Synthesis, spectral analysis and in vitro microbiological evaluation of 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones as a new class of antibacterial and antifungal agents

Article abstract of DOI:10.1016/j.bmcl.2009.11.074

In the present work, a new series of bis hybrid heterocycle comprising both piperidine and thiohydantoin nuclei together namely 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones 46-60 was synthesized by the treatment of the respective thiosemicarbazones 31-45 with chloroethyl acetate and anhydrous sodium acetate in refluxing ethanol for 4 h and were characterized by melting point, elemental analysis, MS, FT-IR, one-dimensional NMR (¹H, D₂O exchanged ¹H and ¹³C), two dimensional HOMOCOSY and NOESY spectroscopic data. In addition, the title compounds were screened for their antimicrobial activities against a spectrum of clinically isolated microbial organisms. Compounds 47-50, 52-55 and 57-60 with fluoro, chloro, methoxy or methyl functions at the para position of phenyl rings attached to C-2 and C-6 carbons of piperidine moiety along with and without methyl substituent at position C-3 of the piperidine ring exerted potent biological activities against Staphylococcus aureus, β-Hemolytic streptococcus, Vibrio cholerae, Escherichia coli, Pseudomonas aeruginosa, Aspergillus flavus, Candida albicans, Candida 6 and Candida 51 at a minimum inhibitory concentration.

Full text of DOI:10.1016/j.bmcl.2009.11.074

Bioorganic & Medicinal Chemistry Letters 20 (2010) 713–717
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, spectral analysis and in vitro microbiological evaluation
of 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones
as a new class of antibacterial and antifungal agents
*
J. Thanusu, V. Kanagarajan, M. Gopalakrishnan
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University, Annamalai Nagar 608 002, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present work, a new series of bis hybrid heterocycle comprising both piperidine and thiohydantoin
nuclei together namely 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones 46–60 was
synthesized by the treatment of the respective thiosemicarbazones 31–45 with chloroethyl acetate
and anhydrous sodium acetate in refluxing ethanol for 4 h and were characterized by melting point, ele-
mental analysis, MS, FT-IR, one-dimensional NMR (1H, D2O exchanged 1H and 13C), two dimensional
HOMOCOSY and NOESY spectroscopic data. In addition, the title compounds were screened for their anti-
microbial activities against a spectrum of clinically isolated microbial organisms. Compounds 47–50, 52–
55 and 57–60 with fluoro, chloro, methoxy or methyl functions at the para position of phenyl rings
attached to C-2 and C-6 carbons of piperidine moiety along with and without methyl substituent at posi-
tion C-3 of the piperidine ring exerted potent biological activities againstStaphylococcus aureus, b-Hemo-
lytic streptococcus, Vibrio cholerae, Escherichia coli, Pseudomonas aeruginosa, Aspergillus flavus, Candida
albicans, Candida 6 and Candida 51 at a minimum inhibitory concentration.
Received 21 August 2009
Revised 14 October 2009
Accepted 13 November 2009
Available online 7 December 2009
Keywords:
3-(3-Alkyl-2,6-diarylpiperin-4-ylidene)-2-
thioxoimidazolidin-4-ones
Chloroethyl acetate
Bis hybrid heterocycles
Antibacterial activity
Antifungal activity
Ó 2009 Elsevier Ltd. All rights reserved.
Small heterocyclic compounds act as highly functionalized scaf-
folds and were known pharmacophores of a number of biologically
active and useful molecules. Baliah et al., have reviewed the impor-
tance of piperidin-4-ones as intermediates in the synthesis of sev-
eral physiologically active compounds.1,2 Similarly, Lijinsky and
Taylor3 have found that the presence of substituents at both the
pesticides.22 Additionally, 2-thiohydantoins have been used as
reference standards for the development of C-terminal protein
sequencing,23 as reagents for the development of dyes24 and in
textile printing, metal cation complexation and polymerization
catalysis.25
In connection with our earlier work on the synthesis of struc-
turally diverse biologically active hybrid heterocyclic ring systems
and as part of our ongoing research programme,26 we planned to
design a system, which combines both bioactive piperidine and
thiohydantoin components together to give a new series of bis hy-
brid heterocycles comprising both piperidine and thiohydantoin
nuclei. In the present work, a new series of bis heterocycles com-
prising both piperidine and thiohydantoin nuclei together namely
3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-
ones 46–60 was synthesized by the treatment of the respective
thiosemicarbazones 31–45 with chloroethyl acetate and anhy-
drous sodium acetate in refluxing ethanol for 4 h . The synthetic
route for the formation of compounds 46–60 was given in
Scheme 1. The physical data was given in Table 1. A reaction mech-
anism was proposed and given in Scheme 2. The structures of all
the synthesized compounds 46–60 are discussed with the help of
mp’s, elemental analysis, FT-IR, MS, one-dimensional Proton and
Carbon NMR, D2O exchanged 1H NMR, 13C NMR, HOMOCOSY and
NOESY spectra.27
a-positions to that of N in piperidin-4-one is important to exert
marked biological properties. Bioactive heterocyclic ring systems
having 2,6-diaryl-piperidine-4-one nucleus with different substit-
uents at 3- and 5-positions of the ring have aroused great interest
due to their wide variety of biological properties such as antiviral,
antitumour,4,5 central nervous system,6 local anesthetic,7 antican-
cer,8 antimicrobial activity9 and their derivative piperidine are also
biologically important and act as neurokinin receptor antago-
nists,10 analgesic and anti-hypertensive agents.11
Thiohydantoins are sulfur analogs of hydantoins with one or
both carbonyl groups replaced by thiocarbonyl groups.12 Among
the known thiohydantoins, 2-thiohydantoins were most notably
known due of their wide applications as hypolipidemic,13 anticar-
cinogenic,14 antimutagenic,15 antithyroidal16 antiviral (e.g., against
herpes simplex virus, HSV),17 human immunodeficiency virus
(HIV)18 and tuberculosis19), antimicrobial (antifungal and antibac-
terial),20 anti-ulcer and anti-inflammatory agents,21 as well as
In order to find the effect of potency of inhibitions in the title
compounds 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimi-
* Corresponding author. Tel.: + 91 4144 228 233.
E-mail address: profmgk@yahoo.co.in (M. Gopalakrishnan).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.074

714
J. Thanusu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 713–717
O
O
R1
R1
R2
EtOH
warm, 15 min.
H3C
O
R2
HCl
H
O
H
N
H
.HCl
(1-15)
+
X
X
Aqu. NH3
Ice, 200C
CH3
+
NH4
-O
X
X
X
O
R1
Compounds
R2
O
R1
R2
1,16,31,46
2,17,32,47
3,18,33,48
4,19,34,49
5,20,35,50
6,21,36,51
7,22,37,52
8,23,38,53
9,24,39,54
10, 25,40,55
11,26,41,56
12,27,42,57
13,28,43,58
14,29,44,59
15,30,45,60
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
H
F
Cl
OCH3
CH3
H
F
Cl
OCH3
CH3
H
F
Cl
H
N
H
(16-30)
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
X
X
S
EtOH
reflux, 2h
H2N
N
NH2
H
CH3 OCH3
CH3
CH3
O
S
H2N
5
2
4
ClCH2CO2Et
Anhyd.CH3COONa
1
HN
3 N
NH
EtOH
reflux, 4 h
N
N
S
R1
R2
R1
R2
4
1
5
6
3
2
N
H
N
H
(31-45)
(46-60)
X
X
X
X
Scheme 1. Synthetic route for the formation of 3-(3-substituted-2,6-diaryl-piperidin-4-ylideneamino)-2-thioxoimidazolidin-4-ones.
ylidene)-2-thioxoimidazolidin-4-ones. Compounds, 46–60 were
Table 1
Physical data for the title compounds 46–60
assessed to elicit their antibacterial activity in vitro against
Staphylococcus aureus, b-Hemolytic streptococcus, Vibrio cholerae,
Escherichia coli, and Pseudomonas aeruginosa. The antibacterial po-
tency of the synthesized compounds was compared with broad
spectrum antibiotic namely Ciprofloxacin and their minimum
inhibitory concentration (MIC) values were summarized in Table
2. A close survey of the MIC values indicate that all the compounds
exhibited a varied range (6.25–200 lg/mL) of antibacterial activity
against all the tested bacterial strains except 50 and 59 which did
not show activity against S. aureus and E. coli even at a maximum
concentration of 200 lg/mL. The compounds without any substit-
uents at the para position of the phenyl groups at the C-2 and
C-6 positions of the piperidine ring (46, 51 and 56) showed anti-
bacterial activity in the range of 25–200 lg/mL. Compounds 47
and 48, which were having electron withdrawing fluoro and chloro
substitutions, respectively, at the para position of phenyl rings at-
tached to C-2 and C-6 carbons of piperidine moiety shows fourfold
increased activity against b-H. streptococcus and P. aeruginosa at a
Compounds
R1
R2
X
Yield (%)
Mp (°C)
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
H
H
H
H
H
H
H
H
H
H
H
F
Cl
OCH3
CH3
H
F
Cl
OCH3
CH3
H
F
Cl
74
78
67
72
70
75
78
75
72
70
76
77
75
72
71
108
103
167
158
142
171
182
187
182
136
148
134
176
132
124
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
CH3
CH3
CH3
CH3
CH3
OCH3
CH3
dazolidin-4-ones 46–60 by in vitro method, we modified different
substituents at the phenyl rings in 3-(3-alkyl-2,6-diarylpiperin-4-
MIC value of 6.25 lg/mL and shows twofold increased activity

J. Thanusu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 713–717
715
O
Cl
H
N
O
O
CH3
H
N
S
S
Anhyd. CH3COONa
H
EtOH, Δ, 4h
O
O
HN
N
Anhyd. CH3COONa
N
N
CH3
H
EtOH, Δ, 4h
+
H2C
O
CH3
R1
R1
R2
-HCl
R2
N
H
N
H
(31-45)
X
X
X
X
H3C
O
O
O
H
HN
HN
N
N
N
N
R1
R2
R1
R2
S
S
N
H
N
H
(46-60)
X
X
X
X
Scheme 2. Proposed reaction mechanism for the formation of target molecules 46–60.
against V. cholerae and E. coli at a MIC value of 12.5
l
g/mL. Electron
were having electron donating methoxy and methyl substitutions,
respectively, at the para position of phenyl rings attached to C-2
and C-6 carbons of piperidine moiety shows moderate antibacte-
rial activity against all the tested bacterial strains in the range of
withdrawing substituents like fluoro and chloro substituted 2,6-
diarylpiperidone derivatives exerted excellent antibacterial and
antifungal activities.26c,d Fluorination increases the lipophilicity
due to strong electron withdrawing capability of fluorine.28 More-
over, fluorine substitution was commonly used in contemporary
medicinal chemistry to improve metabolic stability, bioavailability
and protein ligand interactions.29 Compounds 49 and 50, which
100–25 lg/mL. Introduction of mono methyl or dimethyl groups
at C-3 of the piperidine ring in compounds 52 and 57, which also
having electron withdrawing fluoro substitution at the para posi-
tion of phenyl rings attached to C-2 and C-6 carbons of piperidine
moiety exerted excellent activity with a MIC value of 6.25–
12.5 lg/mL against all the tested bacterial strains. Compound 53,
Table 2
which have electron donating methyl group at C-3 of the piperi-
dine ring and having electron withdrawing fluoro substitution at
the para position of phenyl rings attached to C-2 and C-6 carbons
of piperidine moiety shows good antibacterial activity against
In vitro antibacterial activity of compounds 46–60 against clinically isolated bacterial
strains
Compounds
Minimum inhibitory concentration (MIC) in
lg/mL
S. aureus and V. cholerae at a MIC of 6.25 and 12.5 lg/mL, respec-
S. aureus b-H. streptococcus V. cholerae E. coli P. aeruginosa
tively. Compound 58, which have electron donating dimethyl
groups at C-3 of the piperidine ring and also have electron with-
drawing chloro substitution at the para position of phenyl rings
attached to C-2 and C-6 carbons of piperidine moiety exerted good
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
100
50
50
50
—
200
6.25
6.25
50
50
100
12.5
12.5
50
100
50
6.25
12.5
50
100
100
12.5
50
50
50
6.25
6.25
100
100
100
12.5
50
25
50
25
6.25
12.5
50
25
50
12.5 6.25
12.5 6.25
50
200
50
12.5 6.25
50
100
50
100
6.25 6.25
100
25
50
activity against b-H. streptococcus with a MIC value of 12.5 lg/mL.
Moreover, introduction of electron donating dimethyl group at C-3
of the piperidine ring in compounds 59 and 60, which were having
electron donating methoxy and methyl substitutions, respectively,
at the para position of phenyl rings attached to C-2 and C-6 carbons
of piperidine moiety exerted modest antibacterial activity against
all the tested bacterial strains in the range of 25–200 lg/mL. Com-
pound 51, which have CH3 group at C-3 position of the piperidine
ring exerted moderate activity against all the tested bacterial
50
25
50
100
25
100
12.5
25
200
25
50
—
50
25
25
50
100
25
100
100
50
Ciprofloxacin 25
strains at a MIC of 200
lg/mL when compared to compounds 46,
‘—’ no inhibition even at a higher concentration of 200
l
g/mL.
which was having no CH3 group at C-3 position of the piperidine

716
J. Thanusu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 713–717
ring. Mono methyl substituted compounds 52 and 53 at C-3 of
piperidine ring were more active against S. aureus and they show
fourfold increases in activity when compared to the standard drug
Ciprofloxacin. Compound 52 show eightfold increases in activity
against b-H. streptococcus and P. aeruginosa whereas fourfold in-
creases in activity against E. coli was noted when compared to
the standard antibacterial drug. Compound 53, which have CH3
group at C-3 position of the piperidine ring exerted a fourfold in-
crease in activity against V. cholerae whereas compound 58, a di-
methyl substituted compound at position C-3 of piperidine ring
exerted equal activity as that of the antibacterial drug. Compounds
54 and 55, which were having electron donating methoxy and
methyl substitutions, respectively, at the para position of phenyl
rings attached to C-2 and C-6 carbons of piperidine moiety and
have electron donating methyl group at C-3 of the piperidine ring
shows modest antibacterial activity against all the tested bacterial
MIC value of 12.5 lg/mL. Compounds 47 and 48, which have
electron withdrawing fluoro or chloro substitution at the para
position of phenyl rings attached to C-2 and C-6 carbons of piper-
idine moiety exerted threefold increased in antifungal activity
against A. flavus and Candida 6 at a MIC value of 12.5 lg/mL,
respectively. Compounds 49 and 50, which were having electron
donating methoxy and methyl substitutions, respectively, at the
para position of phenyl rings attached to C-2 and C-6 carbons of
piperidine moiety shows admirable antifungal activity against all
the tested fungal strains in the range of 6.25–12.5
compound 49 which did not show activity against Candida 51 even
at a higher concentration of 200 g/mL. Compound 51, which have
lg/mL except
l
electron donating mono methyl group at position C-3 of the piper-
idine ring, exerted reasonable antifungal activity against all the
tested strains at a MIC value of 50 lg/mL. In addition to electron
donating mono methyl group at position C-3 of the piperidine ring,
compound 52 have electron withdrawing fluoro substitution at the
para position of phenyl rings attached to C-2 and C-6 carbons of
piperidine moiety exerted activity in the range of 6.25–12.5
strains in the range of 25–100 lg/mL. Dimethyl substitution at po-
sition C-3 of the piperidine ring for compound 56 exerted moder-
ate activity similar to that of compounds 51 and 46. There was
no change in activity by incorporating two methyl groups at C-3
position. But for compound 57, which was having strong electron
withdrawing fluoro function groups at the phenyl rings along with
two methyl groups at C-3 position of the piperidine ring exerted
lg/mL. Compound 53, which have electron withdrawing chloro
substitution at the para position of phenyl rings attached to C-2
and C-6 carbons of piperidine moiety as well electron donating
methyl substituent at position C-3 of the piperidine ring exerted
good antifungal activity against A. flavus and Candida 51 at a MIC
strong activity against S. aureus at a MIC of 12.5 lg/mL when com-
pared to that of compound 46 which have no substitution at the
of 12.5 lg/mL. Compounds 54 and 55 which have electron donat-
C-3 position. Also, dimethylated compound 59 did not show any
activity against E. coli even at a higher concentration of 200 lg/mL
whereas as unsubstituted compound 49 and mono methyl
substituted compound 54 exerted activity at a MIC of 50 and
ing methoxy and methyl substitution, respectively, at the para po-
sition of phenyl rings attached to C-2 and C-6 carbons of piperidine
moiety as well electron donating methyl substituent at position
C-3 of the piperidine ring were potent against A. flavus, Candida 6
and Candida 51. Besides having electron donating dimethyl group
at C-3 of the piperidine ring, compounds 59 and 60 which were
having electron donating methoxy and methyl substitutions at
the para position of phenyl rings attached to C-2 and C-6 carbons
of piperidine moiety shows admirable antifungal activity against
100 lg/mL.
The in vitro antifungal activity of 3-(3-alkyl-2,6-diarylpiperin-
4-ylidene)-2-thioxoimidazolidin-4-ones 46–60 was studied
against the fungal strains viz., Aspergillus flavus, Candida albicans,
Candida 6 and Candida 51. Fluconazole was used as a standard drug.
Minimum inhibitory concentration (MIC) in
lg/mL values was
all the tested fungal strains in the range of 6.25–25 lg/mL. Di-
reproduced in Table 3. A close survey of the MIC values indicates
that all the compounds 46–60 exhibited a varied range (6.25–
200 lg/mL) of antifungal activity against all the tested fungal
methyl substituted compound 56 did not exhibit antifungal activ-
ity against A. flavus, whereas monomethyl substituted compound
51 at position C-3 of piperidine ring and unsubstituted compound
strains except compounds 49 and 56 which were not having anti-
fungal activity against Candida 51 and A. flavus. Compound 46,
which have no substituent at the para position of the phenyl groups
at the C-2 and C-6 positions of the piperidine ring showed threefold
increase in antifungal activity against A. flavus and C. albicans at a
46 exerted activities at a MIC of 50 and 12.5 lg/mL, respectively.
Electron donating dimethyl substituents at position C-3 of the
piperidine ring in compound 59 exerted excellent antifungal activ-
ity against all the tested A. flavus strains whereas mono methyl
substituted compound 54 and C-3 unsubstituted compound 49 ex-
erted activity at a MIC of 12.5 lg/mL. Two and fourfold increased in
activities were noticed for monomethyl substituted compound 54
and dimethyl substituted compound 59, respectively, when com-
pared to that of the standard antifungal drug Fluconazole. Fluoro
substituted compound 52, which have methyl group at position 3
of the piperidine ring exerted excellent antifungal activity against
all the tested fungal strains. Eightfold increased in activity was
noted against A. flavus, C. albicans and Candida 51 and a fourfold in-
creased in activity when compared to standard drug was noticed
against Candida 6 for compound 52. But compound 47 which have
no methyl substitution pronounced moderate activity against all
the tested fungal strains except A. flavus, which exhibit fourfold in-
creased in antifungal activity when compared to that of the drug,
Fluconazole. Compound 60 which have dimethyl substituents at
C-3 position of the phenyl ring exhibit fourfold and twofold in-
creased in activity against Candida 6 and Candida 51, respectively,
whereas monomethyl substituted compound 55 and compound
50 which have no methyl substituent at C-3 of piperidine ring ex-
erted fourfold increased in activity against all the tested fungal
strains when compared to Fluconazole.
Table 3
In vitro antifungal activity of compounds 46–60 against clinically isolated fungal
strains
Compound
Minimum inhibitory concentration (MIC) in lg/mL
A. flavus
C. albicans
Candida 6
Candida 51
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12.5
12.5
50
12.5
6.25
50
12.5
50
50
12.5
12.5
50
50
50
12.5
6.25
6.25
50
100
50
25
—
6.25
50
6.25
12.5
12.5
12.5
—
6.25
50
50
50
50
12.5
50
12.5
6.25
100
50
6.25
12.5
12.5
12.5
50
25
25
50
50
50
50
50
6.25
25
12.5
25
50
25
6.25
25
6.25
12.5
25
In crisp, we have synthesized a novel biologically active 3-(3-al-
kyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones and
their structures were characterized by their spectral and analytical
Fluconazole
50
‘—’ no inhibition even at a higher concentration of 200
lg/mL.

J. Thanusu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 713–717
717
9. Mokio, I. G.; Soldatenkov, A. T.; Federov, V. O.; Ageev, E. A.; Sergeeva, N. D.; Lin,
S.; Stashenku, E. E.; Prostakov, N. S.; Andreeva, E. I. Khim. Farm. Zh. 1989, 23,
421.
10. Dimmock, J. R.; Kumar, P. Curr. Med. Chem. 1997, 4, 1.
11. Kubota, H.; Kakefuda, A.; Okamoto, Y.; Fujii, M.; Yamamoto, O.; Yamgiwa, Y.;
Orita, M.; Ikeda, M.; Takenchi, M.; Shibanuma, T.; Fsomura, Y. Chem. Pharm.
Bull. 1998, 46, 1538.
12. Johnson, T. B.; Chernoff, L. H. J. Am. Chem. Soc. 1913, 35, 1208.
13. Tompkins, J. E. J. Med. Chem. 1986, 29, 855.
14. Al-Obaid, A. M.; El-Subbagh, H. I.; Khodair, A. I.; Elmazar, M. M. Anticancer
Drugs 1996, 7, 873.
15. Froelich, E.; Fruehan, A.; Jackman, M.; Kirchner, F. K.; Alexander, E. J.; Archer, S.
J. Am. Chem. Soc. 1954, 76, 3099.
16. Marx, J. V.; Richert, D. A.; Westerfeld, W. W. J. Med. Chem. 1970, 13, 1179.
17. El-Barbary, A. A.; Khodair, A. I.; Pedersen, E. B.; Nielsen, C. J. Med. Chem. 1994,
37, 73.
18. Chérouvrier, J. R.; Carreaux, F.; Bazureau, J. P. Molecules 2004, 9, 867.
19. Archer, S.; Unser, M. J.; Froelich, E. J. Am. Chem. Soc. 1956, 78, 6182.
20. Marton, J.; Enisz, J.; Hosztafi, S.; Timar, T. J. Agric. Food Chem. 1993, 41,
148.
data. A close survey of the in vitro antibacterial and antifungal
activity profile of the new 3-(3-alkyl-2,6-diarylpiperin-4-yli-
dene)-2-thioxoimidazolidin-4-ones 46–60 against the tested clini-
cally isolated bacterial and fungal strains gave a clear picture about
the structure–activity correlations among compounds 45–60 un-
der study. Compounds 47–50, 52–55 and 57–60 with fluoro,
chloro, methoxy or methyl functions at the para position of phenyl
rings attached to C-2 and C-6 carbons of piperidine moiety along
with and without methyl substituent at position C-3 of the piper-
idine ring exerted a varied range of biological activities, while the
activity was not significant for compounds 46, 51 and 56 without
any substituents at C-3 of the piperidine ring and the para position
of the phenyl groups. Furthermore, the observed marked antibac-
terial and antifungal activities may be considered as key steps for
the building of novel chemical entities with comparable pharmaco-
logical profiles to that of the standard drugs.
21. Curran, A. C. W. U.S. Pat. 3, 984,430, 1976.
22. Nagpal, K. L. U.S. Pat.4, 473,393, 1984.
23. Cromwellt, L. D.; Stark, G. R. Biochemistry 1969, 8, 4735.
24. Nelson, J. V.; Helber, M. J.; Brick, M. U.S. Pat. 5, 695,917, 1997.
25. Kandil, S. S.; El-Hefnawy, G. B.; Baker, E. A. Thermochim. Acta 2004, 414,
105.
Acknowledgments
Authors are thankful to NMR Research Centre, Indian Institute
of Science, Bangalore for recording spectra. One of the authors
namely V. Kanagarajan is grateful to Council of Scientific and
Industrial Research (CSIR), New Delhi, Republic of India for provid-
ing financial support in the form of CSIR-Senior Research Fellow-
ship (SRF) in Organic Chemistry. Another author J. Thanusu is
highly thankful to Annamalai University authorities for providing
University Studentship.
26. (a) Gopalakrishnan, M.; Sureshkumar, P.; Thanusu, J.; Kanagarajan, V. Chem.
Heterocycl. Comp. 2008, 44, 950; (b) Gopalakrishnan, M.; Sureshkumar, P.;
Thanusu, J.; Kanagarajan, V. J. Enzyme Inhib. Med. Chem. 2008, 23, 974; (c)
Gopalakrishnan, M.; Sureshkumar, P.; Thanusu, J.; Kanagarajan, V. J. Enzyme
Inhib. Med. Chem. 2008, 23, 347; (d) Gopalakrishnan, M.; Thanusu, J.;
Kanagarajan, V. Med. Chem. Res. 2007, 16, 392.
27. Spectral data for compound 46: IR (KBr) (cmÀ1): 3400, 3306, 3060, 3029, 2980,
2896, 2797, 1728, 1635, 1598, 1215, 701, 758, 1041; MS: m/z = 365 (M+1)+.
Elemental Anal. Calcd: C, 65.91; H, 5.53; N, 15.37. Found: C, 65.87; H, 5.50; N,
15.33. 1H NMR (d ppm): 1.97–2.05 (m, 1H, H3a), 2.37–2.41 (dd, 1H, H3e
,
J3e,3a = 13.64 Hz, J3e,2a = 2.96 Hz); 2.43–2.52 (m, 1H, H5a), 2.83 (s, 1H, NH of
piperidine), 3.62–3.66 (dd, H5e, J5e,5a = 2.96 Hz, J5e,6a = 13.52 Hz), 3.80 (s, 2H,
CH2 of imidazolidine), 3.88–3.92 (dd, 1H, H2a, J2a,3e = 3.08 Hz, J2a,3a = 11.76 Hz),
4.15–4.19 (dd, 1H, H6a, J6a,5e = 3.20 Hz, J6a,5a = 11.88 Hz), 7.23–7.50 (m, 10H,
Ar–H’s), 11.78 (s, NH of imidazolidine); In the D2O exchanged 1H NMR
spectrum, two peaks at 2.83 ppm and 11.78 ppm which resonances due to NH
of piperidine and imidazolidine, respectively, disappeared; 13C NMR (d ppm):
29.6 C-3, 37.3 C-5, 43.6 CH2 of imidazolidine, 60.2 C-2, 61.1 C-6, 126.5–128.1
Ar–C’s, 144.0, 144.1 ipso-C, 163.1 C@N, 167.6 C@O, 173.8 C@S. In six-
membered heterocycles, a decrease in electronegativity of a group in the
ring deshields b-carbons and shields b-protons. Hence for compound 46, the
deshielding of anti b-C-6 carbon with respect to thioxoimidazoline ring was in
accordance with the expected electronegativity effect whereas the syn b-C-2
carbon was shielded.30
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.11.074.
References and notes
1. Baliah, V.; Jeyaraman, R.; Chandrasekaran, L. Chem. Rev. 2008, 83, 379.
2. Noller, C. R.; Baliah, V. J. Am. Chem. Soc. 1948, 70, 3853.
3. Lijinsky, W.; Taylor, H. Int. J. Cancer 1975, 16, 318.
4. El-Subbagh, H. I.; Abu-Zaid, S. M.; Mahran, M. A.; Badria, F. A.; Alofaid, A. M. J.
Med. Chem. 2000, 43, 2915.
5. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nugh, J. Phytochemistry
2001, 56, 265.
6. Ganellin, C. R.; Spickett, R. G. J. Med. Chem. 1965, 8, 619.
7. Hagenbach, R. E.; Gysin, H. Experimentia 1952, 8, 184.
8. Ileana, B.; Dobre, V.; Nicluescu-Duvaz, I. J. Prakt. Chem. 1985, 327, 667.
28. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.
1997, 23, 3.
29. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320.
30. Pandiarajan, K.; Sabapathi Mohan, R. T.; Hasan, M. U. Magn. Reson. Chem. 1986,
24, 312.