Synthesis of some 2-Thioxo-imidazolidin-4-one derivatives and its antimicrobial activity

Article abstract of DOI:10.1155/2010/292461

Series of newly prepared 3-{[2,6-bis(4-substituted phenyl)-1-methylpiperidin-4-ylidene] amino}-2-thioxo-imidazolidin-4-one derivatives (3a-3f) have been synthesized by the cyclization of compound (2a-2f), ethyl chloro acetate and fused sodium acetate. The

Full text of DOI:10.1155/2010/292461

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2010, 7(4), 1320-1325
http://www.e-journals.net
Synthesis of Some 2-Thioxo-imidazolidin-4-one
Derivatives and its Antimicrobial Activity
A. JAMAL ABDUL NASSER§*, A.IDHAYADHULLA§,
R.SURENDRA KUMAR§ and J.SELVIN
§P.G & Research Department of Chemistry,
Jamal Mohamed College, Tiruchirapalli-620020, Tamilnadu, India.
Department of Microbiology, Bharathidasan University,
Tiruchirapalli-620024, Tamilnadu, India.
idhaya25chem@yahoo.co.in
Received 26 March 2009; Revised 8 June 2009; Accepted 2 August 2009
Abstract: Series of newly prepared 3-{[2,6-bis(4-substituted phenyl)-1-
methylpiperidin-4- ylidene] amino}- 2-thioxo-imidazolidin-4-one derivatives (3a-
3f) have been synthesized by the cyclization of compound (2a-2f), ethyl chloro
acetate and fused sodium acetate. The chemical structures were confirmed
1
by IR, H NMR and elemental analysis. The synthesized compounds were screened
for their antimicrobial activity against four antibacterial and four antifungal organisms.
Keywords: 2,6-Diphenylpiperidine-4-one, 2-Thioxo-imidazolidin-4-one, Antimicrobial activity.
Introduction
Hydantoins [imidazolidin-2,4–dione and 2-thioxo–imidazolin-4-one] are belongs to
heterocyclic compound, which has a wide range of biological and pharmacological
properties such as antimicrobial activity (antifungal, antibacterial)¹, antitumor², anti-
inflammatry², anti HIV³, anti-hypertensive4, hydantoin exhibits diverse biological activities,
such as anticonvulsant5, antifungal activities6, antithyroidal7, antiviral8, anti HIV9, tuber
culosis10, anti arrhythmic11 and anti convulsant12.
Many piperidine derivatives are found possessing pharmacological activities like
anaesthetic activity14 and antimicrobial activity15. 2–Thioxo-imidazolindin-4-one was
prepared from the reaction of aromatic aldehydes and thiosemicarbazide to give alkyl
thiosemicarbazone followed by cyclization with ethyl chloroacetate in the presence of fused
sodium acetate13. Above method was followed in the present study, thiosemicarbazide react
with 2,6-diphenyl piperidin-4-one to give 2,6-disubstituted phenyl-piperidine-4-
thiosemicarbazone followed by cyclization with ethyl chloro acetate and fused sodium acetate.

1321
A. JAMAL ABDUL NASSER et al.
Major role of this study is to synthesis and screen for antimicrobial activity of series of 3-{[2,6-bis
(4-substituted phenyl)-1-methylpiperidin-4-ylidene] amino}-2-thioxo-imidazolidin-4-one (3a-3f).
Experimental
Melting points were recorded in open capillary tubes and are uncorrected. IR(cm-1) was recorded
in KBr on a FT-IR shimadzu 8201 pc (4000-400 cm -1 ) and ¹H NMR and Elemental analysis
(C,H,N and S) was undertaken using an Elemental analyzer model vario EL III. The purity of the
compounds was checked by thin layer chromatography (TLC) with silica gel plates.
General procedure for synthesis of 1-methyl-2,6-diphenylpiperidin-4-
thiosemicarbazone (2a-2f)
A mixture of 1-methyl-2,6-disubstituted phenyl-piperidin-4-one (0.01 mol) and thiosemicarbazide
(0.01 mol) in ethanol was heated under reflux for 6 h. The reaction mixture was cooled and
poured into crushed ice. The resulting solid produced was filtered, dried and recrystallized
from suitable alcohols (Scheme 1).
S
NH
2
S
NH
O
H2N
N
NHNH2
N
N
CH
3
CH
3
R
R
2
R
R
2
1
1
( 1a-f )
( 2 a-f )
Cl
Fused sodium acetate
O
EtO
H
N
S
N
N
O
N
CH
3
R
1
R
2
( 3a-f )
Scheme 1. Synthesis of 4-thioxo-imidazolidin-2-one derivatives
1-Methyl-2,6-diphenylpiperidin-4-thiosemicarbazone (2a)
IR(KBr,cm-1): 3475(NH2), 3060(Ar-CH str), 2960(NH), 1616(C=N), 1495(C=S), 727(N-C-
N); ¹H NMR-(DMSO-d6, δ (ppm)):11.01 (s, 1H, =N-NH), 7.23-6.56 (m,4H,Ar-H),
6.73(s,1H,NH2), 3.74 (s, 2H, 2,6-H in pipridine ring), 2.26 (s,3H, N-CH3), 2.17(s,2H, 3,5-H
in pipridine ring); Elemental analysis: Calculated for C19H22N4S: C,67.36; H,6.50; N,16.54;
S, 9.45; Found: C, 67.34; H, 6.57; N, 16.52; S, 9.48%.
2,6-Bis(4-chlorophenyl)-1-methylpiperidin-4-thiosemicarbazone (2b)
IR(KBr, cm -1): 3432(NH2), 3022(Ar-Ch Str), 2961(NH), 1632(C=N), 1423(C=S), 1082(N-
C-N), 811(Ar–Cl); ¹H NMR-(DMSO-d6,δ(ppm)):11.21(s,1H, =N-NH), 7.81-7.20 (m,4H,Ar-H),

Synthesis of Some 2-Thioxo-imidazolidin-4-one Derivatives
1322
7.15(s,2H,NH2), 3.68 (s, 2H, 2,6-H in pipridine ring), 2.18 (s,3H, N-CH3), 2.14(s,2H, 3,5-H
in pipridine ring); Elemental analysis: Calculated for C19H20Cl2N4S: C, 55.97;
H,4.90;N,13.74;S,7.85 ; Found: C, 55.94; H, 4.87; N, 13.71 S, 7.81%.
2, 6-Bis (4-hydroxy phenyl)-1-methylpiperidin-4-one thiosemicarbazone (2c)
IR(KBr, cm-1 ): 3473(NH2), 3121( Ar-CH Str), 2931 (NH), 1626 (C=N), 1450(Ar-OH str), 1136
(C=S), 1122(N-C-N); ¹H NMR- (DMSO-d6, δ (ppm)) : 11.96(s, 1H,Ar-OH), 10.91(s, 1H, =N-
NH ), 7.51-7.34(m,4H,Ar-H), 7.20(s,2H,NH2), 3.54 (s, 2H, 2,6-H in pipridine ring) 2.28 (s,3H,
N-CH3), 2.20(s,2H, 3,5-H in pipridine ring); Elemental analysis: Calculated for C19H22N4O2S:
C,33.12; H,5.01; N,14.05; S,8.02; Found: C,33.09; H,5.04;N,14.02; S,8.04%.
2,6-Bis(4- methoxyphenyl)-1-methylpiperidin-4-one thiosemicarbazone (2d)
IR(KBr,cm -1 ): 3465(NH2), 3145(Ar-H), 2902(NH), 1675 (C=N), 1138(C=S), 1022(N-C-N);
¹H NMR-(DMSO-d6, δ (ppm)) : 11.12 (s, 1H, =N-NH), 7.61-7.49 (m,4H,Ar-H), 7.30
(s,2H,NH2), 4.12 (s,3H,Ar-CH3O), 3.54 (s, 2H, 2,6-H in pipridine ring) 2.39 (s,3H,
N-CH3); 2.20(s,2H, 3,5-H in pipridine ring); Elemental analysis: Calculated for C19H22N4S:
C,63.36; H,6.53; N,14.57; S,8.44; Found: C,63.34; H,6.50; N,14.50; S,8.48%.
2,6-Bis(4-nitro phenyl)-1-methylpiperidin-4-one thiosemicarbazone (2e)
IR(KBr,cm-1): 3445(NH2), 3092 (Ar-H), 2960(NH),1617 (C=N), 1550(Ar-NO2), 1131(C=S),
1042(N-C-N);¹H NMR-(DMSO-d6, δ (ppm)):11.24(s, 1H, =N-NH ),7.59-7.49(m,4H,Ar-H),
7.32 (s,2H,NH2), 3.45 (s, 2H, 2,6-H in pipridine ring), 2.23 (s,3H, N-CH3); 2.11(s,2H, 3,5-H
in pipridine ring); Elemental analysis: Calculated for C19H20N6O4S: C,53.21; H,4.66;
N,19.60; S,7.46 ; Found: C, 53.27; H, 4.63; N, 19.57; S, 7.42%.
2,6-Bis(4-dimethyl amine phenyl)-1-methylpiperidin-4-one thiosemicarbazone (2f)
IR(KBr, cm -1 ): 3388(NH2), 3112(Ar-H), 2927(NH), 1676 (C=N), 1127(C=S), 1052(N-C-
N); ¹H NMR- (DMSO-d6, δ(ppm)): 11.30 (s,1H,=N-NH), 7.51-7.47(m,4H,Ar-H), 7.39
(s,2H,NH2), 2.72(s,6H,Ar-N(CH3)2), 3.88 (s, 2H, 2,6-H in pipridine ring), 2.28 (s,3H, N-
CH3); 2.17(s,2H, 3,5-H in pipridine ring); Elemental analysis: Calculated for C23H32N6S:
C,65.00; H,7.53;N,19.78;S,7.53; Found: C, 65.05; H, 7.57; N, 19.75; S, 7.55%.
General procedure for synthesis of 3-[(1-methyl-2, 6-diphenylpiperidin-4-ylidene)
amino]-2-thioxo-imidazolidin-4-one (3a-3f)
A mixture of compound 3-[(1-Methyl-2,6-disubstituted phenylpiperidin-4-ylidene)amino]-2-
thioxo-imidazolidin-4-one (2a-2f) (0.1 mol), ethyl chloroacetate (0.1 mol) and fused sodium
acetate (0.1 mole) in ethanol, the mixture was heated under reflux for 6 h. The reaction
mixture was cooled and poured into crushed ice. The resulting solid product was filtered,
dried and recryatallized from absolute ethanol (Table 1).
Table 1. Characterization data of the compounds (3a-3f)
Compd.no
R1
- H
R2
-H
m.p °C
231
240
Yield %
54
59
57
51
48
57
3a
3b
3c
3d
3e
3f
-Cl
-OH
-Cl
-OH
252
211
-OCH3
-NO2
-N(CH3)2
-OCH3
-NO2
-N(CH3)2
227
238

1323
A. JAMAL ABDUL NASSER et al.
3-[(1-Methyl-2, 6-diphenylpiperidin-4-ylidene) amino]-2-thioxo-imidazolidin-4-one (3a)
IR(KBr cm-1 ): 3084(NH),1722(C=O), 1664 (C=N),1495(C=S); ¹H NMR -(DMSO-d6, δ (ppm) ):
δ10.32(s,1H NH), 7.58-7.21(m,4H,Ar-H), 3.90(s,2H, 5CH2), 3.54 (s, 2H, 2,6-H in pipridine ring),
2.41(s,2H,3,5-H in pipridine ring) 2.18 (s,3H, N-CH3), Elemental analysis: Calculated for
C21H22N4OS : C,66.58; H,5.81;N,14.79;S,16.90; Found: C, 66.55; H, 5.79; N, 14.75; S, 16.88%.
3-{[2,6-Bis(4-chlorophenyl)-1-methylpiperidin-4-ylidene]amino}-2-thioxo-imidazolidin-4-
one (3b)
IR(KBr, cm -1 ): 3021(NH), 1723(C=O), 1666(C=N), 1520(C=S), 751 (Ar–Cl); ¹H NMR-
(DMSO-d6, δ (ppm)): δ10.23(s,1H NH), 7.58-7.31(m,4H,Ar-H), 3.42(s,2H, 5CH2), 3.54 (s,
2H, 2,6-H in pipridine ring), 2.41(s,2H,3,5-H in pipridine ring), 2.12 (s,3H, N-CH3);
Elemental analysis: Calculated for For C21H20Cl2N4OS : C,56.32; H,4.47;N,12.51;S,7.15;
Found: C,56.30; H,4.42; N,12.54; S,7.12%.
3-{[2,6-Bis(4-hydroxy phenyl)-1-methylpiperidin-4-ylidene]amino}-2-thioxo-imidazolidin-
4-one (3c)
IR(KBr, cm -1 ): 3032(NH), 1722(C=O), 1664 (C=N), 1459(Ar-OH), 1432(C=S); ¹H NMR-
(DMSO-d6, δ (ppm) ): δ11.21 (s,1H,Ar-OH), δ10.11(s,1H, NH), 7.58-7.11(m,4H,Ar-H),
4.21(s,2H, 5CH2), 3.54 (s, 2H, 2,6-H in pipridine ring), 2.20 (s,3H, N-CH3); 2.41(s,2H,3,5-
H in pipridine ring), 2.20 (s,3H, N-CH3); Elemental analysis: Calculated for C21H22N4O3S :C,
61.39; H,5.35;N,13.64;S,7.79; Found: C,61.28; H,5.32; N,13.61; S,7.75%.
3-{[2,6-Bis(4-methoxy phenyl)-1-methylpiperidin-4-ylidene]amino}-2-thioxo-imidazolidin-
4-one (3d)
IR(KBr, cm -1 ): 3051(NH), 1783(C=O), 1675 (C=N), 1432 (C=S); ¹H NMR-(DMSO-d6, δ
(ppm) ): δ10.67(s,1H NH), 7.44-7.21(m,4H,Ar-H), 4.12(s, 3H,Ar-OCH3), 4.07(s,2H, CH2),
3.54 (s, 2H, 2,6-H in pipridine ring), 2.48 (s,3H, N-CH3); 2.41(s,2H,3,5-H in pipridinering);
Elemental analysis: Calculated for C23H26N6O3S:C,62.93; H,5.92;N,19.15;S,7.29; Found:
C,62.90; H,5.93; N,19.12; S,7.25%.
3-{[2,6-Bis(4-nitro phenyl)-1-methylpiperidin-4-ylidene]amino}-2-thioxo-imidazolidin-4-
one (3e)
IR(KBr , cm -1 ): 3014(NH),1742(C=O), 1674(C=N),1553(Ar-NO2),1438(C=S); ¹H NMR -
(DMSO-d6, δ (ppm)): δ10.29(s,1H NH), 7.28-6.97(m,4H,Ar-H), 3.97(s,2H, 5CH2), 2.14
(s,3H, N-CH3); 2.41(s,2H,3,5-H in pipridine ring), 3.54 (s, 2H, 2,6-H in pipridine ring);
Elemental analysis: Calculated for C21H20N6O5S:C,53.79; H,4.26;N,17.93;S,6.83; Found: C,
53.75; H, 4.21; N, 17.90 S, 6.80%.
3-{[2,6-Bis(4-dimethylamine phenyl)-1-methylpiperidin-4-ylidene]amino}-2-
thioxo-imidazolidin-4-one (3f)
IR(KBr,cm-1): 3045(NH), 1736(C=O), 1652 (C=N), 1437(C=S); ¹H NMR(DMSO-d6,
δ(ppm)): 10.69(s,1H NH), 7.42-7.30(m,4H,Ar-H), 3.72(s,2H, 5CH2), 3.54 (s, 2H, 2,6-H in
pipridine ring), 2.79(s,6H,Ar-N(CH3)2), 2.41(s,2H,3,5-H in pipridine ring) , 2.28 (s,3H,
N-CH3); Elemental analysis: Calculated for C25H32N6OS : C,64.56; H,6.88;N,18.07;S,6.88;
Found: C, 64.54; H, 6.85; N, 18.02; S, 6.82%.
Results and Discussion
The IR spectrum of compounds (2a-2f), show an absorption band at 3488-3432, 1676-1616, 1138-
1127 cm-1due to corresponding to the NH2, C=N and C=O groups respectively. The IR spectrum

Synthesis of Some 2-Thioxo-imidazolidin-4-one Derivatives
1324
of compounds (3a-3f), show an absorption band at 3014-3084, 1783-1722, 1652-1675 and
1432-1520 cm-1 due to corresponding to the NH, C=O, C=N and C=S groups respectively.
1
The H NMR spectrum of compounds (2a-2f), show a singlet at δ 11.30-10.91 ppm
attributable to C=N-NH protons. The compounds (3a-3f) have very important signal at
δ 10.69-10.11 and 4.27 -3.97 ppm corresponding to the NH, CH2 N protons respectively.
Antimicrobial activity
In vitro antibacterial screening
The compounds (3a-3f) were evaluated for their in vitro antibacterial activity against
Staphylococcus aureus (MTCC-96), Enterococcus faecalis (MTCC-439), Escherchia coli
(MTCC-739), Pseudomonas aeruginosa (MTCC-2453) by agar dilution method18,19 was
performed using Mueller –Hinton agar (Hi-Media) medium. Each compound was tested at a
concentration of 100 µg/mL in DMSO. The zone of inhibition was measured after 24 h
incubation at 37 ºC. Inhibition zone of the compounds clearly indicate the (3f) compound
was highly active against S.aureus. The results are presented in Table 2. Inhibition of the
compounds (3a-3f) were clearly observed in NO2 substituted at benzaldehyde containing
compound (3e) showed maximum antibacterial potency. Compound (3c) has nearly activity
against Staphylococcus aureus, Enterococcus faecalis and compound (3d) has less activity
compared with norfloxacin against all bacterial organisms.
Table 2. Antibacterial activity of the compounds (3a-3f)
Compounds S. aureus E.faecalis
E. coli P. aeruginosa
20
19
21
12
22
23
22
14
12
13
-
16
20
20
18
21
13
24
13
16
8
3a
3b
3c
3d
-
13
8
15
10
21
3e
3f
Standard
15
Zone of the inhibition measured in (mm). Indicate bacteria’s are resistant to the compound 10 µg/mL
Norfloxacin is used as the standard drug 100 µg/mL
In vitro antifungal screening
The compounds (3a-3f) were evaluated for their in vitro antifungal activity against
Aspergillus niger, Candia albicans, Aspergillus fumigatus and Cryptococcus neoformans
using an agar dilution method20 with sabouraud’s dextrose agar (Hi-Media). Each compound
was tested at a concentration of 100 µg/mL in DMSO. The zone of inhibition was measured
after incubating at 37 °C for 24 h. It was evident from screening results that only 4-OH
phenyl substituted compound (3c) has remarkably enhanced the antifungal action. When
compared to ketoconazole, compound (3b) is moderately active against all antifungal
organisms. Compounds (3a, 3d, 3e and 3f) are less active against all antifungal organisms.
All compounds are compared with ketoconazole the results are presented in Table 3.
Conclusion
The series of compound (3a-3f) 2-thioxo-imidazolidin-4-one derivatives were synthesized
and screened for their antimicrobial activity. The compound (3f) has highly anti bacterial
activity against S.aureus compared with norfloxacin standard and compound (3c) has
highly antifungal activity aganist A. niger and A.fumigates compared with a ketoconazole
standard.

1325
A. JAMAL ABDUL NASSER et al.
Table 3. Antifungal activity of the compounds (3a-3f)
Compounds
A. niger,
C.albicans
A .fumigatus Cr.neoformans
12
19
24
13
8
10
19
23
12
10
8
12
14
18
16
12
-
13
16
14
14
8
3a
3b
3c
3d
3e
3f
Standard
12
22
-
18
24
16
Zone of the inhibition measured in (mm). Indicate fun gals are resistant to the compound 100 µg/mL
Ketoconazole is used as the standard 100 µg/mL
Acknowledgment
We wish to thank the state Government, for providing state government fellowship and
extending financial support. We wish to thank one of the authors Dr. J. Selvin, Department
of Microbiology, Bharathidasan University, for his help in microbial activities. We sincerely
thank Dr.M. Sheik Mohamed, Principal Jamal Mohamed College, for providing Laboratory
facilities.
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