Synthesis and biological evaluation of 5,7-diaryl-4,4-dimethyl-4,5,6,7- tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles

Article abstract of DOI:10.1007/s00044-007-9051-6

New 5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3- thiadiazoles 23-27 are synthesized, characterized by melting point, elemental analysis, magnetic spectroscopy (MS), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) (¹H and ¹³C) spectra and evaluated for their in vitro antibacterial and antifungal activities. Compounds 23-27 are more potent against Gram-positive bacterial strains, namely Staphylococcus aureus and β-Haemolytic streptococcus. However compounds 23-27 possess potent activity against Klebsiella pneumonia, a Gram-negative bacterial strain, compared to the standard drug used, ciprofloxacin. In general, all the synthesized compounds exert a wide range of modest in vitro antifungal activity against Rhizopus and Microsporum gypsuem than the standard drug, fluconazole.

Full text of DOI:10.1007/s00044-007-9051-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2007) 16:392–401
DOI 10.1007/s00044-007-9051-6
ORIGINAL RESEARCH
Synthesis and biological evaluation of 5,7-diaryl-4,4-
dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-
thiadiazoles
M. Gopalakrishnan Æ J. Thanusu Æ V. Kanagarajan
Received: 4 August 2007 / Accepted: 5 November 2007 / Published online: 11 December 2007
¨
Ó Birkhauser Boston 2007
Abstract New 5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-thiadi-
azoles 23–27 are synthesized, characterized by melting point, elemental analysis,
magnetic spectroscopy (MS), Fourier-transform infrared spectroscopy (FT-IR), nuclear
magnetic resonance (NMR) (1H and 13C) spectra and evaluated for their in vitro
antibacterial and antifungal activities. Compounds 23–27 are more potent against
Gram-positive bacterial strains, namely Staphylococcus aureus and b-Haemolytic
streptococcus. However compounds 23–27 possess potent activity against Klebsiella
pneumonia, a Gram-negative bacterial strain, compared to the standard drug used,
ciprofloxacin. In general, all the synthesized compounds exert a wide range of modest
in vitro antifungal activity against Rhizopus and Microsporum gypsuem than the stan-
dard drug, fluconazole.
Keywords 3,3-dimethyl-2,6-diarylpiperidin-4-one Á 1,2,3-thiadiazoles Á
Thionyl chloride Á Antibacterial activity Á Antifungal activity
Introduction
It is well known that a number of heterocyclic compounds containing sulfur
possess different pharmacophoric properties (Shafiee et al., 1973; Katritzky, 1985;
Balasankar et al., 2007) 1,2,3-Thiadiazoles are useful intermediates in organic
synthesis (Rovira, 1994), as well as being an important of class of biologically
M. Gopalakrishnan (&) Á J. Thanusu Á V. Kanagarajan
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Annamalai University,
Annamalainagar 608 002, Tamil Nadu, India
e-mail: profmgk@yahoo.co.in

Med Chem Res (2007) 16:392–401
393
active compounds (Stanetty et al., 1998; Britton et al., 1984; Stanetty et al., 1996;
Lewis et al., 1979). For instance, 4,5-bis(4’-methoxyphenyl)-1,2,3-thiadiazoles has
been found to be an active inhibitor of collagen-induced platelet aggregation
in vitro (Thomas et al., 1985). Originally, 1,2,3-thiadiazoles were synthesized
from the reaction of a-methylene (or ethyl) hydrazones (Hurd et al., 1955). Many
other methods have since been developed for the synthesis of 1,2,3-thiadiazoles
(Thomas et al., 1984; Fujita et al., 1993), of which the Hurd–Mori cyclization
(Byron et al., 1966; Tumkevicius et al., 2003; Ghandi et al., 2000; Smeets et al.,
1998) of a-methylene ketones offers the most convenient methodology.
Piperidin-4-one nuclei have aroused great interest, both in the past and in recent
years, due to their wide variety of biological properties, such as being antiviral,
antitumor (El-Subbagh et al., 2000; Watson et al., 2001), having central nervous
system effects (Ganellin et al., 1965), local anesthetic properties (Hagenbach et al.,
1952), and anticancer (Ileana et al., 1989) and antimicrobial activity (Mokio et al.,
1989). Their derivative, piperidine, is also biologically important and act as a
neurokinin receptor antagonist (Dimmock et al., 1997), an analgesic and an anti-
hypertensive (Kubota et al., 1998).
In recent years there has been a great deal of interest in exploiting multiple
proximal functional groups in the design of novel structures capable of performing a
variety of functions. One such functional addition is the a-keto methylene group,
which has been used as a building block for 1,2,3-thiadiazoles. These observations
place new emphasis on the synthesis of 2,6-diarylpiperidin-4-one derivatives with a
view to incorporation of a bioactive heterocyclic nucleus, such as 1,2,3-thiadiazoles,
intact, for the evaluation of associated antibacterial and antifungal activity.
Synthesis of molecules that are novel but still resemble 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 design. In continuation of
our earlier work on 3-alkyl-2,6-diarylpiperidin-4-one derivatives (Gopalakrishnan
et al., 2007; Gopalakrishnan et al., 2007), and 1,2,3-thiadiazoles (Balasankar et al.,
2005), we report the synthesis of 3,3-dimethyl-2,6-diarylpiperidin-4-ones that
posses an a-keto methylene group, thus permitting the preparation of a new class of
compounds,
thiadiazoles.
5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-
Chemistry
The only available method for synthesis of the target molecule is the conversion
of semicarbazones of the respective 3,3-dimethyl-2,6-diarylpiperidin-4-ones by
thionyl chloride in dichloromethane. The schematic representation and analytical
data for the synthesized compounds 23–27 are furnished Scheme 1 and Table 1,
respectively. A four-step synthetic strategy yields compounds 23–27. A mixture
of 3-methyl-butan-2-one (1), the appropriate benzaldehyde (2–6), and ammonium
acetate (7) in the ratio of 1:2:1, is warmed for 15 minutes and hydrochloric acid
is then added to afford 3,3,-dimethyl-2,6-diaryl-piperidin-4-ones hydrochloride 8–

394
Med Chem Res (2007) 16:392–401
O
O
CH3
HO
CH3
, warm, 15 min
HCl
N
H
1
H
O
H
O
.HCl
+
X
X
8-12
Ice
30 min
NH4 OH-
+
O
X
X
CH3
+
2-6
NH4
2-6
CH3
-O
O
N
H
7
13-17
X
X
X=H, CH3, OCH3, Cl or F
H2NNHCONH2.HCl
CH3COONa.3H2O
HO
reflux, 30 min
H2N
O
N
HN
3
2
N
a
N
b
1
c
S
SOCl2
CH3
CH3
d
CH3
CH3
9
4
5
8
CH2Cl2
stirring, 0-5 C
°
7
6
1 hr
N
H
N
H
18-22
23-27
X
X
X
X
Scheme. 1 Synthetic pathway for the synthesis of novel bioactive 5,7-Diaryl-4,4-dimethyl-4,5,6,7-
tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles
12, which upon neutralization with aqueous ammonia at 0°C give the respective
3,3,-dimethyl-2,6-diaryl-piperidin-4-ones 13–17. Piperidones are converted into
their semicarbazones 18–22 and are eventually cyclized into 5,7-diaryl-4,4-
dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles 23–27 using thionyl
chloride in dichloromethane. The structures of the compounds are elucidated by
melting points, elemental analysis, MS, FT-IR, NMR (1H and 13C) spectroscopic
data.

Med Chem Res (2007) 16:392–401
395

396
Med Chem Res (2007) 16:392–401
Results and discussion
Biological evaluation
Antibacterial activity
All of the newly synthesized novel target molecule 5,7-diaryl-4,4-dimethyl-4,5,6,7-
tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles 23–27 were tested for their antibacte-
rial activity in vitro (Table 2) against Staphylococcus aureus, b-Haemolytic
streptococcus, Vibreo cholerae, Salmonella typhii, Shigella felxneri, Escherichia
coli, Klebsiella pneumonia, and Pseudomonas. Ciprofloxacin, at a concentration of
5 lg/disc was used as standard drug for comparison, whose zone of inhibition
values (mm) for S. aureus, b-Haemolytic streptococcus, V. cholerae, S. typhii, S.
felxneri, E. coli, K. pneumonia and Pseudomonas, are 25, 28, 23, 22, 23, 24, 26, and
23 mm, respectively. In general, the synthesized novel 5,7-diaryl-4,4-dimethyl-
4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles 23–27 exerted a wide range of
modest antibacterial activity in vitro against Gram-positive bacterial strains,
namely, S. aureus and b-Haemolytic streptococcus than the standard drug,
ciprofloxacin. However, compounds 23–27 display potent activity against
K. pneumonia, a Gram-negative bacterial strain.
Antifungal activity
The in vitro antifungal activity (Table 2) of the synthesized novel heterocyclic
compounds 23–27, was studied against the fungal strains viz., Aspergillus flavus,
Mucor, Rhizopus, and Microsporum gypsuem. Fluconazole, at 100 units/disc
concentration, was used as a standard drug whose zone of inhibition values (mm)
for A. flavus, Mucor, Rhizopus and M. gypsuem, are 20 0.5 mm against all of the
tested fungi. In general, the synthesized compounds exerted a wide range of modest
in vitro antifungal activity against Rhizopus and M. Gypsuem, compared to the
standard drug, fluconazole, but their activity decreased upon dilution.
Conclusion
In vitro antibacterial and antifungal activity profiles in differently substituted novel
5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles 23–27
against the tested bacterial strains, viz., S. aureus, b-Haemolytic streptococcus, V.
cholerae, S. typhii, E. coli, K. pneumonia, Pseudomonas, and the fungal strains, viz.,
A. flavus, A. fumigatus, Mucor, and Rhizopus, respectively, provide a useful
structure–activity relationship correlate. This may be summarized as follows: the
results of this study show that the presence of both electron-donating substituent
(methyl, methoxy) and electron-withdrawing substituent (chloro, fluoro) at the para
positions on the phenyl ring in compounds 23–27 are responsible for the activity
against gram positive bacterial strains, namely, S. aureus, b-Haemolytic

Med Chem Res (2007) 16:392–401
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Med Chem Res (2007) 16:392–401
streptococcus. However, compounds 23–27 possess potent activity against
K. pneumonia, a Gram-negative bacterial strain than the standard drug, ciproflox-
acin. All the synthesized compounds 23–27 against Rhizopus and M. gypsuem, exert
a wide range of modest in vitro antifungal activity, compared to the standard drug,
fluconazole.
Experimental section
Microbiology
Materials
All of the bacterial strains, namely S. aureus, b-Haemolytic streptococcus,
V. cholerae, S. typhii, S. felxneri, E. coli, K. pneumonia, Pseudomonas, and fungal
strains, namely, A. flavus, Mucor, Rhizopus and M. gypsuem, were obtained from
the Faculty of Medicine, Annamalai University, Annamalainagar-608 002, Tamil
Nadu, India.
In vitro antibacterial and antifungal activity
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 bacteria by the disc diffusion method (Maruzella, 1958). The respective
hydrochlorides of the test compounds 23–27 were dissolved in water to obtain 1 mg
ml-1 stock solution and the different concentrations (100, 200, 500 ppm) are
prepared from the stock solution. Seeded broth (containing microbial spores) was
prepared in NB from 24 hour-old bacterial cultures grown on nutrient agar (Hi-
media, Mumbai) at 37 1°C, while fungal spores from one- to seven-day-old
Sabourauds agar (Hi-media, Mumbai) slant cultures were suspended in SDB. Sterile
paper discs of 5 mm diameter were saturated with the three different concentrations
and then placed in each of the seeded agar plates. The Petri dishes are incubated in a
BOD incubator at 37°C for bacteria and 28°C for fungi. The zone of inhibition is
recorded by visual observations after 24 hours for bacteria and after 72–96 hours for
fungi. Moreover, the zone of inhibition is measured by excluding the diameter of the
paper disc. Ciprofloxacin was used as the standard for bacteria and fluconazole as
the standard for fungi, under analogous conditions. Ciprofloxacin, 5 lg/disc
concentration, was used as the standard drug, whose zone of inhibition values
(mm) for S. aureus, b-Haemolytic streptococcus, V. cholerae, S. typhii, S. felxneri,
E. coli, K. pneumonia and Pseudomonas are 25, 28, 23, 22, 23, 24, 26, and 23 mm
respectively. Fluconazole, at a concentration of 100 units/disc, was used as a
standard drug whose zone of inhibition (mm) value for A. flavus, Mucor, Rhizopus
and M. gypsuem is 20 0.5 mm.

Med Chem Res (2007) 16:392–401
399
Chemistry
Thin-layer chromatography (TLC) was used to assess the reactions and the purity of
the products. All the reported melting points were taken in open capillaries and were
uncorrected. Infrared (IR) spectra were recorded in KBr (pellet form) on a Nicolet-
Avatar-330 FT-IR spectrophotometer and only noteworthy absorption values
(cm-1) are listed. 1H and 13C NMR spectra were recorded at 400 MHz and
100 MHz respectively on Bruker AMX 400 NMR spectrometer using CDCl3 as
solvent. The electrospray ionization (ESI) positive MS spectra were recorded on a
Bruker Daltonics liquid chromatography (LC) -MS spectrometer. Satisfactory
microanalysis was obtained on a Carlo Erba 1106 CHN analyzer.
3,3-Dimethyl-2,6-diarylpiperidin-4-ones were prepared 8–17 by adopting the
precedent set in the literature (Noller and Balaiah, 1948; Pandiarajan et al., 1991).
General method of preparation of 3,3-dimethyl-2,6-diarylpiperidin-4-one
semicarbazones (18–22)
A mixture of 3,3-dimethyl-2,6-diarylpiperidin-4-one (0.01 mol), semicarbazide
hydrochloride (0.01 mol) and sodium acetate (0.02 mol) in ethanol (40 mL) was
refluxed on a steam bath for 30 minutes and was then concentrated to one-third of
its original volume. After cooling, the mixture was poured over crushed ice. The
solid product thus obtained was then filtered off and recrystallized from ethanol
twice to give 3,3-dimethyl-2,6-diarylpiperidin-4-one semicarbazones as crystalline
solids.
Typical procedure for the synthesis of 5,7-diphenyl-4,4-dimethyl-4,5,6,7-
tetrahydropyridino[3,4-d]-1,2,3-thiadiazoles (23)
A
solution of 3,3-dimethyl-2,6-diphenylpiperidin-4-one semicarbazone (18)
(0.005 mol) in dichloromethane (50 mL) was treated with thionyl chloride
(0.01 mol) and stirred for one hour at 0–5°C. The reaction mixture was decomposed
with an ice-cold solution of sodium carbonate solution. The organic layer was
washed with brine solution, then washed with excess of water and finally dried over
anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure,
a gummy mass was obtained that solidified after treatment with petroleum ether
(40–60). Final purification was done using column chromatography using silica gel
(100–200 mesh), with dichloromethane-petroleum ether (40–60°C) (5 : 1) as eluent.
IR (KBr) (cm1): 3304, 3061, 3030, 2967, 2922, 2881, 2796, 1583, 684, 764, 705;
1H NMR (d ppm): 1.24 (s, 3H, CH3 at C-4), 1.69 (s, 3H, CH3 at C-4), 1.93 (s, 1H,
H6); 4.79 (s, 1H, H5), 5.37 (s, 1H, H7), 7.20–7.58 (m, 10H, Harom); 13C NMR (d
ppm): 26.3 CH3 at C-4, 28.0 CH3 at C-4, 37.4 C-4, 69.3 C-5, 73.8 C-7, 126.7–128.6
–Carom ,140.6, 142.7 ipso-C, 159.0 C-8, 170.6 C-9.
Compounds 24–27 were synthesized similarly.

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Med Chem Res (2007) 16:392–401
5,7-Bis(p-methylphenyl)-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-
thiadiazoles (24)
1
IR (KBr) (cm1): 3301, 3024, 2966, 2925, 2855, 1582, 817,675; H NMR (d ppm):
1.20 (s, 3H, CH3 at C-4), 1.70 (s, 3H, CH3 at C-4), 2.26 (s, 1H, H6); 2.32 (s, 6H, CH3
at Arom. ring), 4.84 (s, 1H, H5), 5.40 (s, 1H, H7), 7.14–7.25 (m, 8H, Harom); 13C
NMR (d ppm): 21.0 CH3 at Arom. ring, 26.7 CH3 at C-4, 28.3 CH3 at C-4, 37.7 C-4,
68.3 C-5, 73.4 C-7, 127.2–142.4 –Carom , 158.4 C-8, 170.1 C-9.
5,7-Bis(p-methoxylphenyl)-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-
thiadiazoles (25)
1
IR (KBr) (cm-1):3313, 2957, 2924, 2921, 1576, 834, 678; H NMR (d ppm): 1.37
(s, 3H, CH3 at C-4), 1.53 (s, 3H, CH3 at C-4), 2.34 (s, 1H, H6); 3.82 (s, 6H, OCH3 at
Arom. ring), 4.78 (s, 1H, H5), 5.35 (s, 1H, H7), 7.21–7.41 (m, 8H, Harom); 13C NMR
(d ppm): 24.4 CH3 at C-4, 25.4 CH3 at C-4, 37.6 C-4, 55.1, 55.4 -OCH3 at Arom.
ring, 68.1 C-5, 73.3 C-7, 113.7–131.8, 159.3, 159.6 –Carom ,158.4 C-8, 170.3 C-9.
5,7-Bis(p-chlorophenyl)-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-
thiadiazoles (26)
IR (KBr) (cm-1): 3325, 3291, 2928, 2861, 1578, 834, 686; 1H NMR (d ppm): 1.21
(s, 3H, CH3 at C-4), 1.70 (s, 3H, CH3 at C-4), 2.14 (s, 1H, H6), 4.47 (s, 1H, H5), 5.08
(s, 1H, H7), 7.18–7.47 (m, 8H, Harom); 13C NMR (d ppm): 26.2 CH3 at C-4, 28.3
CH3 at C-4, 37.3 C-4, 68.7 C-5, 73.0 C-7, 128.0–138.7 –Carom , 158.5 C-8, 170.7
C-9.
5,7-Bis(p-fluorophenyl)-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-
thiadiazoles (27)
1
IR (KBr) (cm1): 3318, 3297, 2924, 2857, 1574, 1211, 825, 681; H NMR (d ppm):
1.22 (s, 3H, CH3 at C-4), 1.76 (s, 3H, CH3 at C-4), 2.18 (s, 1H, H6), 4.55 (s, 1H, H5),
5.08 (s, 1H, H7), 7.26–7.47 (m, 8H, Harom); 13C NMR (d ppm): 26.6 CH3 at C-4,
28.5 CH3 at C-4, 37.7 C-4, 69.0 C-5, 73.4 C-7, 128.5–139.4 –Carom , 159.1 C-8,
171.5 C-9.
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