Synthesis and antimicrobial screening of 4-thiazolidinone and 2-azetidinone derivatives of piperazine

Article abstract of DOI:10.1007/s00044-012-0063-5

The Schiff's bases 3a-3h were synthesized by reacting substituted/ unsubstituted aromatic aldehydes 2a-2h with 1-(2-aminoethyl)-piperazine 1. A series of novel aryl-3-(2-piperazin-1-ylethyl)-1,3-thiazolidin-4-one 4a-4h and 3-chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-arylazetidin-2-one 5a-5h were synthesized from the Schiff's bases of 1-(2-aminoethyl)-piperazine 3a-3h. The structures of synthesized compounds were confirmed by analytical (C, H, and N) and spectral (FT-IR, ¹H NMR, ¹³C NMR, and Mass) data. The compounds 4a-4h and 5a-5h were screened for antimicrobial activity. The compounds 4a, 4d, 4f, 4g, 5a, 5d, 5f, and 5g exhibited substantially significant antibacterial as well as antifungal activity.

Full text of DOI:10.1007/s00044-012-0063-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:699–706
DOI 10.1007/s00044-012-0063-5
ORIGINAL RESEARCH
Synthesis and antimicrobial screening of 4-thiazolidinone
and 2-azetidinone derivatives of piperazine
•
Sunil G. Shingade Sanjaykumar B. Bari
Received: 14 June 2011 / Accepted: 16 April 2012 / Published online: 27 April 2012
Ó Springer Science+Business Media, LLC 2012
Abstract The Schiff’s bases 3a–3h were synthesized
by reacting substituted/unsubstituted aromatic aldehydes
2a–2h with 1-(2-aminoethyl)-piperazine 1. A series of
novel aryl-3-(2-piperazin-1-ylethyl)-1,3-thiazolidin-4-one
4a–4h and 3-chloro-1-{2-[4-(chloroacetyl)piperazin-1-
yl]ethyl}-4-arylazetidin-2-one 5a–5h were synthesized
from the Schiff’s bases of 1-(2-aminoethyl)-piperazine 3a–
3h. The structures of synthesized compounds were con-
firmed by analytical (C, H, and N) and spectral (FT-IR, 1H
NMR, 13C NMR, and Mass) data. The compounds 4a–4h
and 5a–5h were screened for antimicrobial activity. The
compounds 4a, 4d, 4f, 4g, 5a, 5d, 5f, and 5g exhibited
substantially significant antibacterial as well as antifungal
activity.
Foroumadi et al., 2006, 2007; Tomar et al., 2007), anti-
plasmodial (Cunico et al., 2009; Martyn et al., 2010;
Ryckebusch et al., 2003, 2005), anti-inflammatory (Pa-
padopoulou et al., 2005), antioxidant (Kimura et al., 2004),
antihistaminic (Choo et al., 1999; Terzioglu et al., 2004;
Yoo et al., 2010), and antipsychotic activity (Bali et al.,
2009, 2010). The penicillins and cephalosporins are widely
used therapeutic agents against bacterial infection and
diseases. The antimicrobial activity of these compounds is
mainly associated with the b-lactam ring. They inhibit the
cell wall synthesis by binding with membrane-bound bac-
terial transpeptidase, also known as penicillin binding
proteins (PBP’s). The 2-azetidinones possess b-lactamase
inhibitory activity and hence became an attractive nucleus for
development of new antimicrobial agents. Numerous 2-aze-
tidinone derivatives were reported to exhibit antibacterial and
antifungal activity (Arnould et al., 1992; Halve et al., 2007;
Keri et al., 2009). The 4-thiazolidinones are of great interest
in diverse areas of medicinal chemistry because of their dif-
ferent pharmacological activities like antimicrobial (Vicini
et al., 2008), anti-HIV (Chen et al., 2009; Rao et al., 2004;
Rawal et al., 2005), anticancer (Abdel-Aziz et al., 2010; Lv
et al., 2010) and antihypertensive activity (Bhandari et al.,
2009).
Keywords Piperazine Á Schiff bases Á 4-Thiazolidinone Á
2-Azetidinone Á Antimicrobial activity
Introduction
Piperazine and substituted piperazine derivatives have been
found to possess diverse biological activities like antimi-
crobial (Chandra et al., 2006; Chaudhary et al., 2006;
Microbial infections are now a days more common than
during the first half of the century. Although, a number of
different classes of antibacterial and antifungal agents have
been discovered during last two decades the use is limited
due to development of microbial resistance. This situation
highlights the need for development of novel, potent, and
safe antimicrobial agents. Therefore, in continuation of our
studies on synthesis of 4-thiazolidinone and 2-azetidinone
heterocycles (Shingade et al., 2011), we were interested to
synthesize 4-thiazolidinone and 2-azetidinone derivatives
of piperazine with a view to find the antimicrobial efficacy.
S. G. Shingade (&) Á S. B. Bari
Department of Pharmaceutical Chemistry,
R. C. Patel Institute of Pharmaceutical Education & Research,
Shirpur, Dhule, Maharashtra 425 405, India
e-mail: sunilshingade@gmail.com
S. B. Bari
e-mail: sbbari@rediffmail.com
123

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Med Chem Res (2013) 22:699–706
Results and discussion
1,700–1,710 cm-1 for (C=O), and 735–760 cm-1 for (C–
Cl) in IR spectra. The formation of 2-azetidinone deriva-
tives 5a–5h was also supported by the presence of singlet
at d 4.12–4.78 for one proton of (CH–Cl) and a singlet at d
5.4–5.6 for one proton of (CH–Ar) in 1H NMR spectra and
peaks at d 60.7–62.8 for one carbon of (CH–Cl), d
54.2–61.2 for one carbon of (CH–Ar), and at d 166–166.7
for one carbon of (C=O b-lactam) in 13C NMR spectra.
Chemistry
The synthetic routes of compounds are outlined in Scheme 1.
The 1-(2-aminoethyl)-piperazine 1 was condensed with dif-
ferent substituted/unsubstituted aromatic aldehydes 2a–2h in
acetonitrile yielded the corresponding Schiff bases 3a–3h.
The Schiff bases 3a–3h, undergoes cyclization with thio-
glycolic acid in the presence of anhydrous ZnCl2 to afford
aryl-3-(2-piperazin-1-ylethyl)-1,3-thiazolidin-4-one 4a–4h.
The compound 3-chloro-1-{2-[4-(chloroacetyl)piperazin-1-
yl]ethyl}-4-arylazetidin-2-one 5a–5h were obtained by
cyclization of Schiff’s bases 3a–3h with chloroacetyl chlo-
ride in the presence of triethylamine (Et3N). The thiazolidi-4-
ones and azetidi-2-ones were formed by cycloaddition
mechanism (Soleiman, 2011).
Antimicrobial activity
All the synthesized compounds were screened for their
possible antibacterial and antifungal activities by deter-
mining MIC values in lg mL-1 against selected strains.
The MIC values were determined by broth dilution method
(Srinivas et al., 2006). The antibacterial and antifungal
activities (MIC) were determined using Ciprofloxacin and
Clotrimazole as standard control and the results are pre-
sented in Tables 1 and 2, respectively. The MIC values of
12 derivatives against tested organisms exhibited signifi-
cant activity with a degree of variation. The compound 4a,
4d, 4f, 4g, 5a, 5d, 5f, and 5g exhibited substantially sig-
nificant activity. The compound 4c, 4e, 5c, and 5e showed
significant activity, while compound 4b, 4h, 5b, and 5h are
found to be inactive against all screened strains of bacteria
and fungi.
The formation of Schiff bases 3a–3h were confirmed by
the presence of a band at 1,638–1,650 cm-1 for (N=CH) in
the IR spectrum, appearance of a singlet between d 8.4–8.8
for one proton of (N=CH) in the H NMR spectra and a
peak at d 160.7–163.9 for one carbon of (N=CH) in the 13
1
C
NMR spectra.
The appearance of band between 1,700 and 1,733 cm-1
for (C=O b-thialactam), singlets at d 3.25–3.9 for two
protons of (CH2 of thiazolidinone ring) and at d 5.0–5.5 for
one proton of (CH–Ar) and peaks at d 31.7–34.5 for one
carbon of (CH2 of thiazolidinone ring), at d 52.5–63.7 for
one carbon of (–CH–Ar), and at d 171–171.3 for one car-
Conclusion
bon of (C=O b-thialactam) in IR, H NMR, and 13C NMR
1
spectra, respectively, confirmed the formation of 4-thia-
zolidinone derivatives 4a–4h. The formation of 2-azetidi-
none derivatives 5a–5h was evidenced by the appearance
of a band at 1,720–1,740 cm-1 for (C=O b-lactam),
In the present study, we report a simple and highly effec-
tive method for synthesis of Schiff bases from 1-(2-ami-
noethyl)-piperazine, while the 4-thiazolidinones and
2-azetidinones were synthesized by conventional methods
Scheme 1 a 3-hydroxy-
Ar
NH2
S
4-methoxyphenyl, b
2-hydroxyphenyl, c
3-hydroxyphenyl, d
Ar
N
O
N
N
SHCH2COOH
anhy. ZnCl2
ACN
4-hydroxyphenyl, e phenyl,
Ar
CHO
+
N
f 4-hydroxy-3-methoxyphenyl,
g 4-methoxyphenyl, and
h 2-furan
N
N
H
N
H
1
2a-h
N
H
3a-h
4a-h
ClCH2COCl
Et3N
Cl
O
N
N
Cl
O
N
Ar
5a-h
123

Med Chem Res (2013) 22:699–706
701
Table 1 Antibacterial activity of the compounds: MIC in lg mL-1
Comp.
code
Name of microorganism (MIC in lg mL-1
)
B. S. M. S. S. P.
subtilis epidermidis luteus aureus hominis pumilus cereus vulgaris mirabilis typhi pneumonia coli aeruginosa
B.
B.
P.
P.
S.
K.
E.
4a
4b
4c
4d
4e
4f
9.37
75
9.37
75
9.37
150
9.37
150
9.37
75
9.37
150
37.5
9.37
75
4.68
75
9.37
150
9.37
150
9.37 4.68
75 75
9.37 9.37
75 75
37.5
4.68
37.5
9.37
9.37
75
18.75
9.37
75
18.75 37.5
37.5
9.37
37.5
9.37
4.68
75
18.75 37.5
18.75
9.37
37.5
9.37
9.37
150
18.75 37.5
9.37 9.37
18.75 37.5
9.37 9.37
4.68 9.37
37.5 37.5
4.68 9.37
37.5 37.5
9.37 9.37
9.37 9.37
9.37
75
9.37
37.5
9.37
9.37
150
9.37
75
9.37
37.5
9.37
4.68
150
4.68
18.75
9.37
9.37
150
9.37
9.37
300
9.37
150
18.75
9.37
37.5
9.37
4.68
75
4.68
9.37
75
9.37
9.37
150
9.37
75
4g
4h
5a
5b
5c
5d
5e
5f
75
4.68 9.37
75 150
150
75
75
4.68
150
18.75
9.37
75
4.68
75
9.37
150
37.5
9.37
9.37
150
9.37
75
9.37
75
9.37 9.37
150 75
18.75 37.5
9.37 9.37
37.5
9.37
18.75
9.37
9.37
75
37.5
9.37
18.75
4.68
37.5
9.37
18.75
9.37
9.37
150
37.5 37.5
9.37 9.37
37.5 37.5
4.68 9.37
9.37 9.37
18.75 37.5
4.68 9.37
37.5 18.75
9.37 4.68
4.68 9.37
18.75 18.75 37.5
18.75 37.5
9.37
9.37
150
4.68
9.37
150
9.37
9.37
150
9.37
4.68
75
9.37
9.37
75
9.37
9.37
75
5g
5h
150
75
75
150
Standarda 2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34 2.34
2.34 2.34
MIC minimum inhibitory concentration
a
Ciprofloxacin
Table 2 Antifungal activity of the compounds: MIC in lg mL-1
Comp. code Name of microorganism (MIC in lg mL-1
A. niger A. awamori C. albicans A. alternate M. canis R. solani T. longiformis F. solani T. viride A. flavus A. fumigatus
)
4a
18.75
300
9.37
300
37.5
18.75
75
9.37
150
18.75
150
9.37
300
9.37
150
18.75
300
18.75
300
18.75
300
9.37
150
9.37
150
4b
4c
37.5
18.75
75
37.5
9.73
37.5
18.75
9.73
300
75
37.5
18.75
37.5
18.75
18.75
300
37.5
18.75
37.5
18.75
9.73
150
37.5
9.73
75
75
37.5
18.75
75
37.5
18.75
75
37.5
9.37
37.5
18.75
9.73
150
4d
4e
18.75
75
9.73
37.5
9.73
18.75
300
4f
9.73
18.75
300
9.73
9.73
150
18.75
300
75
9.73
18.75
300
9.73
18.75
300
18.75
9.73
150
18.75
18.75
150
4g
4h
5a
18.75
300
18.75
300
9.73
300
18.75
300
18.75
300
9.73
300
18.75
300
18.75
300
18.75
300
18.75
300
5b
5c
37.5
9.37
75
37.5
18.75
75
37.5
18.75
37.5
18.75
9.37
150
75
37.5
9.37
75
75
37.5
18.75
75
37.5
9.37
75
75
75
5d
5e
9.37
75
9.37
75
18.75
37.5
9.37
9.37
300
9.37
75
9.37
75
5f
18.75
18.75
150
18.75
9.37
150
4.68
9.37
18.75
300
18.75
18.75
150
9.37
9.37
300
18.75
18.75
150
18.75
18.75
300
9.37
9.37
300
18.75
9.37
300
5g
5h
Standarda
2.34
2.34
1.17
4.68
2.34
4.68
4.68
2.34
2.34
4.68
MIC minimum inhibitory concentration
a
Clotrimazole
123

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Med Chem Res (2013) 22:699–706
reported previously. The activity data revealed that the
compounds 4a, 4d, 4f, 4g, 5a, 5d, 5f, and 5g having
electron releasing substitution at 4th position of the phenyl
ring exhibit good antibacterial as well as antifungal activ-
ity. The compounds 4c and 5c were having electron
releasing substituents at 3rd position of the phenyl ring and
the compounds 4e and 5e having phenyl ring exhibit
decreased but moderate activity. The compounds 4b, 4h,
5b, and 5h possessing electron releasing substituents at 2nd
position of phenyl ring and heterocyclic ring are found to
be inactive. In conclusion, the electron releasing sub-
stituent at the 4th position may enhance activity, while the
same substituent at 3rd position may decrease the activity
slightly. The electron releasing substituent at 2nd position
may completely decrease the antimicrobial activity.
(CH aliphatic), 1640 (C=N), 1249 (C–O–C); 1H NMR
(D2O) d in ppm: 2.0 (s, 1H), 2.3–2.4 (t, 4H), 2.6–2.7 (m,
4H), 2.8–2.9 (t, 2H), 3.6–3.7 (t, 2H), 3.9 (s, 3H), 7.2–7.3
(m, 2H), 7.4 (s, 1H), 8.7 (s, 1H), 9.8 (s, 1H); 13C NMR
(D2O) d in ppm: 160.9, 152.4, 147.2, 133.9, 123.0, 115.1,
112.3, 59.7, 57.2, 54.9, 52.7, 45.9. Anal. Calcd. for
C14H21N3O2: C: 63.85, H: 8.04, N: 15.96; Found: C: 63.10,
H: 7.85, N: 16.09 %.
2-{[(2-Piperazin-1-ylethyl)imino]methyl}phenol (3b)
Yield 78 %; m. p. 130 °C. IR (KBr, cm-1): 3390 (OH),
3267 (NH), 2958 (CH aromatic), 2837 (CH aliphatic), 2735
(CH aliphatic), 1635 (C=N); 1H NMR (D2O) d in ppm: 1.9
(s, 1H), 2.3–2.4 (t, 4H), 2.6–2.7 (m, 6H), 3.6–3.7 (t, 2H),
7.1–7.2 (m, 2H), 7.5–7.6 (t, 1H), 7.7–7.8 (d, 1H), 8.5 (s,
1H), 11.2 (s, 1H); 13C NMR (D2O) d in ppm: 161.3, 157.7,
132.9, 131.0, 124.6, 121.5, 117.8, 59.5, 54.6, 52.7, 46.2.
Anal. Calcd. for C13H19N3O: C: 66.92, H: 8.21, N: 18.01;
Found: C: 67.08, H: 8.15, N: 17.60 %.
Experimental protocols
General
The 1-(2-aminoethyl)-piperazine was procured from Sigma
Aldrich, India. All other reagents and solvents used in
study are of analytical grade and have been procured
locally. The progress of the reaction is monitored by TLC
and the products are purified through recrystallization. The
melting points (m.p.) were determined in one-end-open
capillary method and are uncorrected. IR spectra were
recorded on Shimadzu FT-IR 8400-S spectrophotometer
using potassium bromide (KBr) pellet. The 1H NMR
spectra were acquired on Varian AMX 300 NMR instru-
ment using D2O or DMSO-d6 as the solvent and TMS as
the internal reference (chemical shifts in d, ppm); 13C
NMR was performed on Varian AMX 300 (100 MHz)
spectrometer using solutions in D2O or DMSO-d6 and mass
spectra were acquired on API 2000 spectrometer. The
elemental analysis (C, H, and N) of compounds was per-
formed on Elementar Vario EL III elemental analyzer.
3-{[(2-Piperazin-1-ylethyl)imino]methyl}phenol (3c)
Yield 85 %; m. p. 180–182 °C. IR (KBr, cm-1): 3390
(OH), 3215 (NH), 3055 (CH aromatic), 2821 (CH ali-
phatic), 2673 (CH aliphatic), 1640 (C=N); 1H NMR (D2O)
d in ppm: 2.0 (s, 1H), 2.35–2.5 (t, 4H), 2.7–2.9 (m, 6H),
3.7–3.8 (t, 2H), 7.0–7.1 (d, 1H), 7.3–7.45 (m, 2H), 7.62 (s,
1H), 8.72 (s, 1H), 9.47 (s, 1H); 13C NMR (D2O) d in ppm:
160.8, 158.4, 141.0, 130.2, 121.9, 118.3, 114.9, 59.6, 54.9,
52.8, 46.2. Anal. Calcd. for C13H19N3O: C: 66.92, H: 8.21,
N: 18.01; Found: C: 66.97, H: 8.19, N: 17.90 %.
4-{[(2-Piperazin-1-ylethyl)imino]methyl}phenol (3d)
Yield 92 %; m. p. 162 °C. IR (KBr, cm-1): 3400 (OH),
3200 (NH), 3010 (CH aromatic), 2860 (CH aliphatic), 2845
(CH aliphatic), 1638 (C=N); 1H NMR (D2O) d in ppm: 1.9
(s, 1H), 2.3–2.4 (t, 4H), 2.6–2.7 (m, 6H), 3.6–3.7 (t, 2H),
6.76–6.9 (d, 2H), 7.6–7.8 (d, 2H), 8.7 (s, 1H), 10.2 (s, 1H);
13C NMR (D2O) d in ppm: 162.1, 160.5, 130.8, 129.1,
116.0, 59.8, 55.2, 53.5, 46.3. Anal. Calcd. for C13H19N3O:
C: 66.92, H: 8.21, N: 18.01; Found: C: 67.00, H: 7.93, N:
18.10 %.
General procedure for synthesis of N-
(arylmethylidene)-2-piperazin-1-ylethanamine (3a–h)
Equimolar quantities of 1-(2-aminoethyl)-piperazine (1, 0.1
mol) and the substituted/unsubstituted aromatic aldehydes
(2a–2h, 0.1 mol) in acetonitrile were stirred for half an hour.
The product thus obtained was filtrated and purified by
washing with acetonitrile to afford compounds (3a–h).
N-[phenylmethylidene]-2-piperazin-1-ylethanamine (3e)
Yield 88 %; m. p. 170–172 °C. IR (KBr, cm-1): 3200
(NH), 3012 (CH aromatic), 2924 (CH aliphatic), 2850 (CH
2-Methoxy-5-{[(2-piperazin-1-ylethyl)imino]methyl}phenol
(3a)
1
aliphatic), 1639 (C=N); H NMR (D2O) d in ppm: 2.0 (s,
1H), 2.35–2.5 (t, 4H), 2.6–2.8 (m, 6H), 3.6–3.75 (t, 2H),
7.37–7.48 (t, 2H), 7.6–7.72 (t, 1H), 7.9–8.0 (d, 2H), 8.8 (s,
1H); 13C NMR (D2O) d in ppm: 160.9, 136.4, 132.1, 130.5,
Yield 89 %; m. p. 158 °C. IR (KBr, cm-1): 3390 (OH),
3225 (NH), 3043 (CH aromatic), 2962 (CH aliphatic), 2825
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Med Chem Res (2013) 22:699–706
703
128.7, 59.6, 54.8, 53.1, 46.5. Anal. Calcd. for C13H19N3: C:
71.85, H: 8.81, N: 19.34; Found: C: 71.60, H: 8.50, N:
19.60 %.
1H), 2.3–2.4 (t, 4H), 2.6–2.76 (m, 4H), 2.8–2.9 (t, 2H),
3.25 (s, 2H), 3.6–3.7 (t, 2H), 3.9 (s, 3H), 5.4 (s, 1H),
6.85–6.95 (s, 1H), 7.3–7.4 (m, 2H), 9.83 (s, 1H); 13C NMR
(DMSOd6) d in ppm: 171.2, 148.5, 147.0, 132.8, 122.1,
114.9, 112.7, 63.7, 55.8, 54.2, 46.3, 42.2, 36.9, 33.9. Anal.
Calcd. For C16H23N3O3S: C: 56.95, H 6.87, N 12.45, S
9.50; Found: C: 56.87, H 6.95, N 12.56, S 9.43 %. MS:
[M]? at m/z 337.
2-Methoxy-4-{[(2-piperazin-1-ylethyl)imino]methyl}phenol
(3f)
Yield 75 %; m. p. 148 °C. IR (KBr, cm-1): 3400 (OH),
3225 (NH), 3043 (CH aromatic), 2962 (CH aliphatic), 2825
(CH aliphatic), 1640 (C=N), 1270 (C–O–C); 1H NMR
(D2O) d in ppm: 2.0 (s, 1H), 2.3–2.4 (t, 4H), 2.6–2.7 (m,
4H), 2.8–2.9 (t, 2H), 3.6–3.7 (t, 2H), 3.9 (s, 3H), 7.15–7.27
(d, 2H), 7.52 (s, 1H), 8.7 (s, 1H), 11.3 (s, 1H); 13C NMR
(D2O) d in ppm: 160.7, 151.2, 149.5, 133.5, 122.9, 117.3,
112.2, 59.3, 57.4, 55.1, 53.3, 46.4. Anal. Calcd. for
C14H21N3O2: C: 63.85, H: 8.04, N: 15.96; Found: C: 63.56,
H: 7.94, N: 16.10 %.
2-(2-Hydroxyphenyl)-3-(2-piperazin-1-ylethyl)-1,3-
thiazolidin-4-one (4b)
Yield 68 % (ethanol); m. p. 284–285 °C. IR (KBr, cm-1):
3400 (OH), 3200 (NH), 2958 (CH aromatic), 2837 (CH
aliphatic), 2735 (CH aliphatic), 1728 (C=O), 700 (C–S–C);
1H NMR (DMSOd6) d in ppm: 1.85–2.0 (s, 1H), 2.3–2.4 (t,
4H), 2.6–2.73 (m, 6H), 3.25–3.3 (s, 2H), 3.6–3.7 (t, 2H),
5.3 (s, 1H), 7.05–7.2 (m, 2H), 7.5-7.6 (t, 1H), 7.68–7.78 (d,
1H), 11.2 (s, 1H); 13C NMR (DMSOd6) d in ppm: 171.2,
153.8, 130.1, 128.6, 124.2, 121.3, 116.1, 54.9, 52.5, 46.4,
42.2, 36.8, 33.9. Anal. Calcd. For C15H21N3O2S: C: 58.61,
H 6.89, N 13.67, S 10.43; Found: C: 58.67, H 7.05, N
13.59, S 10.36 %. MS: [M]? at m/z 307.
N-[(4-methoxyphenyl)methylidene]-2-piperazin-1-
ylethanamine (3g)
B. P. 210 °C. IR (KBr, cm-1): 3275 (NH), 3072 (CH
aromatic), 2955 (CH aliphatic), 2839 (CH aliphatic), 1645
1
(C=N), 1253 (C–O–C); H NMR (D2O) d in ppm: 1.9 (s,
1H), 2.3–2.4 (t, 4H), 2.5–2.72 (m, 6H), 3.4–3.52 (t, 2H),
3.9 (s, 3H), 7.55–7.65 (d, 2H), 7.8–7.9 (d, 2H), 8.8 (s, 1H);
13C NMR (D2O) d in ppm: 162.7, 160.8, 130.2, 128.3,
114.5, 59.2, 56.9, 55.0, 53.1, 46.2. Anal. Calcd. for
C14H21N3O: C: 67.98, H: 8.56, N: 16.99; Found: C: 68.15,
H: 8.35, N: 16.88 %.
2-(3-Hydroxyphenyl)-3-(2-piperazin-1-ylethyl)-1,3-
thiazolidin-4-one (4c)
Yield 86 % (methanol); m. p. 158 °C. IR (KBr, cm-1):
3390 (OH), 3215 (NH), 3055 (CH aromatic), 2943 (CH
aliphatic), 2821 (CH aliphatic), 1700 (C=O), 680 (C–S–C);
1H NMR (DMSOd6) d in ppm: 1.95–2.1 (s, 1H), 2.3–2.45
(t, 4H), 2.7–2.9 (m, 6H), 3.35–3.45 (t, 2H), 3.7 (s, 2H),
7.02–7.1 (d, 2H), 7.15–7.25 (d, 1H), 7.35 (s, 1H), 7.6–7.7
(t, 1H), 9.35 (s, 1H); 13C NMR (DMSOd6) d in ppm: 171.3,
156.9, 140.6, 130.0, 119.6, 116.3, 114.5, 64.1, 54.8, 46.2,
42.2, 37.1, 34.2. Anal. Calcd. For C15H21N3O2S: C: 58.61,
H 6.89, N 13.67, S 10.43; Found: C: 58.55, H 6.78, N
13.61, S 10.49 %. MS: [M]? at m/z 307.
N-[furan-2-ylmethylidene]-2-piperazin-1-ylethanamine
(3h)
B. P. 178 °C. IR (KBr, cm-1): 3270 (NH), 3020 (CH aro-
matic), 2935 (CH aliphatic), 2812 (CH aliphatic), 1650
(C=N), 1155 (C–O–C); 1H NMR (D2O) d in ppm: 1.9 (s, 1H),
2.3–2.4 (t, 4H), 2.5–2.72 (m, 6H), 3.4–3.52 (t, 2H), 6.5–6.65
(t, 1H), 6.9–7.02 (d, 1H), 7.7–7.8 (d, 1H), 8.4 (s, 1H); 13C
NMR (D2O) d in ppm: 163.9, 149.2, 144.5, 119.0, 112.4,
59.2, 54.8, 50.7, 46.6. Anal. Calcd. for C11H17N3O: C: 63.74,
H: 8.27, N: 20.27; Found: C: 63.83, H: 7.90, N: 20.10 %.
2-(4-Hydroxyphenyl)-3-(2-piperazin-1-ylethyl)-1,3-
thiazolidin-4-one (4d)
Yield 79 % (methanol); m. p. 208–210 °C. IR (KBr,
cm-1): 3400 (OH), 3200 (NH), 3044 (CH aromatic), 2960
(CH aliphatic), 2845 (CH aliphatic), 1705 (C=O), 660 (C–
Synthesis of 2-aryl-3-(2-piperazin-1-ylethyl)-1,3-
thiazolidin-4-one (4a–h) (Shingade et al., 2011)
1
S–C); H NMR (DMSOd6) d in ppm: 1.85–1.97 (s, 1H),
2-(3-Hydroxy-4-methoxyphenyl)-3-(2-piperazin-1-ylethyl)-
1,3-thiazolidin-4-one (4a)
2.3–2.4 (t, 4H), 2.6–2.72 (m, 6H), 3.48 (s, 2H), 3.6–3.7 (t,
2H), 5.0 (s, 1H), 6.76–6.88 (d, 2H), 7.6-7.75 (d, 2H), 10.1-
10.3 (s, 1H); 13C NMR (DMSOd6) d in ppm: 171.3, 158.0,
136.4, 130.7, 115.9, 63.5, 54.8, 46.5, 42.4, 37.1, 34.5. Anal.
Calcd. For C15H21N3O2S: C: 58.61, H 6.89, N 13.67, S
10.43; Found: C: 58.56, H 6.79, N 13.57, S 10.39 %. MS:
[M]? at m/z 307.
Yield 73 % (ethanol); m. p. 185 °C. IR (KBr, cm-1): 3390
(OH), 3225 (NH), 3043 (CH aromatic), 2962 (CH ali-
phatic), 2825 (CH aliphatic), 1733 (C=O), 1271 (C–O–C),
1
710 (C–S–C); H NMR (DMSOd6) d in ppm: 1.9–2.1 (s,
123

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Med Chem Res (2013) 22:699–706
2-Phenyl-3-(2-piperazin-1-ylethyl)-1,3-thiazolidin-4-one
(4e)
NMR (DMSOd6) d in ppm: 1.85–1.97 (s, 1H), 2.3–2.4 (t,
4H), 2.5–2.73 (m, 6H), 3.3 (s, 2H), 3.4–3.55 (t, 2H), 5.2 (s,
1H), 6.2–6.3 (d, 1H), 6.4–6.5 (t, 1H), 7.6–7.7 (d, 1H); 13C
NMR (DMSOd6) d in ppm: 171.3, 151.6, 142.2, 110.5,
107.1, 55.4, 53.6, 46.3, 39.8, 36.4, 31.7. Anal. Calcd. For
C13H19N3O2S: C: 55.49, H 6.81, N 14.93, S 11.40; Found:
C: 55.56, H 6.88, N 15.00, S 11.32 %. MS: [M]? at m/
z 281.
Yield 81 % (ethanol); m. p. 265–266 °C. IR (KBr, cm-1):
3205 (NH), 3060 (CH aromatic), 2924 (CH aliphatic), 2850
(CH aliphatic), 1700 (C=O), 680 (C–S–C); 1H NMR
(DMSOd6) d in ppm: 1.95–2.05 (s, 1H), 2.35–2.47 (t, 4H),
2.6–2.8 (m, 6H), 3.65 (s, 2H), 3.7–3.82 (t, 2H), 5.2 (s, 1H),
7.35-7.47 (t, 1H), 7.6–7.72 (t, 2H), 7.9–8.0 (d, 2H); 13C
NMR (DMSOd6) d in ppm: 171.0, 144.1, 130.6, 127.7,
126.8, 63.7, 54.7, 46.1, 42.3, 36.7, 34.1. Anal. Calcd. For
C15H21N3OS: C: 61.82, H 7.26, N 14.42, S 11.00; Found:
C: 61.75, H 7.31, N 14.50, S 10.94 %. MS: [M]? at m/
z 291.
Synthesis of 3-chloro-1-{2-[4-(chloroacetyl)piperazin-
1-yl]ethyl}-4-arylazetidin-2-one (5a–h)
To a stirred solution of N-[(1)-arylmethylidene]-2-piper-
azin-1-ylethanamine (3a–h, 0.1 mol) in dioxan (100 mL),
chloroacetylchloride (0.2 mol) was added dropwise at
0–5 °C temperature in the presence of triethylamine. The
reaction mixture was stirred for about 8 h and the precip-
itate of amine hydrochloride was filtered off. The excess of
dioxan was distilled off. The mass thus obtained was
cooled, poured in ice-cold water, filtered, washed, dried,
and recrystallized from appropriate solvents to furnish
compounds 5a–h.
2-(4-Hydroxy-3-methoxyphenyl)-3-(2-piperazin-1-ylethyl)-
1,3-thiazolidin-4-one (4f)
Yield 59 % (ethanol); m. p. 124–126 °C. IR (KBr, cm-1):
3400 (OH), 3220 (NH), 3045 (CH aromatic), 2960 (CH
aliphatic), 2830 (CH aliphatic), 1710 (C=O), 1260 (C–O–
C), 700 (C–S–C); 1H NMR (DMSOd6) d in ppm: 1.95–2.05
(s, 1H), 2.3–2.4 (t, 4H), 2.6–2.8 (m, 6H), 3.3 (s, 2H),
3.6–3.7 (t, 2H), 3.9 (s, 3H), 5.4 (s, 1H), 7.05–7.18 (d, 1H),
7.3–7.4 (d, 1H), 7.54 (s, 1H), 11.18 (s, 1H); 13C NMR
(DMSOd6) d in ppm: 171.2, 149.2, 147.3, 132.7, 122.4,
116.2, 114.3, 63.7, 56.2, 54.1, 46.3, 42.1, 36.8, 33.7. Anal.
Calcd. For C16H23N3O3S: C: 56.95, H 6.87, N 12.45, S
9.50; Found: C: 57.00, H 6.81, N 12.49, S 9.58 %. MS:
[M]? at m/z 337.
3-Chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-(3-
hydroxy-4-methoxyphenyl)azetidin-2-one (5a)
Yield 72 % (ethanol); m. p. 215 °C. IR (KBr, cm-1): 3400
(OH), 3020 (CH aromatic), 2970 (CH aliphatic), 2800 (CH
aliphatic), 1735, 1705 (C=O), 1265 (C–O–C), 750 (C–Cl);
1H NMR (DMSOd6) d in ppm: 2.4–2.5 (t, 4H), 2.6–2.7
(t, 2H), 3.18–3.3 (t, 2H), 3.4–3.5 (t, 4H), 3.92 (s, 3H), 4.13
(s, 2H), 4.67–4.75 (d, 1H), 5.6 (s, 1H), 7.08–7.15 (m, 2H),
7.4 (s, 1H), 9.4–9.6 (s, 1H); 13C NMR (DMSOd6) d in ppm:
166.4, 164.5, 148.4, 146.3, 132.0, 120.5, 114.7, 112.8,
62.8, 61.2, 56.3, 54.1, 46.9, 45.3, 41.1, 37.4. Anal. Calcd.
For C18H23Cl2N3O4: C: 56.69, H 3.08, N 11.67; Found: C:
56.60, H 2.98, N 11.56 %. MS: [M]? at m/z 415.
2-(4-Methoxyphenyl)-3-(2-piperazin-1-ylethyl)-1,3-
thiazolidin-4-one (4g)
Yield 88 % (ethanol); m. p. 248–250 °C. IR (KBr, cm-1):
3285 (NH), 3072 (CH aromatic), 2955 (CH aliphatic), 2839
(CH aliphatic), 1700 (C=O), 1253 (C–O–C), 710 (C–S–C);
1H NMR (DMSOd6) d in ppm: 1.85–1.97 (s, 1H), 2.3–2.4
(t, 4H), 2.5–2.73 (m, 6H), 3.3 (s, 2H), 3.4–3.55 (t, 2H), 3.9
(s, 3H), 5.47 (s, 1H), 7.55–7.65 (d, 2H), 7.8–7.9 (d, 2H);
13C NMR (DMSOd6) d in ppm: 171.2, 159.2, 136.3, 129.6,
114.0, 63.5, 56.6, 54.7, 46.3, 42.2, 36.9, 34.1. Anal. Calcd.
For C16H23N3O2S: C: 59.78, H 7.21, N 13.07, S 9.98;
Found: C: 59.83, H 7.14, N 13.00, S 10.05 %. MS: [M]? at
m/z 321.
3-Chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-(2-
hydroxyphenyl)azetidin-2-one (5b)
Yield 84 % (ethanol); m. p. 208–210 °C. IR (KBr, cm-1):
3390 (OH), 3040 (CH aromatic), 2960 (CH aliphatic), 2830
1
(CH aliphatic), 1730, 1710 (C=O), 745 (C–Cl); H NMR
(DMSOd6) d in ppm: 2.3–2.4 (t, 4H), 2.5–2.62 (t, 2H), 3.1-
3.2 (t, 2H), 3.38–3.5 (t, 4H), 4.15 (s, 2H), 4.7–4.8 (d, 1H),
5.57 (s, 1H), 7.1–7.24 (m, 2H), 7.36–7.5 (m, 2H), 9.65 (s,
1H); 13C NMR (DMSOd6) d in ppm: 166.7, 164.6, 155.0,
129.3, 127.4, 125.7, 121.3, 115.8, 62.7, 56.2, 54.2, 46.4,
44.5, 40.8, 37.4. Anal. Calcd. For C17H21Cl2N3O3: C:
52.86, H 5.48, N 10.88; Found: C: 52.90, H 5.42, N
10.92 %. MS: [M]? at m/z 385.
2-Furan-2-yl-3-(2-piperazin-1-ylethyl)-1,3-thiazolidin-4-
one (4h)
Yield 63 % (methanol); m. p. 138oC. IR (KBr, cm-1): 3124
(NH), 3065 (CH aromatic), 2935 (CH aliphatic), 2818 (CH
1
aliphatic), 1705 (C=O), 1155 (C–O–C), 756 (C–S–C); H
123

Med Chem Res (2013) 22:699–706
705
3-Chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-(3-
hydroxyphenyl)azetidin-2-one (5c)
2H), 4.6–4.7 (d, 1H), 5.4 (s, 1H), 7.2-7.32 (m, 2H), 7.7 (s,
1H), 11.02 (s, 1H); 13C NMR (DMSOd6) d in ppm: 166.5,
164.6, 149.1, 147.2, 132.1, 120.3, 115.5, 111.2, 62.6, 61.0,
56.4, 54.0, 47.7, 45.8, 41.2, 37.4. Anal. Calcd. For
C18H23Cl2N3O4: C: 51.93, H 5.57, N 10.09; Found: C:
52.00, H 5.51, N 10.02 %. MS: [M]? at m/z 415.
Yield 72 % (ethanol); m. p. 222–224 °C. IR (KBr, cm-1):
3380 (OH), 3035 (CH aromatic), 2950 (CH aliphatic), 2800
1
(CH aliphatic), 1725, 1700 (C=O), 760 (C–Cl); H NMR
(DMSOd6) d in ppm: 2.39–2.5 (t, 4H), 2.6–2.7 (t, 2H),
3.18–3.27 (t, 2H), 3.4–3.5 (t, 4H), 4.13 (s, 2H), 4.68–4.76
(d, 1H), 5.6 (s, 1H), 7.08–7.16 (d, 1H), 7.2–7.3 (d, 1H), 7.4
(s, 1H), 7.65–7.74 (t, 1H), 9.5 (s, 1H); 13C NMR
(DMSOd6) d in ppm: 166.0, 164.4, 156.8, 139.7, 129.9,
120.3, 115.2, 113.7, 62.3, 60.9, 54.0, 46.9, 45.3, 40.8, 37.4.
Anal. Calcd. For C17H21Cl2N3O3: C: 52.86, H 5.48, N
10.88; Found: C: 52.91, H 5.55, N 10.85 %. MS: [M]? at
m/z 385.
3-Chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-(4-
methoxyphenyl)azetidin-2-one (5g)
Yield 78 % (ethanol); m. p. 166–168 °C. IR (KBr, cm-1):
3040 (CH aromatic), 2950 (CH aliphatic), 2840 (CH ali-
phatic), 1735, 1705 (C=O), 1250 (C–O–C), 760 (C–Cl); 1H
NMR (DMSOd6) d in ppm: 2.39–2.49 (t, 4H), 2.6–2.7 (t,
2H), 3.17-3.3 (t, 2H), 3.4–3.5 (t, 4H), 3.93 (s, 3H), 4.23 (s,
2H), 4.6-4.72 (d, 1H), 5.4 (s, 1H), 7.2–7.3 (d, 2H),
7.45–7.55 (d, 2H); 13C NMR (DMSOd6) d in ppm: 166.5,
164.3, 158.7, 130.8, 127.7, 114.1, 62.3, 60.6, 55.9, 53.8,
47.1, 45.2, 40.9, 37.2. Anal. Calcd. For C18H23Cl2N3O3: C:
54.01, H 5.79, N 10.50; Found: C: 53.96, H 5.71, N
10.56 %. MS: [M]? at m/z 399.
3-Chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-(4-
hydroxyphenyl)azetidin-2-one (5d)
Yield 75 % (ethanol); m. p. 258–260 °C. IR (KBr, cm-1):
3400 (OH), 3030 (CH aromatic), 2965 (CH aliphatic), 2850
1
(CH aliphatic), 1730, 1705 (C=O), 740 (C–Cl); H NMR
(DMSOd6) d in ppm: 2.4–2.5 (t, 4H), 2.6–2.7 (t, 2H), 3.18-
3.28 (t, 2H), 3.4–3.5 (t, 4H), 4.13 (s, 2H), 4.6–4.7 (d, 1H),
5.4 (s, 1H), 7.1–7.2 (d, 2H), 7.4–7.5 (d, 2H), 9.5 (s, 1H);
13C NMR (DMSOd6) d in ppm: 166.7, 164.3, 157.1, 130.8,
128.0, 115.9, 62.5, 61.0, 54.0, 46.6, 44.7, 40.9, 37.3. Anal.
Calcd. For C17H21Cl2N3O3: C: 52.86, H 5.48, N 10.88;
Found: C: 52.81, H 5.54, N 10.81 %. MS: [M]? at m/z 385.
3-Chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-
furan-2-ylazetidin-2-one (5h)
Yield 81 % (methanol); m. p. 154–155 °C. IR (KBr,
cm-1): 3030 (CH aromatic), 2940 (CH aliphatic), 2800
(CH aliphatic), 1720, 1700 (C=O), 1270 (C–O–C), 740 (C–
Cl); 1H NMR (DMSOd6) d in ppm: 2.32–2.43 (t, 4H),
2.53–2.62 (t, 2H), 3.1–3.2 (t, 2H), 3.4–3.5 (t, 4H), 4.16 (s,
2H), 4.7-4.78 (d, 1H), 5.43 (s, 1H), 6.4–6.56 (m, 2H),
7.6–7.7 (d, 1H); 13C NMR (DMSOd6) d in ppm: 166.3,
164.5, 151.1, 141.4, 111.0, 109.2, 60.7, 58.4, 53.9, 46.5,
43.0, 40.9, 36.6. Anal. Calcd. For C15H19Cl2N3O3: C:
50.01, H 5.32, N 11.66; Found: C: 49.95, H 5.28, N
11.57 %. MS: [M]? at m/z 359.
3-Chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-
phenylazetidin-2-one (5e)
Yield 90 % (ethanol); m. p. 91–93 °C. IR (KBr, cm-1):
3030 (CH aromatic), 2930 (CH aliphatic), 2860 (CH ali-
phatic), 1725, 1700 (C=O), 735 (C–Cl); 1H NMR
(DMSOd6) d in ppm: 2.4–2.5 (t, 4H), 2.6–2.7 (t, 2H),
3.2–3.29 (t, 2H), 3.4–3.5 (t, 4H), 4.12 (s, 2H), 4.6–4.7 (d,
1H), 5.4 (s, 1H), 7.22–7.34 (t, 1H), 7.48–7.6 (t, 2H),
7.78–7.85 (d, 2H); 13C NMR (DMSOd6) d in ppm: 166.4,
164.3, 138.4, 130.8, 128.9, 127.1, 62.4, 60.8, 54.2, 47.0,
45.4, 40.8, 37.6. Anal. Calcd. For C17H21Cl2N3O2: C:
55.14, H 5.72, N 11.35; Found: C: 55.19, H 5.80, N
11.31 %. MS: [M]? at m/z 369.
Antibacterial and antifungal activity (MIC-minimum
inhibitory concentration)
The microbial strains were procured from the National
Chemical Laboratory (NCL), Pune, India. The synthesized
compounds were screened against the following bacterial
strains: Bacillus subtilis ATCC 6633, Staphylococcus epi-
dermidis ATCC 12228, Micrococcus luteus ATCC 4698,
Staphylococcus aureus ATCC 25923, Staphylococcus
hominis ATCC 27844, Bacillus pumilus ATCC 14884,
Bacillus cereus ATCC 11778, Proteus vulgaris ATCC
13315, Proteus mirabilis ATCC 49565, Salmonella typhi
ATCC 19430, Klebsiella pneumonia ATCC 13883, Esch-
erichia coli ATCC 25922, and Pseudomonas aeruginosa
ATCC 10145.
3-Chloro-1-{2-[4-(chloroacetyl)piperazin-1-yl]ethyl}-4-(4-
hydroxy-3-methoxyphenyl)azetidin-2-one (5f)
Yield 69 % (methanol); m. p. 175 °C. IR (KBr, cm-1):
3390 (OH), 3040 (CH aromatic), 2950 (CH aliphatic), 2840
(CH aliphatic), 1740, 1705 (C=O), 1270 (C–O–C), 750 (C–
Cl); 1H NMR (DMSOd6) d in ppm: 2.4–2.5 (t, 4H), 2.6–2.7
(t, 2H), 3.2–3.3 (t, 2H), 3.4–3.5 (t, 4H), 3.8 (s, 3H), 4.13 (s,
123

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Med Chem Res (2013) 22:699–706
of levofloxacin derivatives with certain bulky residues on
piperazine ring. Eur J Med Chem 42:985–992
The synthesized compounds were also screened against
the following fungal strains: Aspergillus niger ATCC 9142,
Aspergillus awamori ATCC 22342, Candida albicans
ATCC 10231, Alternaria alternate ATCC 66868, Micros-
porum canis ATCC 11622, Rhizoctonia solani ATCC
76131, Trichophyton longiformis ATCC 22397, Aspergil-
lus flavus ATCC 15517, Fusarium solani ATCC 38136,
and Trichoderma viride ATCC 52440.
Halve AK, Bhadauria D, Dubey R (2007) N/C-4 substituted azetidin-
2-ones: synthesis and preliminary evaluation as new class of
antimicrobial agents. Bio Med Chem Lett 17:341–345
Keri RS, Hosamani KM, Shingalapur RV, Reddy HRS (2009)
2-Azetidinone derivatives: design, synthesis, in vitro anti-
microbial, cytotoxic activities and DNA cleavage study. Eur J
Med Chem 44:5123–5130
Kimura M, Masuda T, Yamada K, Kawakatsu N, Kubota N, Mitani
M, Kishii K, Inazu M, Kiuchi Y, Oguchid K, Namikia T (2004)
Antioxidative activities of novel diphenylalkyl piperazine deriv-
atives with high affinities for the dopamine transporter. Bio Med
Chem Lett 14:4287–4290
Lv P, Zhou CF, Chen J, Liu PG, Wang KR, Mao WJ, Li HQ, Yang Y,
Xiong J, Zhu HL (2010) Design, synthesis and biological
evaluation of thiazolidinone derivatives as potential EGFR and
HER-2 kinase inhibitors. Bio Med Chem 18:314–319
Martyn DC, Cortese JF, Tyndall E, Dick J, Mazitschek R, Munoz B,
Clardy J (2010) Antiplasmodial activity of piperazine sulphona-
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The minimum inhibitory concentration was done by broth
dilution method (Shingade et al., 2011; Srinivas et al., 2006).
Acknowledgments Sunil G. Shingade is thankful to UGC New
Delhi, India for the award of J. R. F.; Rajiv Gandhi National Junior
Research Fellowship and financial support for this work.
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