30); 6.98 (m,
2H, J = 4.8, H-40 and 50); 7.149 (s, 1H, H-2); 8.18 (d, 1H,
J = 5.1, H-60); 8.05 (d, 1H, J = 3.9, H-6); HRMS calcd
for C16H9ClFN3O3S: 377.7774, found 377.9906.
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Med Chem Res (2012) 21:3263–3271
2-(3-chloro-4-fluorophenylimino)-5-(3-nitrobenzylidene)-
4-thiazolidinone (6f)
stretch 3413; –NH– bend 1490; –C–N 1245; C=N 1606; C–H
stretch (aromatic) 2908; C=C 1649; Ar–Cl 1091; C–H bend
(aromatic ortho) 756; C–H bend (aromatic para) 825;
1HNMR (DMSO-d6, 300 MHz) (d, ppm): 11.78 (s, 1H, NH);
7.63-7.59 (m, 2H, H-2 and 6); 7.82 (d, 2H, J 6.9, H-3 and 5);
6.99 (s, 1H, CH); 7.60 (d, 1H, J 9.3 H-30); 7.45 (d, 2H, J 8.4,
H = 40 and 50); 7.55 (d, 1H, J 9.3, H-60); HRMS calcd for
C16H10Cl2N2OS: 347.9891, found 349.0129.
Reaction time 6.5 h; yield 63%; Light brown crystals; mp
240–245°C (from dioxane); Rf value: 0.72 (Toluene:Etha-
nol, 8:2); kmax 339 nm; IR (KBr,cm-1) m: –C=O: 1681;
–NH– stretch: 3421; –NH– bend: 1637; C=N: 1600; –C–N:
1263; C=C: 1637; C–H stretch (aromatic): 3045; C–H bend
(aromatic meta substituted): 669, 750; C–H bend (aromatic
para substituted): 819; Ar–NO2: 1350 (sym), 1498 (asym);
2-(4-chlorophenylimino)-5-(4-chlorobenzylidene)-4-
thiazolidinone (7c)
1
Ar–Cl: 1056; Ar–F: 1184; HNMR (DMSO-d6, 300 MHz)
(d, ppm): 12.4 (s, 1H, NH); 8.39 (d, 1H, J = 11.4, H-5);
8.24(d, 1H, J = 3.3, H-50); 8.06 (d, 1H, J = 8.1, H-40);
7.822 (d, 1H, J = 7.8, H-6); 7.822 (m, 2H, J = 14.7, H-20
and 60); 7.575 (s, 1H, CH); HRMS calcd for
C16H9ClFN3O3S: 377.7774, found 378.0016.
Reaction time 5 h; yield 70%; Off-white crystals; mp
320–325°C (from dioxane); Rf value: 0.90 (Toluene:Etha-
nol, 8:2); kmax 263 nm; IR (KBr,cm-1) m: –C=O 1722;
–NH– stretch 3413; –NH– bend 1505; –C–N 1247; C=N
1605; C–H stretch (aromatic) 3051; C=C 1649; Ar–Cl
1091; C–H bend (aromatic ortho) 732; C–H bend (aromatic
para) 821; 1HNMR (DMSO-d6, 300 MHz) (d, ppm):
10.908 (s, 1H, NH); 7.063 (d, 2H, J 7.5, H-2 and 6);
7.755(d, 2H, J 17.7, H-3 and 5); 7.633 (s, 1H, CH); 7.542-
7.441 (m, 4H, H-20, 30, 50 and 60); HRMS calcd for
C16H10Cl2N2OS: 347.9891, found 349.0129.
2-(3-chloro-4-fluorophenylimino)-5-(4-hydroxy-3-
methoxybenzylidene)-4-thiazolidinone (6g)
Reaction time 7 h; yield 58%; mustard colored crystals; mp
198–201°C (from dioxane); Rf value: 0.77 (Toluene:Etha-
nol, 8:2); kmax 267 nm; IR (KBr,cm-1) m: –C=O 1728,
–NH– stretch 3251, –NH– bend 1614, C=N 1585, –C–N
1259, C=C 1650; C–H stretch (aromatic) 3040; Ar-OH
3452 (Broad band); C–H bend (aromatic ortho) 765; C–H
bend (aromatic meta) 821 and 871, C–H bend (aromatic
para) 805; 1HNMR (DMSO-d6, 300 MHz) (d, ppm): 12.91
(s, 1H, NH), 7.78 (s, 1H, H-2), 7.40-6.91 (m, 2H, H-5 and
6), 7.781 (s, 1H, CH), 7.67 (s, H-20), 7.58 (m, 2H, H = 50
and 60), 10.20 (s, OH); HRMS calcd for C17H12ClFN2O3S:
378.0241, found 380.9928.
2-(4-chlorophenylimino)-5-(4-hydroxybenzylidene)-4-
thiazolidinone (7d)
Reaction time 9 h; yield 72%; Mud colored crystals; mp
235–240°C (from dioxane); Rf value: 0.71 (Toluene:Etha-
nol, 8:2); kmax 269 nm; IR (KBr,cm-1) m: –C=O 1701;
–NH– stretch 3421; –NH– bend 1505; –C–N 1255; C=N
1575; C–H stretch (aromatic) 2979; C=C 1639; Ar–Cl
1080; Ar-OH 3421 (Broad band); C–H bend (aromatic
para) 740 and 821; 1HNMR (DMSO-d6, 300 MHz) (d,
ppm): 11.268 (s, 1H, NH); 6.977 (d, 2H, J 7.2, H-2 and 6);
7.44(d, 2H, J 8.1, H-3 and 5); 7.897 (s, 1H, CH); 7.06 (d,
2H, J 7.8, H-20 and 60); 7.730 (d, 2H, J 6.3, H = 30 and 50);
10.288 (s, OH); HRMS calcd for C16H11ClN2O2S:
330.0230, found 331.0551.
2-(4-chlorophenylimino-5-arylidene-4-thiazolidinone) (7a)
Reaction time 5 h; yield 72%; Buff colored crystals; mp
280–283°C (from dioxane); Rf value: 0.72 (Toluene:Etha-
nol, 8:2); kmax 346 nm; IR(KBr,cm-1) m: –C=O 1674;
–NH– stretch 3413; –NH– bend 1564; –C–N 1245; C=N
1564; C–H stretch (aromatic) 2963; C=C 1639; Ar–Cl
1087; C–H bend (aromatic para) 761; 1HNMR (DMSO-d6,
300 MHz): (d, ppm): 11.31 (s, 1H, NH); 7.07 (d, 2H, J 7.5,
H-2,6); 7.734(d, 2H, J 8.1, H-3 and 5); 6.985 (s, 1H, CH);
7.218 (d, 2H, J 13.8, H-20 and 60); 7.557-7.441 (m, 3H,
H = 30, 40 and 50); HRMS calcd for C16H11ClN2OS:
314.0281, found 315.0595.
2-(4-chlorophenylimino)-5-(2-nitrobenzylidene)-4-
thiazolidinone (7e)
Reaction time 9 h; yield 63%; Rust crystals; mp
218–220°C (from dioxane); Rf value: 0.79 (Toluene:Etha-
nol, 8:2); kmax 278 nm; IR (KBr,cm-1) m: –C=O 1678;
–NH– stretch 3255; –NH– bend 1500; –C–N 1238; C=N
1550; C–H stretch (aromatic) 2983; C=C 1618; Ar–Cl
1083; Ar-NO2 1338 (Sym) 1517 (Asym); C–H bend (aro-
2-(4-chlorophenylimino)-5-(2-chlorobenzylidene)-4-
thiazolidinone (7b)
1
matic ortho) 756; C–H bend (aromatic para) 821; HNMR
Reaction time 5.5 h; yield 62%; Off-white crystals; mp
310–312°C (from dioxane); Rf value: 0.69 (Toluene:Etha-
nol, 8:2); kmax 276 nm; IR (KBr,cm-1) m: –C=O 1724; –NH–
(DMSO-d6, 300 MHz) (d, ppm): 11.272 (s, 1H, NH); 7.03
(d, 2H, J 7.8, H-2 and 6); 7.415 (d, 2H, J 7.5, H-3 and 5);
7.927 (s, 1H, CH); 7.797 (d, 1H, J 7.5, H-30); 7.70 (m, 2H, J
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Med Chem Res (2012) 21:3263–3271
3267
8.7, H = 40 and 50); 7.511 (d, 1H, J 8.4, H 60); HRMS calcd
263 nm; IR (KBr,cm-1) m: –C=O 1722; –NH– stretch 3423;
–NH– bend 1509; –C–N 1247; C=N 1599; C–H stretch
(aromatic)2966;C=C1654;Ar–Cl1039;C–Hbend(aromatic
meta) 862; C–H bend (aromatic para) 765.; 1HNMR (DMSO-
d6, 300 MHz) (d, ppm): 11.7 (s, 1H, NH), 7.593 (s, 1H, H-2),
7.204 (d, 1H, J 28.5, H-4), 7.071-6.985 (m, 2H, H 5 and 6),
7.628 (s, 1H, CH), 7.577 (d, 1H, J 3.9, H-30), 7.923-7.723 (m,
3H, H-40, 50, 60); HRMS calcd for C16H10Cl2N2OS: 347.9891,
found 349.0123.
for C16H10ClN3O3S: 359.0131, found 360.0568.
2-(4-chlorophenylimino)-5-(3-nitrobenzylidene)-4-
thiazolidinone (7f)
Reaction time 10 h; yield 65%; Buff colored crystals; mp
280–285°C (from dioxane); Rf value: 0.84 (Toluene:Etha-
nol, 8:2); kmax 255 nm; IR (KBr,cm-1) m: –C=O 1681;
–NH– stretch 3263; –NH– bend 1500; –C–N 1238; C=N
1512; C–H stretch (aromatic) 2975; C–C 1637; Ar–Cl
1091; Ar-NO2 1349 (Sym) 1512 (Asym); C–H bend (aro-
2-(3-chlorophenylimino)-5-(4-chlorobenzylidene)-4-
thiazolidinone (8c)
1
matic meta) 821; C–H bend (aromatic para) 745; HNMR
(DMSO-d6, 300 MHz) (d, ppm): 10.997 (s, 1H, NH); 7.076
(d, 2H, J 8.1, H-2 and 6); 7.91(d, 2H, J 7.5, H-3 and 5);
7.791 (s, 1H, CH); 8.434 (s, 1H, H-20); 8.070 (d, 1H, J 7.5,
H = 40); 8.286-8.208 (m, H 50 and 60); HRMS calcd for
C16H10ClN3O3S: 359.0131, found 360.0568.
Reaction time 9 h; yield 70%; Brown crystals; mp
240–245°C (from dioxane); Rf value: 0.74 (Toluene:Etha-
nol, 8:2); kmax 348 nm; IR (KBr,cm-1) m: –C=O 1672;
–NH– stretch 3265; –NH– bend 1463; –C–N 1251; C=N
1631; C–H stretch (aromatic) 3053; C=C 1631; Ar–Cl
1091; C–H bend (aromatic meta) 821; C–H bend (aromatic
para) 763; 1HNMR (DMSO-d6, 300 MHz) (d, ppm): 10.01
(s, 1H, NH), 7.542 (s, 1H, H-2), 7.063 (d, 1H, J 7.5,H-4),
7.45 (d, 2H, J 7.5, H-5 and 6), 7.633 (s, 1H, CH), 7.633-
7.441 (m, 4H, H-20, 30, 50 and 60); HRMS calcd for
C16H10Cl2N2OS: 347.9891, found 349.0103.
2-(4-chlorophenylimino)-5-(4-hydroxy-3-
methoxybenzylidene)-4-thiazolidinone (7g)
Reaction time 10 h; yield 65%; Fluorescent yellow crys-
tals; mp 220–228°C (from dioxane); Rf value: 0.79 (Tol-
uene:Ethanol, 8:2); kmax 254 nm; IR (KBr,cm-1) m: –C=O
1691; –NH– stretch 3421; –C–N 1263; C=N 1505; C–H
stretch (aromatic) 2974; C=C 1647; Ar–Cl 1091; Ar-OH
3473 (Broad band); C; C–H bend (aromatic meta) 823,
C–H bend (aromatic para) 756; 1HNMR (DMSO-d6,
300 MHz) (d, ppm): 10.9 (s, 1H, NH); 7.067 (d, 2H, J 8.1,
H-2 and 6); 7.44 (d, 2H, J 8.1, H-3 and 5); 7.580 (s, 1H,
CH); 7.635 (s, 1H, H-20); 7.58 (m, 2H, H = 50 and 60);
7.176, (d, 1H, J 18.6, H-50), 7.121 (d, 1H, J 24.3, H-60)
4.009 (s, 3H, OCH3), 9.770 (s, OH); HRMS calcd for
C17H13ClN2O3S: 360.0335, found 361.0767.
2-(3-chlorophenylimino)-5-(4-hydroxybenzylidene)-4-
thiazolidinone (8d)
Reaction time 7 h; yield 72%; Mustard crystals; mp
310–315°C (from dioxane); Rf value: 0.796 (Toluene:Eth-
anol, 8:2); kmax 365 nm; IR (KBr,cm-1) m: –C=O 1677;
–NH– stretch 3413; –NH– bend 1500; –C–N 1244; C=N
1564; C–H stretch (aromatic) 3026; C=C 1650; Ar–Cl
1091; Ar-OH 3469 (Broad band); C–H bend (aromatic
1
meta) 825, 850; C–H bend (aromatic para) 764; HNMR
(DMSO-d6, 300 MHz) (d, ppm): 10.288, (s, 1H, NH),
7.460 (s, 1H, H-2), 7.56 (d, 1H, J 7.5, H-4), 7.258-7.041
(m, 2H, H-5 and 6), 7.433 (s, 1H, CH), 7.741-7.604 (m, 4H,
aromatic), 10.181 (s, 1H, OH); HRMS calcd for
C16H11ClN2O2S: 330.0230, found 331.05.
2-(3-chlorophenylimino-5-arylidene-4-thiazolidinone) (8a)
Reaction time 8 h; yield 72%; Coffee brown crystals; mp
260–262°C (from dioxane); Rf value: 0.72 (Toluene:Etha-
nol, 8:2); kmax 262 nm; IR(KBr,cm-1) m: –C=O 1679;
–NH– stretch 3267; –NH– bend 1504; –C–N 1244; C=N
1595; C–H stretch (aromatic) 3022; C=C 1629; Ar–Cl
2-(3-chlorophenylimino)-5-(2-nitrobenzylidene)-4-
thiazolidinone (8e)
1
1076; C–H bend (aromatic meta) 851 and 875; HNMR
(DMSO-d6, 300 MHz): (d, ppm): 11.31, (S, 1H, NH),
7.509 (s, 1H, H-2), 7.084-6.985 (m, 3H, H-4,5,6), 7.084 (s,
1H, CH), 7.748-7.509 (m, 5H aromatic); HRMS calcd for
C16H11ClN2OS: 314.0281, found 315.0583.
Reaction time 8.5 h; yield 63%; Dark Brown crystals; mp
200–205°C (from dioxane); Rf value: 0.72 (Toluene:Etha-
nol, 8:2); kmax 274 nm; IR (KBr,cm-1) m: –C=O 1685;
–NH– stretch 3265; –NH– bend 1523; –C–N 1236; C=N
1598; C–H stretch (aromatic) 3062; C=C 1639; Ar–Cl
1091; Ar-NO2 1342(sym) 1523 (asym); C–H bend (aro-
matic meta) 772 and 857; C–H bend (aromatic ortho) 754;
1HNMR (DMSO-d6, 300 MHz) (d, ppm): 11.05 (s, 1H,
NH), 7.716 (s, 1H, H-2), 7.701 (d, 1H, J 8.7, H-4), 7.687-
2-(3-chlorophenylimino)-5-(2-chlorobenzylidene)-4-
thiazolidinone (8b)
Reactiontime5 h;yield 60%;Brown crystals;mp 240–242°C
(from dioxane); Rf value: 0.72 (Toluene:Ethanol, 8:2); kmax
123

3268
Med Chem Res (2012) 21:3263–3271
7.638 (m, 2H, H-5 and 6), 7.497 (s, 1H, CH), 7.762 (d, 1H,
J 13.5, H-30), 7.884-7.785 (m, 3H, aromatic); HRMS calcd
for C16H10ClN3O3S: 359.0131, found 360.0572.
determinations. The diameters of the circular zones of
inhibition were measured and are reported in Table 1.
2-(3-chlorophenylimino)-5-(3-nitrobenzylidene)-4-
thiazolidinone (8f)
Results and discussion
Synthesis
Reaction time 8 h; yield 65%; Coffee brown crystals; mp
275–280°C (from dioxane); Rf value: 0.72 (Toluene:Etha-
nol, 8:2); kmax 342 nm; IR (KBr,cm-1) m: -C=O 1677;
–NH– stretch 3261; -NH– bend 1527; –C–N 1242; C=N
1598; C–H stretch (aromatic) 2964; C=C 1629; Ar–Cl
1114; Ar-NO2 1352 (sym) 1510 (asym); C–H bend (aro-
In this study, twenty-one derivatives of 4-thiazolidinone
substituted at position-2 and position-5 were synthesized in
an attempt to find new molecules as antimicrobial agents.
The synthetic pathway leading to the title compounds is
given in Scheme 1. All the synthesized compounds were
characterized by physicochemical and spectral data (UV,
1
matic meta) 765 and 859; HNMR (DMSO-d6, 300 MHz)
1
(d, ppm): 11.01 (s, 1H, NH), 7.726 (s, 1H, H-2), 7.611-
7.510 (m, 3H, H-4,5 and 6), 7.611 (s, 1H, CH), 7.812 (s,
1H, H-20), 7.828 (d, 1H, J 3.6 H-, 7.925-7.844 (m, 2H, H-50
and 60); HRMS calcd for C16H10ClN3O3S: 359.0131, found
360.0572.
IR, HNMR, and HRMS).
The probable mechanism of reaction and the theoreti-
cally tautomeric forms of key intermediate 3 are shown in
Scheme 2 (Vicini et al., 2006). The 3-non substituted
4-thiazolidinones display amino-imino tautomerism. The
hydroxyl tautomer was excluded on the basis of spectral
studies. In IR spectra, appearence of sharp lactam signal at
3400–3100 and C=N between 1,600 and 1,500 helped in
assigning the imino form. Absence of broad band for
alcohol further ruled out the possibility of amino form.
Occurence of downfield values for NH confirmed the same.
In UV spectra of the final compounds 5a–5g, 6a–6g, and
7a–7g, characteristic K bands arising due to C=N chromo-
phoric group were observed at 267–347 nm. Compounds
with nitro and chloro groups showed bathochromic shift.
Title compounds can exist as potential E and Z geometrical
isomers; Z configuration of 5-exocyclic C=C was assigned
on the basis of NMR spectra. The methine proton deshielded
2-(3-chlorophenylimino)-5-(4-hydroxy-3-
methoxybenzylidene)-4-thiazolidinone (8g)
Reaction time 8 h; yield 60%; Dark brown crystals; mp
225–230°C (from dioxane); Rf value: 0.73 (Toluene:Etha-
nol, 8:2); kmax 375 nm; IR (KBr,cm-1) m: –C=O 1701;
–NH– stretch 3265; –NH– bend 1497; –C–N 1255; C=N
1583; C–H stretch (aromatic) 2905; C=C 1641; Ar–Cl
1033; Ar-OH 3425 (Broad band); C–H bend (aromatic
1
meta) 795, 857; C–H bend (aromatic para) 744; HNMR
(DMSO-d6, 300 MHz) (d, ppm): 10.9 (s, 1H, NH), 7.253
(s, 1H, H-2), 7.580-7.431 (m, 3H, H-4, 5 and 6), 7.045 (s,
1H, CH), 7.301 (s, 1H, H-20), 3.839 (s, 3H, OCH3), 9.81 (s,
1H, OH), 7.081-6.966 (d, 2H, H-50 and 60); HRMS calcd
for C17H13ClN2O3S: 360.0335, found 361.0759.
1
by adjacent C=O was detected at 7.70–7.75 in HNMR
spectra as observed for analogous arylidene 2,4 thiazolid-
inedione (Bruno et al., 2002). In E isomers, due to less
deshielding effect of 1-S, such proton resonates at a lower
chemical shift value (Momose et al., 1991). The IR spectra
showed characteristic peaks (cm-1) of lactam –NH at
3400–3100, 1550, C=O at 1,700 and 1,633 for C=C agreed
with the structures. In 1HNMR spectra, –NH proton observed
at 11.8–12.7 ppm shows substitution at 2nd position instead
of 3rd position, which is in agreement with a lactam proton
since imine proton appears at much higher field (Ishida,
1990). Furthermore, HRMS spectra of the compounds
showing corresponding M ? 1 peaks confirmed the molec-
ular weights and purity.
Microbiological studies
The antimicrobial activity of the synthesized compounds
was evaluated by cup plate method (Indian Pharmacopoeia,
1996) against 24 h old subcultures of two gram positive,
two gram negative bacterial strains, and one fungal strain
using ciprofloxacin and fluconazole as standard drugs,
respectively. Microbial strains viz. Bacillus subtilis
(MTCC 121) and Staphylococcus aureus (MTCC 96) for
gram positive bacteria; Escherichia coli (MTCC 739) and
Pseudomonas aeruginosa (MTCC 2453) for gram negative
bacteria; Candida albicans (MTCC 227) for fungus were
procured as pure cultures from IMTECH, Chandigarh.
Solutions of test compounds at concentrations of 50, 100,
200, and 300 lg/ml were prepared in 8% v/v dimethyl
sulfoxide. In all the determinations, tests were performed in
triplicate and the values reported are mean of these
Antimicrobial activity
Title compounds were screened for in vitro antimicrobial
activity against two gram positive bacteria viz. Bacillus
subtilis (MTCC 121), Staphylococcus aureus (MTCC 96),
123

Med Chem Res (2012) 21:3263–3271
3269
Table 1 Diameters of zone of inhibition for compounds 5a–5g, 6a–6g, and 7a–7g
Compound
Diameter of zone of inhibition (mm) (n = 3)
S. aureus B. subtilis
P. aeruginosa
E. coli
Conc. (lg/ml)
50
100
200
300
50
100
200
300
50
100
200
300
50
100
200
300
5a
6
10
11
12
10
12
12
8
10
12
12
10
13
14
9
10
14
14
11
14
16
11
10
10
10
8
6
6
10
14
11
10
13
14
8
12
14
13
11
13
15
10
10
10
10
8
8
10
8
8
8
8
7
8
9
6
7
7
8
7
6
6
7
7
7
8
6
10
10
9
10
12
11
10
10
11
10
8
12
12
12
10
11
12
10
11
9
7
8
9
8
8
7
7
7
9
8
7
6
7
7
7
7
7
7
6
7
7
8
8
12
9
9
8
8
8
9
8
7
8
8
8
7
7
9
7
8
7
8
17
–
11
9
12
10
12
10
12
10
9
5b
10
10
8
10
8
12
10
10
12
12
8
5c
12
10
11
9
5d
9
9
5e
10
11
7
10
12
7
9
5f
10
9
5g
8
6a
5
8
9
5
8
9
8
10
10
7
12
9
6b
8
8
9
8
8
9
9
9
6c
6
8
9
7
8
8
7
8
10
9
9
6d
6
7
7
6
7
7
8
8
8
8
6e
8
9
10
9
10
10
8
8
9
10
10
7
11
11
7
8
8
9
9
9
6f
8
9
9
10
7
9
9
11
9
9
10
9
6g
6
6
7
6
7
8
9
7a
6
7
8
9
6
7
7
7
7
8
9
7
8
7b
7
8
8
9
7
8
8
9
7
7
8
8
8
7c
7
8
9
10
10
10
10
8
7
8
10
8
10
9
8
8
8
9
9
7d
8
9
9
6
7
8
9
10
9
8
9
7e
8
9
10
9
9
9
9
10
10
9
8
9
9
9
7f
8
9
8
9
9
8
9
9
8
8
7g
6
7
8
7
8
8
8
9
9
9
9
Standard
Control
14
–
15
–
15
–
–
–
–
–
–
–
–
–
–
–
–
–
Standard Ciprofloxacin; Control 8%v/v DMSO
– No activity
O
N
O
O
R
R
R
C
S
N
N
H
S
N
H
CH 2Cl
H
N
3-5
2a-c
O
O
OH
N
CH2
HN
N
R
R
R
S
N
S
N
S
N
(3-5) x
(3-5) y
(3-5) z
Scheme 2 Mechanism of formation and existence of 3,4, and 5 as tautomers
two gram negative bacteria viz. Escherichia coli (MTCC
739), Pseudomonas aeruginosa (MTCC 2453), and one
fungal strain viz. Candida albicans (MTCC 227) using cup
plate method (Indian Pharmacopoeia, 1996). Compounds
were used at concentrations of 50, 100, 200, and 300 lg/ml.
The derivatives showed significant activity against the
123

3270
Med Chem Res (2012) 21:3263–3271
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