Synthesis, characterisation and antimicrobial activities of novel 7,9-diphenyl-1,2,4-triaza-8-oxa-spiro[4.5]-decan-3-thiones

Article abstract of DOI:10.1007/s00044-010-9348-8

Some new 7,9-diaryl-1,2,4-triaza-8-oxa-spiro [4.5]-decan-3-thiones has been synthesised and their antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi, and antifungal activity against Candida albicans, Rhizopus sp., Aspergillus flavus and Aspergillus niger were examined. Compounds 14 and 15 against E. coli and S. typhi showed marked antibacterial activity. Similarly, compounds 13 and 15 against Rhizopus sp. and 13 and 14 against A. flavus exerted significant antifungal activities. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-010-9348-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:542–548
DOI 10.1007/s00044-010-9348-8
ORIGINAL RESEARCH
Synthesis, characterisation and antimicrobial activities of novel
7,9-diphenyl-1,2,4-triaza-8-oxa-spiro[4.5]-decan-3-thiones
•
Senthamaraikannan Kabilan Seeman Umamatheswari
Received: 30 December 2009 / Accepted: 3 March 2010 / Published online: 31 March 2010
Ó Springer Science+Business Media, LLC 2011
Abstract Some new 7,9-diaryl-1,2,4-triaza-8-oxa-spiro
[4.5]-decan-3-thiones has been synthesised and their anti-
bacterial activity against Staphylococcus aureus, Esche-
richia coli, Pseudomonas aeruginosa and Salmonella typhi,
and antifungal activity against Candida albicans, Rhizopus
sp., Aspergillus flavus and Aspergillus niger were exam-
ined. Compounds 14 and 15 against E. coli and S. typhi
showed marked antibacterial activity. Similarly, com-
pounds 13 and 15 against Rhizopus sp. and 13 and 14
against A. flavus exerted significant antifungal activities.
Several natural products including antibiotics possess
the oxane (pyran) ring skeleton. The pyran nucleus can
frequently be recognised in the structure of numerous
naturally occurring carbohydrates and synthetic com-
pounds with interesting biological and pharmacological
properties (Stevens et al., 1963, 1964; Heindal and Reid
1980; Bradbury and Revett 1991; Komurcu et al., 1995).
1,2,4-Triazoles and their heterocyclic derivatives repre-
sent an interesting class of compounds possessing a wide
spectrum of biological activities. A large number of
1,2,4-triazole containing ring systems exhibits antibacte-
rial (Demirbas et al., 2005; Holla et al., 2000; Sharma
et al., 2008; Turan-Zitouni et al., 2005), antifungal
(Jalilian et al., 2000), antitubercular (Foroumadi et al.,
2003), analgesic (Turan-Zitouni et al., 2001; Tozkoparan
et al., 2007), insecticide (Chai et al., 2003), antidepres-
sant (Varvaresou et al., 1998), central nervous system
(CNS) (Modzelewska-Banachiewicz et al., 2004)
activities.
Keywords Pyran ꢀ Triazolidine ꢀ Antibacterial activity ꢀ
Antifungal activity
Introduction
Microbial infections are associated with rates of attribut-
able morbidity and mortality (Zanatta et al., 2007). The
resistance of common pathogens to standard antibiotic
therapies is rapidly becoming a major public health prob-
lem throughout the world. The incidence of multi-drug
resistant Gram-positive and Gram-negative bacteria is
increasing and infections caused by them are becoming
problematic now-a-days (Nezhad et al., 2005). There is an
urgent need for the discovery of new compounds endowed
with antimicrobial activity.
In view of the continued interest in synthesis of simpler
and biologically potent heterocyclic system (Ramalingan
et al., 2003; Balasubramanian et al., 2004, 2005, 2006;
Aridoss et al., 2007, 2008, 2009), an efficient method to
synthesise some triazolidinethione of 2,6-diphenylpyran-4-
ones (7–12) and their antimicrobial activities are reported
here.
Synthesis of molecules, which are novel still resembling
known biologically active molecules by virtue of the
presence of some critical structural features, is an essential
component of the search for new leads in drug designing
programme. With the view of the above, we planned to
synthesise some 7,9-diaryl-1,2,4-triaza-8-oxa-spiro[4.5]-
decan-3-thiones and explored their antibacterial and anti-
fungal potency.
S. Kabilan (&) ꢀ S. Umamatheswari
Department of Chemistry, Annamalai University,
Annamalainagar 608 002, Tamil Nadu, India
e-mail: skabilan08@gmail.com
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Med Chem Res (2011) 20:542–548
Results and discussion
Chemistry
543
dicarboxylic acid with benzaldehyde in the presence of
HCl gas. All the pyran-4-ones 1–3 were converted into
corresponding thiosemicarbazones 4–9 by refluxing with
thiosemicarbazide and 40-phenylthiosemicarbazide in the
presence of concentrated hydrochloric acid.
By adopting Japp and Maitland (1904) method the parent
3-alkyl-2,6-diphenylpyran-4-ones (2 and 3) were prepared
by the condensation of appropriate ketones with benalde-
hyde in the presence of KOH in water ethanol medium
whereas 2,6-diphenylpyran-4-one (1) was prepared acetone
1,2,4-Triazolidine-3-thiones were normally obtained
from ketone thiosemicarbazones by oxidative cyclization.
Accordingly, 2,6-diphenyltetrahydropyran-4-one thiosemi-
carbazones 4–6 and 2,6-diphenyltetrahydropyran-4-one
Scheme 1 Schematic diagram
showing the synthesis of
compounds (10–15)
O
O
HOOC
COOH
EtOH/dry HCl gas
+
O
O
H
O
H
O
1
O
R
R
KOH / H2O - EtOH
stirred 15 days
+
O
O
O
H
H
2,3
S
MeOH/H+
Reflux, 2-3 h
H2N
R1
N
N
H
H
R1
S
NH
S
NH
N
HN
N
HN
R1
R
H2O2/CHCl3
R
00C, Stirred 5-8 h
O
O
4-9
10-15
10
11
12
13
14
15
R = H;
R1 = H
R1 = H
R = CH3;
R = CH2CH3; R1 = H
R = H;
R1 = C6H5
R1 = C6H5
R = CH3;
R = CH2CH3; R1 = C6H5
123

544
Med Chem Res (2011) 20:542–548
40-phenyl thiosemicarbazones 7–9 were synthesised from
2,6-diphenyltetrahydrothiopyran-4-ones 1–3 with thiosem-
icarbazide, and 40-phenylthiosemicarbazide, respectively.
Table 2 In vitro antibacterial activity of compounds 10–15
Entry
Minimum inhibitory concentration (MIC) in lg/ml
S. aureus
E. coli
P. aeruginosa
S. typhi
2,6-Diphenyltetrahydropyran-4-one
thiosemicarbazones
4–9 stirred with H2O2 at 0°C afford the desire product
7,9-diphenyl-1,2,4-triazaspiro-8-oxa-(4.5)decan-3-thiones
(10–15) in good yield. The mechanistic pathway for the
conversion of thiosemicarbazones into spiro-1,2,4-triaz-
olidine-3-thione is consistent with a one already reported
for similar cyclizations (Ramalingan et al., 2003). Syn-
thetic strategy is given in Scheme 1 and analytical are
given in Table 1. The structure of the compounds was
elucidated by elemental analysis, MS, FT-IR, NMR (1H
and 13C) spectral data.
10
11
12
13
14
15
12.50
25.00
50.00
50
50.00
100.00
100.00
50
100.00
50.00
100.00
25
25.00
100.00
25.00
50
25
12.5
25
25
25
12.5
12.5
12.5
25
Ciprofloxacin 25
25
50
S
Antibacterial activity
NH
N
NH
All the synthesised novel 7,9-diaryl-1,2,4-triaza-8-oxa-
spiro[4.5]-decan-3-thiones 10–15 were tested for their
antibacterial activity in vitro against Staphylococcus aureus,
Pseudomonas aeruginosa, Escherichia coli and Staphylo-
coccus typhi and ciprofloxacin was used as standard drug
whose minimum inhibitory concentration (MIC) values
were furnished in Table 2. To get clear idea about the
structure activity relationship for the synthesised com-
pounds, numberings of the target compound are done
(Fig. 1).
R1
R
4
3
2
5
6
1
6'
2'
O
2''''
6''''
Fig. 1 A well numbered target molecules (10–15)
(MIC) values were depicted in Table 3. In general, all the
synthesised compounds exerted a wide range of modest in
vitro antifungal activity against all the tested organisms.
Moreover, of all the compounds tested, compounds 13 and
14 were more effective against A. flavus than the standard
drug Amphotericin-B. MIC values in mg/ml for com-
pounds 13 and 14 were 12.5 for A. flavus.
All the compounds 10–15 were active against all the
tested bacterial strains. Compounds 14 and 15 were more
potent against E. coli and S. typhi and compound 10 against
S. aureus and S. typhi than the standard drug ciprofloxacin
with minimum inhibitory concentration (MIC) value in the
range of 12.5–25 mg/ml.
Antifungal activity
Conclusion
The in vitro antifungal studies of all the synthesised com-
pounds 10–15 were tested against C. albicans, Rhizopus
sp., A. niger and A. flavus, Amphotericin-B was used as
reference drug and their minimum inhibitory concentration
A comparison of potency of the compounds 10–15 is given
in the form of Figs. 2 and 3 by employing the following the
equation
Table 1 Analytical data of compounds 10–15
Table 3 In vitro antifungal activity of compounds 10–15
Entry
R
Reaction
time (h)
Yield
(%)
m.p. (°C)
Mass
(M?)
Entry
Minimum inhibitory concentration (MIC) in lg/ml
C. albicans Rhizopus sp. A. niger A. flavus
10
11
12
13
14
15
H
5
6
8
4
5
6
86
82
80
82
89
79
122
146
158
131
138
142
325
339
353
401
415
429
10
11
12
13
14
15
200.00
100.00
100.00
50
100.00
25.00
100.00
12.5
25
50.00
50.00
25.00
50
100.00
50.00
50.00
12.5
12.5
50
CH3
CH2CH3
H
CH3
50
25
CH2CH3
25
12.5
25
25
The micro analysis values for C, H and N were within 0.4% of the
theoretical values
Amphotericin-B 25
50
50
123

Med Chem Res (2011) 20:542–548
545
of biological activities, while the activity was not much
significant for compounds 10–12 without phenyl substitu-
tion at N-4 of triazole moiety.
Among compounds 10–15, 10, 14 and 15 against
S. aureus and against S. typhi, 14 and 15 against E. coli,
were shown to be significant in their antibacterial potency
at 12.5 and 25 lg/ml. Furthermore, their activity was also
on a par with the standard drugs used and for some com-
pounds was even higher than the activity of the standard
drugs.
Similarly, against the tested fungal strains, compound
11, 13, 14 and 15 against Rhizopus sp., 14 and 15 against
A. niger and 13 and 14 against A. flavus recorded enhanced
activity at 12.5 and 25 lg/ml. However, the activity of
compound 15 against all the tested organisms was found to
be superior to the other compounds and with an even
higher activity than the standard against Rhizopus sp. and
A. niger.
Fig. 2 Comparison of potency of compounds 10–15 with Ciproflox-
acin (as standard) against bacterial strains from serial dilution method
Experimental
Chemistry
TLC was carried out to monitor the course of the reaction
and purity of the product. The melting points were recor-
ded in open capillaries and are uncorrected. IR spectra
were recorded in AVATAR-330 FT-IR spectrophotometer
(Thermo Nicolet) and only noteworthy absorption levels
1
Fig. 3 Comparison of potency of compounds 10–15 with Ampho-
tericin-B (as standard) against fungal strains from serial dilution
method
(reciprocal centimetres) are listed. H-NMR spectra were
recorded at 400 MHz on BRUKER AMX 400 MHz spec-
trophotometer using CDCl3 as solvent and TMS as an
internal standard. 13C-NMR spectra were recorded at
100 MHz on BRUKER AMX 400 MHz spectrophotometer
in CDCl3. FAB mass spectra were recorded on a JEOLSX
102/DA-6000 mass spectrometer using Argon/Xenon
(6 kV, 10 mA) as the FAB gas and microanalyses were
performed on Heraeus Carlo Erba 1108 CHN analyzer.
Unless otherwise stated, all the reagents and solvents used
were of high grade and purchased from Fluka and Merck.
All the solvents were distilled prior to use.
MICðlg=mlÞ of reference
Potency ¼
ꢁ 100:
MICðlg=mlÞ of tested compound
From this study, it is clear that presence of a phenyl
group at triazole moiety is considered to be advantageous
for elevated antimicrobial activity. Furthermore, the
observed marked antibacterial and antifungal activities
may be considered as key steps for the building of novel
chemical entities with comparable pharmacological pro-
files to that of the standard drugs after considering results
from toxicology studies.
By employing the literature precedent (Japp and Mait-
land 1904) all the parent 3-alkyl-2,6-diphenylpyran-4-ones
(2 and 3) were prepared by the condensation of appropriate
ketones with benzaldehyde in the presence of KOH in
water ethanol medium whereas 2,6-diphenylpyran-4-one
(1) was prepared acetone dicarboxylic acid with benzal-
dehyde in the presence of HCl gas.
A close survey of the in vitro antibacterial and anti-
fungal activity profile of the new 7,9-diaryl-1,2,4-triza-
8-oxa-spiro[4.5]-decan-3-thiones against the tested bacte-
rial and fungal organisms gives a clear picture about the
structure–activity correlations among compounds 10–15
under study. Compounds 13, 14 and 15 with phenyl sub-
stitution at N-4 of triazole moiety along with and without
alkyl substituent at the C-3 position exerted a varied range
Synthesis of pyran-4-one thiosemicarbazones (4–9)
The mixture of ketone (0.01 mol) and thiosemicarbazide
(0.01 mol) in the presence of concentrated hydrochloric
123

546
Med Chem Res (2011) 20:542–548
acid was refluxed for 3 h in methanol medium. After
cooling, the mixture was poured over crushed ice. The
solid product thus obtained was filtered off and recrystal-
lised twice from methanol to give thiosemicarbazone as
crystalline solid.
57.37 (C-6), 42.33 (C-10), 80.03 (spirocarbon); 141.52–
126.07 (aromatic carbons), 159.59 (C=S), 14.42 (6-CH2CH3),
16.15 (6-CH2CH3). Mass m/z: 353 (molecular ion peak).
7,9-Diphenyl-1,2,4-triazaspiro-8-oxa-(4.5)decan-3-thione
(13)
Synthesis of 7,9-diphenyl-1,2,4-triazaspiro(4.5)decan-
3-thione (10)
IR (cm-1): 3401, 3339, 3278 (NH), 1588 (NH.C=S), 1278
(C=S). 1H NMR d (ppm), 4.32 (2H, dd, J3 = 10.01,
1.98 Hz H-7 and H-9), 3.17 (4H, m, H-6a, H-10a, H-6e and
H-10e), 7.21–7.41 (15H, m, aromatic protons), 7. 62 (1H, b
s, NH at 2), 6.91 (1H, b s NH at 1). 13C NMR d (ppm),
73.76 (C-7 and C-9), 46.12 (C-6 and C-10), 82.32 (spiro-
carbon); 141.23–114.94 (aromatic carbons), 159.33 (C=S),
Mass spectrum m/z: 401 (molecular ion peak).
The solution of 4 (0.005 mol) in chloroform (40 ml) was
treated with excess of hydrogen peroxide (30%, 20 ml) and
stirred 8 h at 0°C. After the completion of reaction the
organic layer was separated and dried over anhydrous
sodium sulphate. The solvent was removed under reduced
pressure. The crude product, thus obtained was purified
over neutral alumina column using n-hexane-ethyl acetate
(5:2) as eluent. IR (cm-1): 3433, 3325, 3310 (NH), 1592
7,9-Diphenyl-6-methyl-1,2,4-triazaspiro-8-oxa-(4.5)decan-
3-thione (14)
1
(NH.C=S), 1272 (C=S). H NMR d (ppm), 4.43 (2H, dd,
J3 = 10.50, 1.57 Hz H-7 and H-9), 3.20 (4H, m, H-6a,
H-10a, H-6e and H-10e), 7.31–7.22 (10H, m, aromatic
protons), 8.78 (2H, b s, NH at 2 and 4), 7.72 (1H, b s NH at
1). 13C NMR d (ppm), 72.34 (C-7 and C-9), 47.92 (C-6 and
C-10), 78.32 (spirocarbon); 140.29–123.85 (aromatic car-
bons), 156.93 (C=S), Mass spectrum m/z: 325 (molecular
ion peak).
IR (cm-1): 3389, 3343, 3286 (NH), 1590 (NH.C=S), 1261
(C=S). 1H NMR d (ppm), 4.60 (1H, d, J3 = 10.00 Hz;
2.00 Hz H-9), 4.17 (1H, d, J3 = 10.08, H-7), 3.16 (2H, m,
H-6a and H-10a), 2.68 (1H, dd, J2 = 12.72 Hz;
J3 = 1.82 Hz, H-10e), 7.22–7.39 (15 H, m, aromatic pro-
tons), 7.61 (1H, b s, NH at 2), 6.61 (1H, b s NH at 1), 0.73
(3H, d, J = 6.5, 6-CH3). 13C NMR d (ppm), 80.82 (C-7),
77.17 (C-9), 49.53 (C-6), 45.28 (C-10), 85.36 (spirocar-
bon); 142.14–115.41 (aromatic carbons), 160.23 (C=S),
11.21 (6-CH3) Mass m/z: 415 (molecular ion peak).
The similar procedure was followed to synthesise
compounds 11–15
7,9-Diphenyl-6-methyl-1,2,4-triazaspiro-8-oxa-(4.5)decan-
3-thione (11)
7,9-Diphenyl-6-ethyl-1,2,4-triazaspiro-8-oxa-(4.5)decan-
3-thione (15)
IR (cm-1): 3424, 3318, 3310 (NH), 1588 (NH.C=S), 1265
(C=S).1H NMR d (ppm), 4.51 (1H, d, J3 = 10.3 Hz;
1.86 Hz H-9), 4.20 (1H, d, J3 = 10.30, H-7), 3.10 (2H, m,
H-6a and H-10a), 2.72 (1H, dd, J2 = 12.72 Hz;
J3 = 1.82 Hz, H-10e), 7.49–7.23 (10H, m, aromatic pro-
tons), 8.90 (2H, b s, NH at 2 and 4), 7.62 (1H, b s NH at 1),
0.79 (3H, d, J = 6, 6-CH3).13C NMR d (ppm), 79.902
(C-7), 76.74 (C-9), 50.26 (C-6), 44.66 (C-10), 81.39 (spi-
rocarbon); 141.70–125.81 (aromatic carbons), 158.66
(C=S), 11.54 (6-CH3) Mass m/z: 339 (molecular ion peak).
IR (cm-1): 3401, 3342, 3289 (NH), 1576 (NH.C=S), 1269
(C=S). 1H NMR d (ppm), 4.27 (1H, dd, J = 10.50;
2.00 Hz, H-9), 3.92 (1H, d, J3 = 10.50 Hz, H-7), 2.82 (2H,
m, H-6a and H-10a), 2.81 (1H, dd, J2 = 13.00 Hz;
J3 = 2.00 Hz, H-10e), 7.20–7.39 (15H, m, aromatic pro-
tons), 7.34 (1H, b s, NH at 2), 6.49 (1H, b s NH at 1), 0.38
(3H, t, 6- CH2CH3), [1.29 (1H, m) and 1.64 (1H, m)
6-CH2CH3]. 13C NMR d (ppm), 72.63 (C-7), 76.07 (C-9),
56.14 (C-6), 41.76 (C-10), 85.45 (spirocarbon);
140.87–115.26 (aromatic carbons), 160.59 (C=S), 14.01
(6-CH2CH3), 16.24 (6-CH2CH3). Mass m/z: 429 (molecular
ion peak).
7,9-Diphenyl-6-ethyl-1,2,4-triazaspiro-8-oxa-(4.5)decan-
3-thione (12)
IR (cm-1): 3416, 3336, 3301 (NH), 1580 (NH.C=S), 1272
(C=S). 1H NMR d (ppm), 4.32 (1H, dd, J = 10.30;
1.86 Hz, H-9), 3.94 (1H, d, J3 = 10.06 Hz, H-7), 2.86 (2H,
m, H-6a and H-10a), 2.78 (1H, dd, J2 = 12.88 Hz;
J3 = 1.65 Hz, H-10e), 7.42–7.21 (10H, m, aromatic pro-
tons), 8.94 (2H, b s, NH at 2 and 4), 7.73 (1H, b s NH at 1),
0.32 (3H, t, 6-CH2CH3), [1.31 (1H, m) and 1.70 (1H, m)
6-CH2CH3]. 13C NMR d (ppm), 76.28 (C-7), 75.57 (C-9),
Microbiology
The in vitro activities of the compounds were tested in
Sabourauds dextrose broth (SDB, Hi-media, Mumbai) for
fungi and Nutrient broth (NB, Hi-media, Mumbai) for
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Med Chem Res (2011) 20:542–548
547
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Acknowledgements We are thankful to Prof. K. Pandiarajan, Head,
Department of Chemistry, Annamalai University for the facilities
provided. One of the authors SK is grateful to Council of Scientific
and Industrial Research, New Delhi, India for financial support in the
form of Research Project. We also thank NMR Research Centre, IISc,
Bangalore for providing all the NMR facilities to record NMR
spectra.
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