Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide derivatives as potent anticonvulsant agents

Article abstract of DOI:10.1016/j.ejmech.2014.01.010

Abstract An efficient synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide derivatives has been achieved under aqueous medium for the first time in good to excellent yields. All the synthesized compounds were tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most broadly employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotarod test. Seven compounds 4a, 4d, 4f, 4h, 4o, 4p and 4q showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 4d showed the MES-induced seizures with ED₅₀ value of 10.2 mg/kg and TD₅₀ value of 288.6 mg/kg after intraperitoneal injection to mice, which provided compound 4d with a protective index (TD₅₀/ED₅₀) of 28.3 in the MES test.

Full text of DOI:10.1016/j.ejmech.2014.01.010

Accepted Manuscript
Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide derivatives
as potent anticonvulsant agents
Naushad Edayadulla, Penugonda Ramesh
PII:
S0223-5234(14)00041-5
10.1016/j.ejmech.2014.01.010
EJMECH 6663
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 21 August 2013
Revised Date: 14 December 2013
Accepted Date: 6 January 2014
Please cite this article as: N. Edayadulla, P. Ramesh, Synthesis of 2,6-dicarbethoxy-3,5-
diaryltetrahydro-1,4-thiazine-1,1-dioxide derivatives as potent anticonvulsant agents, European Journal
of Medicinal Chemistry (2014), doi: 10.1016/j.ejmech.2014.01.010.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide derivatives as
potent anticonvulsant agents
Naushad Edayadullaa,* and Penugonda Rameshb,*
In the present study, synthesis and anticonvulsant activity of 2,6-dicarbethoxy-3,5-
diaryltetrahydro-1,4-thiazine-1,1-dioxide derivatives have been described.
O
O
O
S
O
O
O
N
H
Cl
Cl
4d
*Corresponding author:
aN. Edayadulla, Department of Chemistry,
Mother Teresa Women’s University, Kodaikanal-624 101, Tamil Nadu,
India. Tel.: +91-9865312896. E-mail: edayam2004@gmail.com
bP. Ramesh, Department of Natural Products Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai – 625021, Tamil Nadu,
India. Tel.: 0452- 2458471. E-mail: npc_ramesh@yahoo.co.in

ACCEPTED MANUSCRIPT
Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-
dioxide derivatives as potent anticonvulsant agents
Naushad Edayadullaa,* and Penugonda Rameshb,*
a,*Department of Chemistry, Mother Teresa Women’s University, Kodaikanal-624 101,
Tamilnadu, India.
b,*Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai - 625 021, Tamil Nadu, India.
Abstract
An efficient synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide
derivatives has been achieved under aqueous medium for the first time in good to excellent
yields. All the synthesized compounds were tested for anticonvulsant activity using the maximal
electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most
broadly employed seizure models for early identification of candidate anticonvulsants. Their
neurotoxicity was determined applying the rotarod test. Seven compounds 4a, 4d, 4f, 4h, 4o, 4p
and 4q showed promising anticonvulsant activities in both models employed for anticonvulsant
evaluation. The most active compound 4d showed the MES-induced seizures with ED50 value of
10.2 mg/kg and TD50 value of 288.6 mg/kg after intraperitoneal injection to mice, which
provided compound 4d with a protective index (TD50/ED50) of 28.3 in the MES test.
Keywords: Thiazine-1,1-dioxide derivatives, water medium, epilepsy, anticonvulsant.
*Corresponding author:
N. Edayadulla, Department of Chemistry,
Mother Teresa Women’s University, Kodaikanal-624 101, Tamil Nadu,
India. Tel.: +91-9865312896. E-mail: edayam2004@gmail.com
P. Ramesh, Department of Natural Products Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai – 625021, Tamil Nadu,
India. Tel.: 0452- 2458471. E-mail: npc_ramesh@yahoo.co.in

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1. Introduction
Epilepsy is a neurological disorder that affects a wide range of people throughout the world
due to the disordered, synchronous and rhythmic firing of populations of brain neurons [1]. The
incidence of epilepsy in developed countries is approximately 50 per 100,000 while that in
developing countries is 100 per 100,000 [2]. The WHO estimates of ‘disability adjusted life
years’ (DALYs) suggest that epilepsy accounts for 0.5% of the world’s burden of disease, which
is the same as lung cancer among men or breast cancer among women [3]. It has been observed
that the presently available antiepileptic drugs are unable to control seizures in as many as 25%
of the patients effectively [4]. The conventional antiepileptic agents like phenytoin,
carbamazepine and sodium valproate carry with them several serious side effects notably
neurotoxicity [5]. As majority of antiepileptic drugs are consumed life long, concomitant
administration of other drugs predisposes to the risk of drug interaction. However, newer
antiepileptics like gabapentin, vigabatrin, lamotrigine, etc are used supplemental to the
conventional agents. Thus, it is necessary to investigate for an antiepileptic agent that is highly
efficacious as well as safe in terms of drug related toxicity. The aim of treating an epileptic is not
only to abolish the occurrence of seizures but also to lead a self-sustained life.
Therefore, search for a novel, highly effective and more selective agents with lesser side
effects continues to be an area of investigation of medicinal chemists worldwide. Recently
thiazine derivatives have been recognized as promising nuclei for their anticonvulsant activity
[6-11] and different aryl/heteroaryl moieties have been clubbed to the thiazine pharmacophore as
hydrophobic domain which led to the significant increase in the activity.
In connection with the above issues, our research efforts herein have been directed
towards the synthesis of new as well as already reported 2,6-dicarbethoxy-3,5-diaryltetrahydro-

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1,4-thiazine-1,1-dioxides under water medium and evaluating them for their medicinal
properties.
2. Chemistry
Perusal of literature suggests that the synthesis of thiazine derivatives make use of organic
solvents [12-13]. Owing to the hazardous behaviors of organic solvents, the development of
organic reactions under solvent-free and/or water medium being eco-friendly has attained much
importance and are of current interest which associated with many advantages [14-16]. Only a
very few reports on the synthesis of diaryltetrahydro-1,4-thiazine derivatives in organic solvents
has been documented [17][18]. Although several synthetic approaches for constructing
tetrahydro-1,4-thiazine rings have been reported by other groups [18][19], environmentally
benign and cost-effective approaches are still in demand. To the best of our knowledge, none of
reports on the synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxides in
water as reaction medium. In this regard, we herein submit the first report on water promoted
synthesis of the title compounds in good to excellent yields.
(Scheme 1)
The proposed synthetic protocol (Scheme 1) involves easily accessible starting materials and
simple procedures. Thus, the present strategy is very attractive and convenient route towards
synthesis of various thiazine derivatives in environ-friendly benign conscious. All the
1
13
synthesized compounds were completely characterized by IR, H NMR, and C NMR spectral
techniques. Further, the structure of a representative compound, 4l has been unequivocally
assigned by single crystal X-ray diffraction study [20].
3. Pharmacology results and discussion

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The
synthesized
2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxides
4a-r
derivatives were subjected to anticonvulsant screening according to the anticonvulsant drug
development (ADD) program protocol. The compounds 4a-r were administrated
intraperitoneally (ip) into the mice using dose of 30, 100 and 300 mg/kg and the observations
were taken at two different time intervals (0.5 h and 4.0 h). Neurotoxicity was measured by the
rotarod test. The calculated LogP values were calculated using the software in ACD Labs 8.0
version. The results are shown in Table 1.
The initial anticonvulsant evaluation indicated that all the compounds were effective in ip MES
and/or scPTZ screens. The results are summarized in Table 1. The compounds 4a-r with
substituted phenyl/heterocyclic moieties at the 3, 5-position of 3, 5-diaryltetrahydro-1,4-thiazine-
1,1- dioxides, show varying degree of anticonvulsant activity. In the MES test, all of the
compounds showed protection in half or more of the tested mice after 0.5 h indicative of their
ability to prevent seizure spread. Compounds which were active at 100 mg/kg after 0.5 h in MES
test included 4b, 4c, 4e, 4g, 4j, 4k, 4n and 4r indicative of their good ability to protect from
seizure spread at a higher dose. From these series 4a, 4d, 4f, 4h, 4o, 4p and 4q showed anti-MES
activity at the dose of 30 mg/kg at time periods 0.5 h, the most active compound 4d was active in
the MES test both at 0.5 h and 4.0 h in same dose, which was equivalent to phenytoin used as
reference anticonvulsant drug.
In scPTZ screen, compounds 4a, 4d, 4f, 4h, 4o, 4p and 4q were active after 4.0 h at the dose of
300 mg/kg, the other compounds showed no activity.
In the neurotoxicity screen, Compounds 4a, 4b, 4f, 4h, 4n, 4o, 4p and 4q did not show any
neurotoxicity in the maximum dose administered (300 mg/kg). Compound 4e revealed

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neurotoxicity at a dose of 100 mg/kg. The majority of these compounds exhibited less neurotoxic
than phenytoin.
(Table 1)
As a result of preliminary screening (phase-I) compounds 4a, 4d, 4f, 4h, 4o, 4p and 4q were
subjected to phase-II trials for quantification of the pharmacological parameters (ED50 and
TD50). The results of the quantitative test for these compounds, along with the data on the
standard drugs (phenytoin, carbamazepine, phenobarbital, and valproate) are reported in Table 2.
Interestingly, during the mice MES screen, the tested compounds showed a higher protective
index (PI) than all the standard drugs. Compounds 4a, 4f, 4p and 4q with ED50 value of 14.8,
11.4, 12.4 and 13.2 respectively, were nearly equipotent to the standard drug viz. carbamazepine.
Among the tested compounds, in particular, compound 4d showed an ED50 of 10.2 mg/kg and a
TD50 of 288.6 mg/kg proving its high protection index (PI) that is TD50/ED50, of 28.3 when
compared to standard drugs viz. phenobarbital and valproate. In the mice ip scPTZ screen,
compound 4d gave an ED50 of 50.5 mg/kg and a TD50 of 288.6 mg/kg, resulting in a high
protective index (PI), that is, TD50/ED50, of 5.7 when compared to phenobarbital and valproate.
Compounds 4a, 4d, 4f, 4h, 4o, 4p and 4q were selected for quantification of the pharmacological
parameters (ED50 and TD50). Results of the quantitative test for these compounds, along with the
data on the standard drugs (phenytoin, carbamazepine, phenobarbital, and valproate), are
reported in Table 2. In the mice MES screen, the tested compounds showed a higher protective
index (PI) than all the standard drugs.

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In the mice ip scPTZ screen, compound 4d gave an ED50 of 50.5 mg/kg and a TD50 of 288.6
mg/kg, resulting in a high protective index (PI), that is, TD50/ED50, of 5.7 when compared to
phenobarbital and valproate.
Structure-Activity Relationships
The most common structural elements of the clinically active anticonvulsants can be defined as a
nitrogen heterocyclic system bearing one or two phenyl rings and at least one carbonyl group.
Previous investigations indicated that the presence of at least one aryl group, one or two electron
donor atoms and/or an NH group in a special spatial arrangement seems to be necessary for
anticonvulsant activity [21]. In the present study, 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-
thiazine-1,1-dioxide derivatives were designed and synthesized to meet the structural
requirements for anticonvulsant activity. The results of the preliminary anticonvulsant screening
revealed that thiazine derivatives exhibit a remarkable anticonvulsant activity. The structural
requirement for maintaining the anticonvulsant activity is the presence of a -NH function at the
4- position of the thiazine ring. Here, it has been reported that the presence of a substituted
phenyl ring may acts as a lipophilic domain (Ar), an carbonyl group of the ester acts as electron
donor (D) and -NH function at the 4- position of the thiazine ring acts as hydrogen bonding
domain (HBD) was necessary for anticonvulsant activity, as evidenced by the active drugs, such
as carbamazepine, phenytoin or vinpocetine, fulfilling these demands [22]. This shows that the
synthesized compounds fulfil the structural requirement of hydrophobic moiety for both the
activities. Thus, the synthesized compounds 4a-r may be utilized in the future development of
novel anticonvulsants with broad spectrum of activity.
(Figure 1)

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The phenyl ring substituted with Cl, NO2 and CH3 in para position (4d, 4f, 4h) lead to
compounds with more anticonvulsant activity than ortho, and meta-position (4b, 4c). On the
other hand, the 4-methoxy substituent derivative (4g) was less potent than chloro, nitro and
methyl derivatives. The inclusion of more methoxy groups to phenyl ring (4g, 4r) resulted in
compounds have long duration of action at relatively higher dose (300 mg/kg). It was noteworthy
that the introduction of an aryl group other than phenyl in the tetrahydro-1,4-thiazine structure
had caused a significant reduction or the complete loss of activity (compounds 4i, 4j, 4k, 4l, 4m
and 4n), it seems that phenyl ring play a fundamental role in anti-MES protection [23]. The log P
value of 4p was 4.56, which is considered to be the optimum lipophilicity for the congeners that
act on the central nervous system [24]. This observation indicated the importance of lipophilicity
as well as electronic properties of the substituents on the activity of 3,5-diaryltetrahydro-1,4-
thiazine-1,1- dioxide derivatives. In this study, the compounds 4a, 4d, 4f, 4h, 4o, 4p and 4q were
highly potent in the MES test, and the MES test is known to be sensitive to sodium channel
inhibitors (e.g., phenytoin, carbamazepine), which suggested that the tested compounds may
inhibit voltage-gated ion channels (particularly sodium channels). Possibly the presence of the H
donor part in addition to the two other essential structure elements R and D may be sufficient for
antagonistic activity at the voltage-dependent sodium channel. PTZ has been reported to produce
seizures by inhibiting γ-aminobutyric acid (GABA) neurotransmission [25]. GABA is the main
inhibitory neurotransmitter in the brain, and is widely implicated in epilepsy. Inhibition of
GABAergic neurotransmission or activity has been shown to promote and facilitate seizures
[26], while GABAergic enhancement is known to inhibit or attenuate seizures. The inhibition of
synthesized compound upon the PTZ-induced tonic seizures might be related to the enhancing of
GABAergic neurotransmission or activity [27]. The results suggesting that several different

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mechanisms of action might be involved in its anticonvulsant activity, including the inhibition of
voltage-gated ion channel (sodium channel) and the modulation of GABAergic activity.
However, further studies need to be carried out for precise mechanism and study of
pharmacokinetic parameters.
(Table 2)
4. Conclusions
In summary, the present studies revealed that number of 2,6-dicarbethoxy-3,5-diaryltetrahydro-
1,4-thiazine-1,1-dioxide derivatives were effective in the MES and/or scPTZ screens. The
anticonvulsant activity depended on the kind and position of substituents at the phenyl moiety. In
the neurotoxicity studies some of the active compounds were devoid of toxicity. The most active
was 2,6-dicarbethoxy-3,5-bis(4-chlorophenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4d) which
showed ED50 value of 10.2 mg/kg and a protective index (TD50/ED50) of 28.3 in the MES test in
mice. Further structural modifications of these molecules might lead to the discovery of more
potent anticonvulsant agents with still lower neurotoxicity.
5. Experimental protocols
5.1. Chemistry
5.1.1. General Procedures. All the chemicals and solvent were purchased from commercial
sources. Solvents and reagents were dried and purified according to the literature methods.
Melting points were determined in open capillary tubes and are uncorrected. The structures of
synthesized compounds were assigned based on their analytical and spectroscopic properties. IR
1
spectra were recorded on a Schimadzu FT-IR spectrophotometer using KBr pellets. H- NMR
spectra were recorded on a Bruker Avance 300 MHz instrument, using CDCl3/DMSO-d
6
as
solvent and TMS as internal standard; the chemical shifts (δ) are reported in ppm and coupling

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constants (J) are given in Hz. Signal multiplicities are represented by s (singlet), d (doublet), t
(triplet) and m (multiplet). Elemental analyses were performed on a Perkin-Elmer 2400 Series-II
Analyzer. Analytical figures were within ±/0.4% of the theoretical values. Thin layer
chromatography (TLC) was performed to monitor the progress of the reaction and purity of the
compounds, spot being located under iodine vapour or UV-light.
5.1.2. Synthesis of diethyl 2,2’-thiodiacetate (2)
To a refluxing alcoholic solution of ethyl chloroacetate, 1 (2.0 mol), solution of sodium sulfide
(1.0 mol) in water was added and the mixture was refluxed for an hour. The course of the
reaction was monitored by TLC. After completion of the reaction, the solvent was removed in
vacuo. Then the residue was treated with cold water and neutralized with dil. HCl. The separated
oily product was extracted with dichloromethane (3 x 25 mL) and on evaporation of the solvent
afforded diethyl 2,2’- thiodiacetate (2) as a thick oil in 70% yield; it answered positive test for
sulfur.
5.1.3. Synthesis of diethyl 2,2’-sulfonyldiacetate, 3 [28]
To a stirred solution of diethyl 2,2’-thiodiacetate, 2 (1.0 mol) in methanol (20 mL), a pinch of
selenium dioxide, 30% H2O2 (10 mL) was added drop wise and stirring continued while
o
maintaining the temperature of the reaction mixture at 20 C for about 2 h. The contents were
extracted with dichloromethane (3x 25 mL) and removal of the solvent afforded diethyl 2,2’-
sulfonyldiacetate 3 as a thick oil.
Yield: 88%; 1H NMR (300 MHZ, CDCl3): δ 1.36 (t, 6H, -OCH2CH3), 4.32 (q, 4H, -OCH2CH3),
4.39 (s, 4H, CH2).

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5.1.4. General procedure for the synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-
1,1-dioxides (4 a-r)
To a solution of diethyl 2,2’-sulfonyldiacetate 3 (0.01 mol) and aromatic/heterocyclic aldehydes
(0.02 mol) in 5 mL of water was added ammonium acetate (0.02 mol) at room temperature. The
reaction mixture was stirred at 80 °C for 3 h and then cooled to room temperature. The reaction
mixture was extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. Further
crystallization of crude product by aqueous ethanol afforded pure 2,6-ethyl dicarbethoxy-3,5-
diaryltetrahydro-1,4-thiazine-1,1-dioxides, (4a-r) in good to excellent yield.
5.1.4.1. 2,6-Dicarbethoxy-3,5-bis(3-chlorophenyl)tetrahydro-1,4-thiazine-1,1-dioxide,( 4c)
°
White solid; Yield: 79%; m.p. 183 C; IR (KBr) cm-1 : 3322 (NH str.), 1730 (ester C=O), 1327
1
(S=O unsym. str.), 1122 (S=O sym. str.). H NMR (300 MHZ, CDCl3): δ 1.03 (t, 6H, -
OCH2CH3), 2.0 (broad s, 1H, NH) 4.09 (q, 4H, -OCH2CH3), 4.27 (d, 2H, J=10.2 Hz, H-2/H-6),
4.74 (d, 2H, J=10.5 Hz, H-3/H-5), 7.33-7.52 (m, 8H, Ar-H). 13C NMR (75 MHz): δ 13.89
(OCH2CH3), 61.78 (C-3,C-5), 62.34 (OCH2CH3), 72.67 (C-2,C-6), 127.90, 128.75, 129.12,
130.67, 137.51, 161.06 (C=O).
5.1.4.2. 2,6-Dicarbethoxy-3,5-bis(4-chlorophenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4d)
White solid; Yield: 87%; m.p. 208 °C; IR (KBr) cm-1 : 3326 (NH str.), 1731 (ester C=O), 1313
1
(S=O unsym. str.), 1127 (S=O sym. str.). H NMR (300 MHZ, CDCl3): δ 1.03 (t, 6H, -
OCH2CH3), 2.0 (broad s, 1H, NH) 4.09 (q, 4H, -OCH2CH3), 4.24 (d, 2H, J=10.2 Hz, H-2/H-6),
4.70 (d, 2H, J=10.5 Hz, H-3/H-5), 7.24-7.59 (m, 8H, Ar-H). 13C NMR (75 MHz): δ 13.92
(OCH2CH3), 62.04 (C-3,C-5), 62.66 (OCH2CH3), 72.68 (C-2,C-6), 127.84, 128.79, 129.19,
137.56 (ipso carbon), 160.56 (C=O).
5.1.4.3. 2,6-Dicarbethoxy-3,5-bis(4-nitrophenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4f):

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White solid; Yield: 91%; m.p. 164 °C; IR (KBr) cm-1 : 3328 (NH str.), 1732 (ester C=O), 1321
1
(S=O unsym. str.), 1142 (S=O sym. str.). H NMR (300 MHZ, CDCl3): δ 1.03 (t, 6H, -
OCH2CH3), 2.0 (broad s, 1H, NH) 4.09 (q, 4H, -OCH2CH3), 4.27 (d, 2H, J=10.2 Hz, H-2/H-6),
4.73 (d, 2H, J=10.5 Hz, H-3/H-5), 7.27-7.46 (m, 8H, Ar- H). 13C NMR (75 MHz): δ 13.68
(OCH2CH3), 61.94 (C-3,C-5), 62.48 (OCH2CH3), 72.49 (C-2,C-6), 127.90, 128.75, 129.12,
137.51 (ipso carbon), 161.27 (C=O).
5.1.4.4. 2,6-Dicarbethoxy-3,5-bis(4-methylphenyl)tetrahydro-1,4-thiazine-1,1-dioxide (4h):
°
Colourless solid; Yield: 79%; m.p. 169 C; IR (KBr) cm-1 : 3334 (NH str.), 1737 (ester C=O),
1
1317 (S=O unsym. str.), 1163 (S=O sym. str.). H NMR (300 MH
Z
, CDCl
CH ), 4.16 (d, 2H, J=10.2
Hz, H-2/H-6), 4.66 (d, 2H, J=10.5 Hz, H-3/H- 5), 7.10-7.31 (m, 8H, Ar-H). 13C NMR (75 MHz):
δ 13.61 (OCH CH ), 20.99 (CH ), 61.46 (C-3,C-5), 62.32 (OCH CH ), 72.57 (C-2,C-6), 127.53,
129.24, 134.66, 138.77, 161.06 (C=O).
3
): δ 1.06 (t, 6H, -
OCH
2
CH
3
), 2.17 (s, 1H, NH), 2.30 (s, 6H, CH
3
), 4.06 (q, 4H, - OCH
2
3
2
3
3
2
3
5.1.4.5. 2,6-Dicarbethoxy-3,5-bis(fur-2-yl)tetrahydro-1,4-thiazine-1,1-dioxide (4i):
°
Pale grey solid; Yield: 82%; m.p. 174 C ; IR (KBr) cm-1 : 3314 (NH str.), 1738 (ester C=O),
1
1323 (S=O unsym. str.), 1135 (S=O sym. str.). H NMR (300 MH
Z
, CDCl
), 4.27 (d, 2H, J=10.2 Hz, H-2/H-6),
4.73 (d, 2H, J=10.5 Hz, H-3/H-5), 7.27-7.46 (m, 6H, Ar-H). 13C NMR (75 MHz): δ 13.21
(OCH CH ), 61.94 (C-3,C-5), 62.48 (OCH CH ), 72.49 (C-2,C-6), 110.90, 112.75, 140.60, 148.8
(ipso carbon), 161.95 (C=O).
3
): δ 1.03 (t, 6H, -
OCH
2
CH
3
), 2.0 (broad s, 1H, NH) 4.09 (q, 4H, -OCH
2
CH
3
2
3
2
3
5.1.4.6. 2,6-Dicarbethoxy-3,5-bis(thiophen-2-yl)tetrahydro-1,4-thiazine-1,1-dioxide (4j):
°
Pale yellow solid; Yield: 74%; m.p. 134-135 C; IR (KBr) cm-1 : 3320 (NH str.), 1722 (ester
C=O), 1348 (S=O unsym. str.), 1144 (S=O sym. str.). 1H NMR (300 MH
- OCH CH ), 1.9 (broad s, 1H, NH) 4.19 (q, 4H, -OCH CH ), 4.27 (d, 2H, J=10.2 Hz, H-2/H-6),
Z
, CDCl ): δ 1.13 (t, 6H,
3
2
3
2
3

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4.72 (d, 2H, J=10.5 Hz, H-3/H-5), 6.72-7.31 (m, 6H, Ar-H). 13C NMR (75 MHz): δ 13.64
(OCH
2
CH
3
), 62.70 (C-3,C-5), 62.77 (OCH
2
CH ), 73.14 (C-2,C-6), 137.51 (ipso carbon), 161.25
3
(C=O).
5.1.4.7. 2,6-Dicarbethoxy-3,5-bis(thiophen-3-yl)tetrahydro-1,4-thiazine-1,1-dioxide (4k):
°
Colourless solid; Yield: 80%; m.p. 156 C; IR (KBr) cm-1 : 3311 (NH str.), 1726 (ester C=O),
1
1344 (S=O unsym. str.), 1130 (S=O sym. str.). H NMR (300 MH
Z
, CDCl ): δ 1.03 (t, 6H, -
3
OCH
2
CH
3
), 2.06 (broad s, 1H, NH) 4.07 (q, 4H, -OCH
2
CH
3
), 4.27 (d, 2H, J=10.2 Hz, H-2/H-6),
13
4.71 (d, 2H, J=10.5 Hz, H-3/H-5), 6.87- 7.28 (m, 6H, Ar- H). C NMR (75 MHz): δ 13.69
(OCH
2
CH
3
), 61.94 (C-3,C-5), 62.48 (OCH
2
CH ), 72.49 (C-2,C-6), 137.51 (ipso carbon), 160.89
3
(C=O).
5.1.4.8. 2,6-Dicarbethoxy-3,5-bis(pyridin-2-yl)tetrahydro-1,4-thiazine-1,1-dioxide (4l):
°
White solid; Yield: 85%; m.p. 127 C; IR (KBr) cm-1 : 3320 (NH str.), 1734 (ester C=O), 1351
1
(S=O unsym. str.), 1133 (S=O sym. str.). H NMR (300 MH
Z
, CDCl
), 4.22 (d, 2H, J=10.2 Hz, H-2/H-6),
4.75 (d, 2H, J=10.5 Hz, H-3/H-5), 7.32-7.92 (m, 8H, Ar-H). 13C NMR (75 MHz): δ 14.18
(OCH CH ), 61.86 (C-3,C-5), 62.25 (OCH CH ), 72.36 (C-2,C-6), 127.90, 128.11, 128.75,
129.12, 144.51 (ipso carbon), 161.14 (C=O).
3
): δ 1.06 (t, 6H, -
OCH
2
CH
3
), 2.09 (broad s, 1H, NH) 4.12 (q, 4H, -OCH
2
CH
3
2
3
2
3
5.1.4.9. 2,6-Dicarbethoxy-3,5-bis(pyridin-3-yl)tetrahydro-1,4-thiazine-1,1-dioxide (4m):
°
White solid; Yield: 83%; m.p. 178 C; IR (KBr) cm-1 : 3327 (NH str.), 1738 (ester C=O), 1356
1
(S=O unsym. str.), 1136 (S=O sym. str.) H NMR (300 MH
Z
, CDCl
), 4.27 (d, 2H, J=10.5 Hz, H-2/H-6),
4.69 (d, 2H, J=10.5 Hz, H-3/H-5), 7.46-7.27 (m, 8H, Ar-H). 13C NMR (75 MHz): δ 13.61
(OCH CH ), 61.45 (C-3,C-5), 62.57 (OCH CH ), 72.46 (C-2,C-6), 127.90, 133.75, 140.51 (ipso
carbon), 144.78, 161.59 (C=O).
3
): δ 1.04 (t, 3H, -
OCH
2
CH
3
), 2.07 (broad s, 1H, NH) 4.09 (q, 2H, -OCH
2
CH
3
2
3
2
3

ACCEPTED MANUSCRIPT
5.1.4.10. 2,6-Dicarbethoxy-3,5-bis(1H pyrrole-2-yl)tetrahydro-1,4-thiazine-1,1-dioxide (4n):
°
Pale grey solid; Yield: 88%; m.p. 149 C ; IR (KBr) cm-1 : 3330 (NH str.), 1728 (ester C=O),
1
1349 (S=O unsym. str.), 1143 (S=O sym. str.) H NMR (300 MH
Z
, CDCl
), 4.25 (d, 2H, J=10.2 Hz, H-2/H-6),
4.71 (d, 2H, J=10.5 Hz, H-3/H-5), 6.28-6.63 (m, 6H, Ar-H). 13C NMR (75 MHz): δ 13.66
(OCH CH ), 61.87 (C-3,C-5), 62.44 (OCH CH ), 72.41 (C-2,C-6), 109.90, 112.75, 122.3,136.81
(ipso carbon), 161.22 (C=O).
3
): δ 1.03 (t, 6H, -
OCH
2
CH
3
), 1.94 (broad s, 1H, NH), 4.09 (q, 4H, -OCH
2
CH
3
2
3
2
3
5.1.4.11. 2,6-Dicarbethoxy-3,5-bis(1,3-benzodioxol-6-yl)tetrahydro-1,4-thiazine-1,1- dioxide
(4o):
°
Colourless solid; Yield: 85%; m.p. 189 C; IR (KBr) cm-1 : 3321 (NH str.), 1734 (ester C=O),
1
1350 (S=O unsym. str.), 1135 (S=O sym. str.). H NMR (300 MH
Z
, CDCl ): δ 1.03 (t, 6H, -
3
OCH
4.73 (d, 2H, J=10.5 Hz, H-3/H-5), 6.09 (s, 4H, -OCH
(75 MHz): δ 13.89 (OCH CH ), 61.94 (C-3,C-5), 62.48 (OCH
CH -O-),123.90, 128.75, 147.9 (ipso carbon), 161.06 (C=O).
2
CH
3
), 2.0 (broad s, 1H, NH) 4.09 (q, 4H, -OCH
2
CH
3
), 4.27 (d, 2H, J=10.2 Hz, H-2/H-6),
13
2
O-), 6.97-7.72 (m, 6H, Ar-H). C NMR
2
3
2
CH ), 72.49 (C-2,C-6), 101.7 (-O-
3
2
5.1.4.12. 2,6-Dicarbethoxy-3,5-bis(2-chloroquinolin-3-yl)tetrahydro-1,4-thiazine-1,1-dioxide
(4p):
Yellow solid; Yield: 91%; m.p. 196 °C ; IR (KBr) cm-1 : 3328 (NH str.), 1731 (ester C=O), 1352
1
(S=O unsym. str.), 1131 (S=O sym. str.). H NMR (300 MH
Z
, CDCl
), 4.27 (d, 2H, J=10.2 Hz, H-2/H-6),
4.77 (d, 2H, J=10.5 Hz, H-3/H-5), 7.78-8.16 (m, 10H, Ar-H). 13C NMR (75 MHz): δ 13.67
(OCH CH ), 61.85 (C-3,C-5), 62.27 (OCH CH ), 72.38 (C-2,C-6), 127.90, 128.75, 130.12,
136.21, (ipso carbon), 145.40, 151.89 161.06 (C=O).
3
): δ 1.06 (t, 6H, -
OCH
2
CH
3
), 2.04 (broad s, 1H, NH) 4.11 (q, 4H, -OCH
2
CH
3
2
3
2
3
5.1.4.13. 2,6-Dicarbethoxy-3,5-bis(1H-indol-2-yl)tetrahydro-1,4-thiazine-1,1-dioxide (4q):

ACCEPTED MANUSCRIPT
°
Yellow solid; Yield: 81%; m.p. 174-175 C; IR (KBr) cm-1 : 3334 (NH str.), 1736 (ester C=O),
1
1324 (S=O unsym. str.), 1136 (S=O sym. str.). H NMR (300 MH
Z
, CDCl
), 4.28 (d, 2H, J=10.2 Hz, H- 2/H-6),
4.72 (d, 2H, J=10.5 Hz, H-3/H-5), 7.16-7.67 (m, 10H, Ar-H), 11.02 (s, 2H, indole-NH) 13C NMR
(75 MHz): δ 13.39 (OCH CH ), 61.08 (C-3,C-5), 62.11 (OCH CH ), 71.98 (C-2,C-6), 111.09,
3
): δ 1.03 (t, 6H, -
OCH
2
CH
3
), 2.02 (broad s, 1H, NH) 4.12 (q, 4H, -OCH
2
CH
3
2
3
2
3
113.56,114.54, 120.76, 127.90, 128.75, 129.12, 137.51 (ipso carbon), 161.06 (C=O).
5.1.4.14. 2,6-Dicarbethoxy-3,5-bis(3,4-dimethoxyphenyl)tetrahydro-1,4-thiazine-1,1- dioxide
(4r):
°
White solid; Yield: 89%; m.p. 161 C; IR (KBr) cm-1 : 3338 (NH str.), 1739 (ester C=O), 1338
1
(S=O unsym. str.), 1124 (S=O sym. str.). H NMR (300 MH
Z
, CDCl
), 3.91 (s, 6H, -OCH
), 4.31 (d, 2H, J=10.2 Hz, H-2/H- 6), 4.84 (d, 2H, J=10.5 Hz, H-3/H-5), 7.46-7.27 (m,
CH ), 56.67, 61.50 (C-3,C-5), 62.38 (OCH CH ),
3
): δ 1.09 (t, 6H, -
OCH
2
CH
3
), 2.4 (broad s, 1H, NH), 3.87 (s, 6H, -OCH
3
3
), 4.12 (q, 4H, -
OCH
2
CH
3
6H, Ar-H). 13C NMR (75 MHz): δ 13.78 (OCH
2
3
2
3
70.49 (C-2,C-6), 112.76,114.78, 127.90, 128.75, 129.12, 138.51 (ipso carbon), 148.09, 149.12,
162.15 (C=O).
5.2. Anticonvulsant screening
Swiss albino (male) mice (25-30 g) were used as experimental animals in this study. Animals of
the same age and weight have been selected in order to minimize biological. The mice used in
the present study were maintained in accordance with guidelines of the National Institute of
Nutrition, Indian Council for Medical Research, Hyderabad, India and study approved by
Institutional Animal Ethical Committee (KKP/Ph.D/PMU/2010). All the animals were purchased
from Tamilnadu Veterinary and Animal Sciences University (Chennai, India). The tested
compounds were injected ip to mice as a suspension in 0.5% methylcellulose at dose of 30, 100,
and 300 mg/kg to one to four mice. The anticonvulsant activity of the tested compounds were
evaluated by two models namely, MES and scPTZ models. Phenytoin and ethosuximide were
used as the standard drugs for the comparison. The neurological toxicity was determined in the

ACCEPTED MANUSCRIPT
rotarod test. Procedures employed for evaluation of anticonvulsant activity and neurotoxicity
were described elsewhere [29].
5.2.1. MES-maximal electroshock seizure pattern test
This activity was tested according to the method of Swinyard et al. [30]. In experiments with
mice, a 60-Hz current of 50-mA intensity was applied through corneal electrodes for a 0.25 s
duration; The procedures caused immediate hind limb tonic extension. After 0.5 h and 4.0 h of
drug administration, electroshocks were via corneal electrodes. Absence of tonic extension
suggests that the tested compound was considered as positive criteria. Phenytoin was used as
standard drug.
5.2.2. Pentylenetetrazole (PTZ) induced seizure test
For the chemically induced convulsant test according to the method of Vamecq et al. [31],
pentylenetetrazole was dissolved in sufficient 0.9% saline to allow subcutaneous injections to
mice. Standard drug in this model was ethosuximide. After 0.5 h and 4.0 h of drug administration
the failure to observe even a threshold seizure (a single episode of clonic spasms of at least 5s
duration) is defined as protection.
5.2.3. Neurotoxicity screening
Minimal motor impairment was measured in mice by using standardized rotarod test [32]. The
mouse was placed on a 1 in. diameter knurled plastic rod rotating at 6 rpm. Trained animals were
given an ip injection of the test compounds in doses of 30,100, and 300 mg/kg. Neurotoxicity
was indicated by the inability of the animal to maintain equilibrium on the rod for at least 1 min
in each of the four trials.
Acknowledgements
The authors are highly thankful to Dr. N. Chidambaranathan, K. M. College of
Pharmacy, Uthankudi, Madurai for evaluating samples for anticonvulsant activity and DST for

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providing FT-NMR under UGC-IRHPA programme and one of the authors (N. Edayadulla) is
grateful to DST-CURIE for financial support. This work is dedicated to the Late Prof.
Penugonda Ramesh
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R. Kulandasamy, A.V. Adhikari, J.P. Stables, Eur. J Med. Chem. 44 (2009) 4376-4384.
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[15] P. A. Grieco, Organic Synthesis in Water, Thomson Science, Glasgow, Scotland, 1998.
[16] C. J. Li, Chem. Rev. 105 (2005) 3095-3165.
[17] V. Baliah, T. Rangarajan, J. Chem. Soc. 5295 (1954) 3068-3070.

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E67 (2011) 305.
[21] B. Malawska Mini-Rev. Med. Chem. 3 (2003) 341-348.
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L. Tripathi, P. Kumar, Eur. J. Med Chem. 64 (2013) 477-487.
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Illustration captions
Table 1. Anticonvulsant activity and neurotoxocity of compounds 4a-r administered
intraperitoneally to mice.
Table 2. Phase II quantitative anticonvulsant evaluation in mice (test drug administered i.p.).
Figure 1: Pharmacophoric structural fragments of title compounds. (A) aryl group, (HBD)
NH group as hydrogen binding domain, (D) electron donor group.
Scheme 1. Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1- dioxides (4a-r)

ACCEPTED MANUSCRIPT
Table 1.
Anticonvulsant activity and neurotoxocity of compounds 4a-r administered intraperitoneally to
mice.
Compound
Intraperitoneal injection in micea
MES screeningb scPTZ screeningc NT screeningd
LogPe
0.5 h
30
100
100
30
100
30
4 h
100
300
300
30
0.5 h
300
300
300
100
300
300
300
300
-
4 h
300
-
-
300
-
300
-
300
-
-
-
-
0.5 h
-
-
300
-
100
-
-
-
-
-
-
-
-
4 h
-
-
-
-
300
-
300
-
300
300
300
300
300
-
2.59
3.70
3.70
3.70
-
4a.
4b.
4c.
4d.
300
100
300
100
300
300
300
300
300
300
100
100
100
300
30
4e.
-
4f.
100
30
2.33
3.56
-0.18
2.55
2.44
0.76
-0.09
-0.33
2.15
4.56
1.78
2.08
2.14
0.66
4g.
4h.
4i.
4j.
4k.
4l.
4m.
4n.
4o.
4p.
4q.
4r.
300
100
100
300
300
100
30
30
30
100
30
-
300
300
-
-
-
-
300
300
300
300
300
-
300
-
-
-
-
300
300
300
-
-
-
-
300
100
-
Phenytoinf
Ethosuximideg
-
100
-
100
300
-
aDoses of 30, 100 and 300 mg/kg were administered. The animals were examined 0.5 and 4.0 h after injection were
made. The dash (-) indicates the absence of activity at maximum dose administered (300 mg/kg).
bMaximal electroshock test.
cSubcutaneous pentylenetetrazole test.
dNeurotoxocity screening(rotarod test).
eLog P was calculated using ACD lab version 8.0.
fData from Ref. [33]
gData from Ref. [34]

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Table 2.
Phase II quantitative anticonvulsant evaluation in mice (test drug administered i.p.).
a
b
Compound
ED50
TD50
PIc
scPTZ
MES
scPTZ
MES
8.8
14.8 (12.7-17.2)d 58.6(36.6-82.4)
131.0 (116.2-142.5)
288.6 (276.4-302.1)
190.4 (174.2-209.5)
227.2 (220.7-235.7)
247.6 (242.3-254.1)
128.1 (124.9-134.8)
119.2 (117.8-122.4)
71.6 (45.9-135)
2.2
5.7
4a
4d
4f
10.2 (8.4-13.2)
11.4 (9.6-12.8)
50.5(30.7-72.9)
73.2(51.8-93.5)
28.3
16.7
2.6
14.4 (13.8-16.2) 90.2(92.1-135.5)
27.4 (23.5-31.7) 220.2(190.4-236.2)
12.4 (10.6-14.8) 62.7(40.7-85.8)
13.2 (11.5-15.2) 56.8(34.7-90.3)
15.7
9.0
2.5
4h
4o
4p
4q
1.1
10.3
9.0
2.0
2.1
Carbamazepinee 11.4 (8.5-16.4)
Phenytoine
> 100
> 300
8.1
<0.22
<0.22
9.8 (7.6-11.4)
65.5 (52.5-72.9)
6.9
Phenobarbitale
20.6 (19.8-25.5) 13.2 (5.8 - 15.9)
264 (247-338) 149 (123 - 177)
68.2 (62.8-72.9)
418 (369-450)
3.2
1.6
5.2
2.9
Valproatee
Number of animals used: 10; solvent used: polyethylene glycol (0.1 mL, i.p.).
aDose in milligrams per kilogram body mass.
bMinimal toxicity which was determined by rotorod test 30 min after the test drug was administered.
cProtective index (TD50/ED50).
dDate in parentheses are the 95% confidence limits.
eDate from reference [35].

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Figure 1: Pharmacophoric structural fragments of title compounds. (A) aryl group, (HBD)
NH group as hydrogen binding domain, (D) electron donor group.
D
O
D
O
O
O
S
1
6
O
O
2
2'
3'
5
3
N
H
HBD
A
A
5'
6'
4'
Model Compound Structure

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Scheme 1. Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1- dioxides (4a-r)
O
O
O
1
Na2S
S
Cl
Et
+
O
O
O
EtOH reflux 1 h
2
SeO2 / H2O2
MeOH
O
O
O
O
S
O
O O
O
O
O
Ar-CHO + NH4OAc
S
O
O
Ar
N
Ar
H2O / 50 oC
H
4a-r
3
Scheme 1
Ar
Ar
Ar
4
g
4
a
4
H3CO
m
N
Cl
H3C
b
h
n
N
H
Cl
O
c
i
o
O
O
Cl
j
d
p
S
N
Cl
NO2
k
l
e
q
r
N
S
H
H3CO
H3CO
O2N
N
f

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Research Highlights
ꢀ 3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide derivatives were synthesized.
ꢀ The newly synthesized compounds have been tested for anticonvulsant activity.
ꢀ From the present study, seven compounds have emerged as the lead compounds.
ꢀ Compound 4d exhibits a protective index (TD50/ED50) of 28.3 in the MES test.

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Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-
1,1-dioxide derivatives as potent anticonvulsant agents
Naushad Edayadullaa,* and Penugonda Rameshb,*
a,*Department of Chemistry, Mother Teresa Women’s University, Kodaikanal-624 101,
Tamilnadu, India. Tel.: +91-9865312896. E-mail: edayam2004@gmail.com
b,*Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai - 625 021, Tamil Nadu, India.
SUPPORTING INFORMATION
TABLE OF CONTENTS
I.
Elemental analysis for the synthesized compounds 4a-r
IR spectrum of compound 4h
1H NMR spectrum of compound 4h
2
3
4
5
6
II.
II.
III.
IV.
13C NMR spectrum of compound 4h
DEPT-135 NMR spectrum of compound 4h

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Table: Elemental Analysis for the synthesized compounds 4a-r.
Sl. no
4a.
Mol.formula
Elemental analysis
Calculated(%) Found(%)
C
H
N
C
H
N
3.29
C22H25NO6S
61.24 5.84
3.25
61.25
5.87
C22H23Cl2NO6S 52.81 4.63
C22H23Cl2NO6S 52.81 4.63
C22H23Cl2NO6S 52.81 4.63
2.80
2.80
2.80
8.06
8.06
2.85
3.05
3.40
3.16
3.16
9.69
9.69
10.26
2.70
6.97
8.25
2.54
52.82
52.83
52.82
50.69
50.65
58.66
62.71
52.58
48.77
48.73
55.40
55.44
52.81
55.48
55.85
61.30
56.64
4.65
4.64
4.67
4.49
4.47
5.98
6.35
5.17
4.79
4.76
5.37
5.37
5.67
4.86
4.21
5.37
6.04
2.82
2.84
2.78
8.09
8.08
2.88
3.07
3.44
3.20
3.17
9.72
9.73
10.29
2.73
7.00
8.28
2.52
4b.
4c.
4d.
4e.
4f.
C22H23N3O10S
C22H23N3O10S
C24H29NO8S
C24H29NO6S
C18H21NO8S
C18H21NO6S3
C18H21NO6S3
C20H23N3O6S
C20H23N3O6S
C18H23N3O6S
C24H25NO10S
50.67 4.45
50.67 4.45
58.64 5.95
62.73 6.36
52.55 5.14
48.74 4.77
48.74 4.77
55.42 5.35
55.42 5.35
52.80 5.66
55.49 4.85
4g.
4h.
4i.
4j.
4k.
4l.
4m.
4n.
4o.
4p.
4q.
4r.
C28H25Cl2N3O6S 55.82 4.18
C26H27N3O6S
C26H33NO10S
61.28 5.34
56.61 6.03

ACCEPTED MANUSCRIPT
O
O
O
O
S
O
O
N
H
H3C
CH3
Spectral Chart. 2A.1.1 IR spectrum of 2,6-Dicarbethoxy-3,5-bis(4-methylphenyl)tetrahydro-1,4-thiazine-1,1-dioxide

ACCEPTED MANUSCRIPT
O
O
O
O
S
O
O
N
H
H3C
CH3
Spectral Chart. 2A.1.2 1H NMR spectrum of 2,6-Dicarbethoxy-3,5-bis(4-methylphenyl)tetrahydro-1,4-thiazine-1,1- dioxide