Synthesis, characterization, biological evaluation and docking of some novel substituted 1, 3-thiazine derivatives

Article abstract of DOI:10.22159/ijpps.2017v9i3.16406

Objective: Chalcones and their heterocyclic analogs represent an important class of small molecules which have a wide range of pharmacological activities. Therefore, in this study, synthesis and anticonvulsant and antimicrobial activities of some new 1, 3

Full text of DOI:10.22159/ijpps.2017v9i3.16406

International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491
Vol 9, Issue 3, 2017
Original Article
SYNTHESIS, CHARACTERIZATION, BIOLOGICAL EVALUATION AND DOCKING OF SOME
NOVEL SUBSTITUTED 1, 3-THIAZINE DERIVATIVES
RAVINDAR BAIRAM1*, SRINIVASA MURTHY MUPPAVARAPU2 AND SIVAN SREEKANTH3
1Department of Pharmaceutical Chemistry, Center for Pharmaceutical Sciences, New IST, Jawaharlal Nehru Technological University,
Kukatpally, Hyderabad, Telangana 500085, India, 2Department of Pharmaceutical Chemistry, Vignan Institute of Pharmaceutical Sciences,
Hyderabad, Telangana 508284, India, 3Department of Chemistry, Nizam College, Osmania University, Hyderabad, Telangana 500001, India
Email: ravindarpharma@gmail.com
Received: 30 Nov 2016 Revised and Accepted: 30 Jan 2017
ABSTRACT
Objective: Chalcones and their heterocyclic analogs represent an important class of small molecules which have a wide range of pharmacological
activities. Therefore, in this study, synthesis and anticonvulsant and antimicrobial activities of some new 1, 3-thiazines have been extensively
discussed.
Methods: The reaction mixture of 4-tert-butylcyclohexanone on Claisen-Schmidt condensation with various aromatic aldehydes in the presence of
dilute sodium hydroxide afforded the corresponding chalcones. Further, these compounds were subjected to cocondensation with thiourea, in the
presence of isopropanol, catalyzed by aqueous potassium hydroxide to form 4-aryl 8-arylidene-5, 6-dihydro-2-imino-6-methyl-4H, 7H-(1, 3)
benzothiazines. The structures of the newly synthesized compounds have been established on the basis of their spectral analysis. The newly
synthesized compounds have been tested for their biological screening. Antimicrobial activity by cup plate agar diffusion method and antiepileptic
activity by pentylenetetrazole (PTZ) induced seizures model, using diphenyl hydantain as standard, and also they are subjected to molecular
properties prediction, toxicity, drug-likeness, lipophilicity and solubility parameters determination were done by using Osiris program, Molsoft,
Prototox and ALOGPS 2.1 software. The binding mode of the synthesized compounds with active protein site has been predicted using docking
method.
Results: Most of the compounds have shown good anticonvulsant as well as antimicrobial activities, but it is less than the standard drugs. 1, 3-
thiazines derivatives were more potent, and among them, compounds TB5 and TB7 were the most active compounds in these series; TB5 which
contains isopropyl phenyl moiety, was shown moderate potent activity with onset of convulsion at 14.1 min and TB7 containing 3, 4, 5-
trimethoxyphenyl substituents on the thiazine moiety was more potent as it has prolonged the onset of convulsions by 18.7 min. Whereas in the
case of antimicrobial activity of the compounds, from the results we have observed that TB5 have been shown greatest antimicrobial activity in all
the bacterial and fungal strains, TB2 also shown superior activity, the others have been shown good antimicrobial activity.
Conclusion: According to the activity studies, it is observed that the synthesis and antimicrobial as well as anticonvulsant activities of novel 1, 3-
thiazine derivatives have been shown better activity. Moreover molecular docking results give an insight into how further modification of the lead
compound can be carried out for higher inhibitory activity. In particular, compounds with electron withdrawing substituents along with lipophilic
methoxyl and isopropyl groups were more potent.
Keywords: Thiazine, Anticonvulsant, Antimicrobial activities, Molecular docking
© 2016 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2017v9i3.16406
INTRODUCTION
due need for the development of new antibacterial agents with
divergent and unique structural features, which operate via different
mechanisms of actions to those of existing antimicrobial agents.
Moreover, thiazine nucleus was a pharmacophore of cephalosporins
that occupy a very important place in the field of antibiotics. Search
for new molecules continues because of the fast development of
microbial resistance towards existing molecules, and therefore new
1, 3-thiazine derivatives have been synthesized with an objective to
get potent antimicrobial agents, in the present work the reaction
involves the synthesis of chalcones by using various aryl aldehydes
and aryl ketone (Claisen-Schmidt condensation reaction). Different
chalcone derivatives were used as the initial material for the
synthesis of new thiazines.
Research in pharmaceutical chemistry renders a vital role in the
discovery of newer therapeutic agents. The heterocyclic compounds
[1] which contain nitrogen, sulphur and oxygen possess an
enormous significance in the field of medicinal chemistry,
heterocyclic compounds were abundant in nature and have acquired
more importance, because their structural subunits were exhibited
in many natural products such as vitamins, hormones, antibiotics,
etc. 1, 3-thiazines which contain nitrogen and sulfur in their six-
member heterocyclic ring system (N-C-S), as a pharmacophore and
it was found to be fairly stable, also in some other medicinally
important compounds like xylazine (agonist at the α2-adrenergic
receptor is used for sedation, anesthesia, muscle relaxation, and
analgesia in animals) [2], and chlormezanone (used as an anxiolytic
and a muscle relaxant) [3]. Thiazine derivative moiety results has
shown diverse biological and pharmaceutical profiles such as
anticonvulsant [4], antimicrobial [5-10], analgesic, anti-
inflammatory and ulcerogenic [11-13], anticancer [14-18],
antidiabetic [19], immunotropic [20], antianxiety [21], insecticidal
and pesticidal [22], antitubercular [23], anthelmintic [24], anesthetic
[25], antiviral [26] activities etc. The treatment for bacterial
infection currently represents a significant therapeutic challenge
throughout the world. Since this trend has been changing, there is a
Though a number of drugs are available in the market, they are not
up to the mark. The ALOGPS method is a part of the ALOGPS 2.1
programmer [27], which is used to predict lipophilicity and aqueous
solubility of compounds. The lipophilicity calculation within this
program is based on the associative neural network approach and
the efficient partition algorithm. The LogKow (Kow-WIN) program
estimates the log octanol/water partition coefficient (log p) of
organic chemicals and drugs. An insufficient aqueous solubility is
likely to impede bioavailability of the drugs. It is well known that
insufficient solubility of drugs can lead to poor absorption.

Bairam et al.
Int J Pharm Pharm Sci, Vol 9, Issue 3, 233-242
MATERIALS AND METHODS
General
cyclic NH, 1H), 7.25-7.27 (d, Ar-H, 1H), 7.28-7.41(m, Ar-H, 9H), 7.55
(s, methine H, 1H). [13]C NMR (400 MHz, DMSO-d6, δ ppm): 178.47,
152.03, 151.79. 151.68, 148.41, 142.58, 139.67, 139.26, 137.58,
135.88, 134.53, 133.84, 132.36, 127.53 (C-2' and C-6’), 127.41, (C-3''
and C-5''), 125.82, 125.42, 118.87, 44.15, (-CH2-, C of isobutyl group
at C-4''); 43.95, 36.1, 35.9; 31.54 (-CH-, C of isobutyl group at C-4'').
MS (ESI): m/z = 388.9 [M1+1].
All the chemicals and solvents are procured from Sigma-Aldrich and
Merck, India. The melting points of the synthesized compounds have
been determined in open capillary tubes and are uncorrected. The
infra-red (IR) spectra of the compounds have been recorded on
Perkin Elmer Fourier Transform infrared (FTIR) spectrometer
(Model Shimadzu 8700) in KBr discs method. 1H and 13C nuclear
magnetic resonance (NMR) spectra have been recorded on Bruker
400 MHZ AVANCE instrument in deuterated chloroform (CDCl3) at
399 MHz. The chemical shifts (δ) have been reported in parts per
million (ppm) downfield from internal reference Tetramethylsilane
(TMS). Mass spectra have been recorded on Mass
spectrophotometer (Model Shimadzu 2010A) by LC-MS, using
dimethyl sulfoxide as a solvent. All the compounds have been shown
satisfactory chemical analysis, the homogencity of the compounds
have been checked by thin layer chromatography (TLC) using silica
gel glass plates containing 60 F-254 and n-hexane and ethyl acetate
(8:2) as mobile phase, and visualization on TLC was achieved by
using ultraviolet light. All the compounds have been purified by
column chromatography (Merck), pentylenetetrazole (PTZ) was
procured from sigma and it was dissolved in normal saline. The
healthy albino mice (Wistar, 100–150 g, 5–6 w) were obtained from
Mahaveer enterprises, Kolkata.
8-(3,4-dimethoxybenzylidene)-6-tert-butyl-4-(3,4-dimethoxy-
phenyl)-5,6,7,8-tetrahydro-1H-benzo[d][1,3]thiazin-2(4H)-
imine(TB2)
Yellowish solid, Yield 78%; mp 166-168 °C. Rf: 0.7; IR (KBr, cm−1):
3426.0 (Imine NH-), 3098.0 (cyclic NH-), 1655.0 (C=N), 1067.0 (C-
1
N), 1250.0(C-O-C), 1458.0 (CH3-). H NMR (400 MHz, CDCl3, δ ppm):
0.67-0.86 (m,3× CH3, 9H), 1.20-1.23 (d, CH,1H), 1.82-1.88 (m, CH2,
2H), 1.93-2.07 (m, CH2 2H), 3.41-3.88 (m (4× OCH3, 12H),18H), 4.72
(s, CH-S, 1H), 6.72 (s, imine NH, 1H), 6.74 (s, cyclic NH, 1H), 6.74-
6.98 (m, ArH, 6H), 8.93 (s, methine, 1H). [13]C NMR ((400 MHz,
DMSO-d6, δ ppm): 174.47, 148.47, 147.25, 140.413, 135.05, 129.58,
128.41, 127.44, 126.58, 122.88, 114.66, 58.42, 43.62, 40.61, 39.98,
27.49. MS (ESI): m/z = 509.1[M1+1].
4-((6-tert-butyl-4-(4-(dimethylamino)phenyl)-2-imino-1,2,6,7-
tetrahydro-4H-benzo[d][1,3]thiazin-8(5H)-ylidene)methyl)-N,
N-dimethylbenzenamine (TB3) (fig. 2)
Light brown solid, Yield 69%; mp 142-144 °C; Rf: 0.7; IR (KBr, cm−1):
3425.0 (Imine NH-), 3069.0 (cyclic NH-), 1654.0(C=N), 1116.0 (C-N),
1454.0 (CH3-). 1H NMR (400 MHz, CDCl3, δ ppm): 0.67-0.74 (m, CH3,
3H), 0.81-2.23 (m, 2× CH3, 6H), 1.25 (d, CH, 1H),2.79-2.82 (m, 2× CH2,
4H), 2.84-3.07 (m, 4× NCH3, 12H), 5.38 (s, CH-S, 1H), 6.55 (s, imine
NH, 1H), 6.66 (d, cyclic NH, 1H), 6.67-7.65 (m, ArH, 8H), 7.67 (s,
methine H, 1H). MS (ESI): m/z = 473.2[M1+1].
Experimental part chemical synthesis
General procedure
Preparation of 2, 6-dibenzylidene-4-tert-butyl cyclohexanone
The substituted aromatic aldehyde (0.02 mol) has been added to the
reaction mixture of 30 ml of 10% sodium hydroxide and 4-tert-
butylcyclohexanone (0.01 mol) in 50 ml of ethyl alcohol, which is
maintained at 20-25 °C (fig. 1). This reaction mixture is magnetically
stirred at 500 rpm for a period of 2 hr. The completion of reaction
has been confirmed by TLC method of estimation. Subsequently,
after the 2 hr the reaction mixture was stored in a refrigerator at 0-4
°C temperature for a period of 8 hr. Finally, the obtained residue
product was filtered, and washed with ice cold water followed by
ice-cold ethanol than the washed product was dried and
recrystallized from dimethylformamide gave as yellow crystals [27,
28]. Yields were from 65% to 95%, mp. 126.6–127.0 UV (λmax) of
3a: 396 nm; 1H NMR of 1a: (CDCl3-d6): δ 0.75 (m, 2× CH3, 6H), 0.78
(d, CH3,3H), 1.32-1.34 (d, CH, 1H),1.83-1.87 (m, CH2 2H), 2.88 (s, CH2,
2H), 7.28-7.41 (m, ArH, 10H), 7.55 (s, methine H, 2H). IR (KBr) of 3c:
1657 cm-1 (C=O) 1598, 1554, 1506, 1462 cm-1 (aromatic), 834 cm-1
(C=C); Mass of 3a: MS (ESI): m/z = 388.9 [M1+1].
8-(4-methoxybenzylidene)-6-tert-butyl-4-(4-methoxyphenyl)-
5,6,7,8-tetrahydro-1H-benzo[d][1,3]thiazin-2(4H)-imine (TB4)
Yellowish solid, Yield 89%; mp 189-192 °C; Rf: 0.4; IR (KBr, cm−1): 3384.0
(Imine NH-), 3201.0 (cyclic NH-), 1601.1 (C=N), 1031.0 (C-N), 1248(C-O-
1
C), 1476.0 (CH3-). H NMR (400 MHz, CDCl3, δ ppm): 0.76-0.79 (m, 3 ×
CH3, 9H), 0.84-0.92 (m, CH2, 2H), 1.28-1.34 (m, CH2, 1H), 1.81-1.89 (m,
CH2 1H), 1.96-2.02 (m, CH,1H), 3.81-3.83((m, 2× OCH3, 6H), 6.44 (s, CH-S,
1H), 6.61 (s, imine NH, 1H), 6.88 (s, cyclic NH, 1H), 6.88-6.92 (m, ArH,
4H), 7.19-7.23(m, ArH, 4H), 7.57 (s, methine H, 1H). [13]C NMR ((400
MHz, DMSO-d6, δ ppm):174.37, 149.14, 148.90, 135.27, 135.27, 128.50,
122.75, 119.33, 114.36, 111.98, 58.33, 55.78, 43.73, 39.55, 27.87; MS
(ESI): m/z = 448.9 [M1+1].
8-(4-isopropylbenzylidene)-6-tert-butyl-4-(4-isopropyl-
phenyl)-5,6,7,8-tetrahydro-1H-benzo[d][1,3]thiazin-2(4H)-
imine (TB5)
Preparation of 8-benzylidene-6-tert-butyl-4-phenyl-5, 6, 7, 8-
tetrahydro-1H-benzo-1, 3-thiazin-2-imine
White solid, Yield 88%; mp 180-182 °C; Rf: 0.5; IR (KBr, cm−1): 3426.0
(Imine NH-), 3064.0 (cyclic NH-), 1650.0 (C=N), 1159.0 (C-N),
1457.0 (CH3-). 1H NMR (400 MHz, CDCl3, δ ppm): 0.71-0.86 (m, 3 ×
CH3, 9H), 0.87-0.97 (m, CH2, 2H), 1.28-1.34 (m, CH2, 1H), 1.81-1.89
(m, CH2 1H), 1.96-2.40 (m, CH,1H), 2.40-2.44 (m, CH,1H), 3.13-
3.89((m, 2× CH3, 6H), 4.84 (s, CH-S, 1H), 6.4 (s, imine NH, 1H), 6.88
(s, cyclic NH, 1H), 6.88-6.92 (m, ArH, 4H), 7.61-7.73(m, ArH, 4H),
7.75 (s, methine H, 1H). MS (ESI): m/z = 742.7 [M1+1].
To
a mixture containing 2, 6-dibenzylidene-4-tert-butylcyclo-
hexanone (0.01 mol), thiourea (0.015 mol) and potassium hydroxide
(0.01 mol) were dissolved in specified amount (5 ml) of water which
was refluxed in isopropyl alcohol (100 ml) for a period of 16 hr.
Later, the formation of the product was confirmed by thin layer
chromatography (TLC). Finally the left over solvent was removed
under reduced pressure by distillation and the residue obtained was
cooled, treated with ice cold water, followed by ice cold ethanol,
then filtered, dried and the dried residue was purified by silica gel
column chromatography (Ethyl acetate/Hexane) to give respective
8-(4-chlorobenzylidene)-6-tert-butyl-4-(4-chlorophenyl)-5,6,
7,8-tetrahydro-1H-benzo[d][1,3]thiazin-2(4H)-imine (TB6)
compounds (TB1-TB12
recrystallized from ethyl alcohol [29, 30]. The physical data of the
compounds is given in table 1.
)
and the precipitate obtained was
White solid, Yield 80%; mp 222-224 °C; Rf: 0.7; IR (KBr, cm−1):
3424.0 (Imine NH-), 3275.5 (cyclic NH-), 1615.0 (C=N), 1089.0 (C-
N), 1487.0 (CH3-); Ar-Cl-809.0. 1H NMR (400 MHz, CDCl3, δ ppm):
0.75 (m, 2× CH3, 6H), 0.78 (d, CH3, 3H), 1.32-1.34 (d, CH, 1H), 1.83-
1.87 (m,-CH2-, 2H), 2.88 (s, CH2, 2H), 4.93 (s, CH-S, 1H), 6.51 (s, imine
NH, 1H), 6.64 (s, cyclic NH, 1H), 7.25-7.27 (d, Ar-H, 1H), 7.28-7.41(m,
Ar-H, 9H), 7.55 (s, methine H, 1H). MS (ESI): m/z = 456.7 [M1+1].
Spectral data of the synthesized compounds
8-benzylidene-6-tert-butyl-4-phenyl-5,6,7,8-tetrahydro-1H-
benzo[d][1,3]thiazin-2(4H)-imine (TB1)
Yellow solid, Yield 90%; mp 184-186 °C. Rf: 0.7; IR (KBr, cm−1):
3399.9 (Imine NH-), 3207.0 (cyclic NH-), 1609.3 (C=N), 1077 (C-N),
1476.2 (CH3-). 1H NMR (400 MHz, CDCl3, δ ppm): 0.75 (m, 2× CH3,
6H), 0.78 (d, CH3, 3H), 1.32-1.34 (d, CH, 1H), 1.83-1.87 (m,-CH2-, 2H),
2.88 (s, CH2, 2H), 4.93 (s, CH-S, 1H), 6.51 (s, imine NH, 1H), 6.64 (s,
8-(4-fluorobenzylidene)-6-tert-butyl-4-(4-fluorophenyl)-5,6,
7,8-tetrahydro-1H-benzo[d][1,3]thiazin-2(4H)-imine (TB7)
White solid, Yield 82%; mp 243-245 °C; Rf: 0.6; IR (KBr, cm−1):
3256.0 (Imine NH-), 2921.0 (cyclic NH-), 1693.0 (C=N), 1115.0 (C-
234

Bairam et al.
Int J Pharm Pharm Sci, Vol 9, Issue 3, 233-242
N), 1412.0 (CH3-), Ar-F-934.9. 1H NMR (400 MHz, CDCl3, δ ppm):
0.75-0.78 (m, 3 × CH3, 9H), 1.32-1.34 (d, CH, 1H), 1.61 (d, CH2 2H),
1.83-2.03 (m, CH2, 2H), 4.93 (s, CH-S, 1H), 6.51 (s, imine NH, 1H),
6.64 (s, cyclic NH, 1H), 7.25-7.39 (m, ArH, 8H), 7.59 (s, methine H,
1H). [13]C NMR ((400 MHz, DMSO-d6, δ ppm): 190.28 (C-1), 184.30,
172.64, 163.28, 154.62, 150.37, 131.99, 128.19, 127.95, 112.70,
107.50, 59.33, 44.33, 40.57, 39.94, 27.88. MS (ESI): m/z = 425.1
[M1+1].
8-(4-ethylbenzylidene)-6-tert-butyl-4-(4-ethylphenyl)-5, 6, 7, 8-
tetrahydro-1H-benzo[d][1,3]thiazin-2(4H)-imine(TB10
)
Yellow solid, Yield 76%; mp 178-180 °C; Rf: 0.6; IR (KBr, cm−1):
3380.0 (Imine NH-), 3201.0 (cyclic NH-), 2934.0(Ar-C2H5).
1611.0(C=N), 1060.0(C-N), 1475.0 (CH3-), 735.6 (Ar-NH2). 1H NMR
(400 MHz, CDCl3, δ ppm): 0.76-0.79 (m, 3× CH3, 9H), 0.82-0.86 (m,
2× CH2, 4H), 0.92 (m, CH, 1H), 1.21-1.27 (m, 2× CH2, 4H), 2.62-2.69
(m, 2× CH3, 6H), 6.47(s, CH-S, 1H), 6.59 (s, imine NH, 1H), 7.20 (s,
cyclic NH, 1H), 7.20-7.22 (m, ArH, 8H), 7.58 (s, methine H, 1H). [13]C
NMR ((400 MHz, DMSO-d6, δ ppm): 174.48, 163.36, 162.52, 160.94,
139.22, 133.88, 131.51, 129.56, 128.31, 122.14, 116.08, 114.83,
57.89, 43.69, 39.35, 27.96. MS (ESI): m/z = 444.9 [M1+1].
8-(3,4,5-trimethoxybenzylidene)-6-tert-butyl-4-(3,4,5-tri-
methoxyphenyl)-5,6,7,8-tetrahydro-1H-benzo[d][1,3]thiazin-
2(4H)-imine (TB8)
Yellowish solid, Yield 94%; mp 210-212 °C; Rf: 0.5; IR (KBr,
cm−1): 3663.0 (Imine NH-), 3291.0 (cyclic NH-), 1673.0(C=N),
1065.0 (C-N), 1263.0(C-O-C), Ar-Trisubstituted, 1419.0 (CH3-).
1H NMR (400 MHz, CDCl3, δ ppm): 0.71-0.79 (m, CH3)2, 6H), 0.81-
0.83 (d, CH3, 3H), 1.22 (s, CH, 1H),1.24-1.99 (m, CH2 2H), 2.08-
2.99 (s, CH2, 1H), 2.48 (s, CH2, 1H), 3.61-3.84 (m (6× OCH3, 18H),
4.44 (s, CH-S, 1H), 6.57 (s, imine NH, 1H), 6.58 (s, cyclic NH, 1H),
6.62-6.64 (m, ArH, 4H), 8.96 (s, methine H, 1H). MS (ESI): m/z =
569.1[M1+1].
8-(3-Nitrobenzylidene)-6-tert-butyl-4-(3-nitrophenyl)-5,6,7,8-
tetrahydro-1H-benzo[d][1,3]thiazin-2(4H)-imine (TB11
)
Light brown solid, Yield 65%; mp 182-184 °C; Rf: 0.7; IR (KBr, cm−1):
3418.0 (Imine NH-), 3087.0 (cyclic NH-), 1601.0(C=N), 1060.0(C-N),
1462.0 (CH3-), 832.1 (Ar-NO2). 1H NMR (400 MHz, CDCl3, δ ppm):
0.63-0.65 (d, CH3, 3H), 0.70-0.92 (m, 2× CH3, 6H), 1.00-1.02 (d, CH,
1H), 1.12-1.16 (m, CH2, 2H), 1.71-2.37 (m, CH2, 2H), 4.96-5.21 (m, CH-
S, 1H), 6.42 (t, imine NH, 1H), 6.57 (s, cyclic NH, 1H), 6.66-6.91 (d,
ArH, 1H), 7.07-7.23 (d, ArH, 1H), 7.65-7.89(m, ArH, 4H),7.92(d, ArH,
2H), 8.31 (s, methine H, 1H). MS (ESI): m/z = 478.56 [M1+1].
4-((4-(4-aminophenyl)-6-tert-butyl-2-imino-1,2,6,7-tetrahydro-
4H-benzo[d][1,3]thiazin-8(5H)-ylidene)methyl) benzenamine
(TB9)
4-((6-tert-butyl-4-(3,4-dihydroxyphenyl)-2-imino-1,2,6,7-
tetrahydro-4H-benzo[d][1,3]thiazin-8(5H)-ylidene)methyl)
Light brown solid, Yield 70%; mp 156-158 °C; Rf: 0.6; IR (KBr, cm−1):
3441.0 (Imine NH-), 3063.0 (cyclic NH-), 1653.0(C=N), 1092.0 (C-N),
1456.0 (CH3-), 735.6 (Ar-NH2). 1H NMR (400 MHz, CDCl3, δ ppm):
0.67-0.75 (m, 3× CH3, 9H), 1.13-1.19 (d, CH, 1H), 1.73-1.79 (m, CH2,
2H), 1.95-2.05 (m, CH2, 1H), 2.812.85 (d, CH2, 1H), 4.81-4.84 (d, CH-S,
1H), 6.96 (s, imine NH, 1H), 7.06 (s, cyclic NH, 1H),7.16-7.73 (m, ArH,
8H), 9.04 (s, methine H, 1H). [13]C NMR ((400 MHz, DMSO-d6, δ
ppm): 174.48, 163.36, 162.52, 160.94, 139.22, 133.88, 131.51,
129.56, 128.31, 122.14, 116.08, 114.83, 57.89, 43.69, 39.35, 27.96.
MS (ESI): m/z = 418.5 [M1+1].
benzene-1,2-diol (TB12
)
Light white solid, Yield 65%; mp 177-179 °C; Rf: 0.5; IR (KBr, cm−1):
3444.0 (Imine NH-), 2951.0 (cyclic NH-), 1593.0(C=N), 1027.0(C-N),
1466.0 (CH3-), 774.3 (Di-substituted). 1H NMR (400 MHz, CDCl3, δ
ppm): 1.5-2.4 (m, (CH2)2, 4H), 2.4 (m, CH2, 2H), 4.3 (s, CH-S, 1H), 6.9
(s, imine, 1H), 6.9(s, cyclic NH, 1H), 7.0-7.7(m, ArH, 8H), 7.7 (s,
methine, 1H). [13]C NMR ((400 MHz, DMSO-d6, δ ppm): 174.65,
153.45, 138.29, 137.57, 136.85, 133.03, 131.93, 129.40, 128.57,
123.04, 114.60, 107.09, 104.71, 60.52, 58.60, 43.73, 40.60, 39.97,
27.40. MS (ESI): m/z = 451.4 [M1+1].
Scheme of work
Ar
Ar
CH3
CH3
C
CH3
C
CH
H3C
C
H3C
a
H3C
S
2ArCHO
b
N
H
O
NH
O
CH3
CH3
2
CH3
1
CH
Ar
CH
Ar
3
4
Fig. 1: a) Ar-CHO, substituted aromatic aldehydes, ethanol, sodium hydroxide (NaOH), b) thiourea, aqueous potassium hydroxide (KOH),
isopropyl alcohol, reflux, 14 hr, reaction scheme for synthesis of title compounds
Fig. 2: 3 Dimensional (3D) structural representation of TB3 molecule
235

Bairam et al.
Int J Pharm Pharm Sci, Vol 9, Issue 3, 233-242
Table 1: Physical and analytical data for compounds [TB1-TB12
]
Entry
TB1
TB2
TB3
TB4
TB5
TB6
TB7
TB8
TB9
TB10
TB11
TB12
Ar
C6H5
P-ClC6H4
P-FC6H4
4-(OMe)C6H4
P-CH(Me)2C6H4
3,4,-(OMe)2C6H3
3,4,5-(OMe)3C6H2
P-N(Me)2C6H4
P-NH2C6H4
P-C2H5C6H4
P-NO2C6H4
2,4-(OH)2C6H5
Mol.formula
C25H28N2S
C25H26 Cl2N2S
C25H26 F2N2S
C27H32N2 O2S
C31H40N2S
C29H36N2 O4S
C31H40N2O6S
C29H38N4S
C25H30N4S
C29H36N2S
C25H26N4O4S
C25H28N2O4S
Mol. wt
388.56
457.45
424.54
448.62
472.72
508.67
568.72
474.70
418.59
444.67
478.56
452.56
Melting point ( °C)
184-186
222-224
243-245
189-192
180-182
166-168
210-212
142-144
156-158
178-180
182-184
177-178
Rf
% Yield
95
80
82
89
88
78
94
69
70
76
65
65
0.71
0.78
0.65
0.48
0.56
0.71
0.54
0.76
0.69
0.66
0.78
0.52
Ar-aromatic, retardation factor (Rf), TLC solvent system(x: y) n-hexane and ethyl acetate (8:2)
tonic convulsion episode. Hind limb extension was taken as a tonic
convulsion. Latency of convulsion, % of convulsion, time of death, % of
survival was recorded. The number of animals protected from hind limb
tonic extension seizures (HLTE) and the time spent in this position were
determined, for each dose group (mean±SEM) in PTZ induced method.
The onset of tonic convulsions and the number of animals convulsing, or
not convulsing within the observation period were noted. The ability of
the test compounds to prevent or delay the onset of the hind limb
extension exhibited by the animals was taken as an indication of
anticonvulsant activity.
Biological evaluation
Acute oral toxicity studies
Maximum tolerated dose (MTD) study was carried out as per the
Organization of Economical Co-Operation and Development (OECD)
guidelines 423 [31, 32]. All the synthesized compounds treated animals,
showed only mounting and genital licking to a mild degree while all the
other responses were normal when compared to control at 24 hr
observation. The 48 and 72 hr observation revealed no changes in any of
the normal behavioural pattern of the treated groups to that of the
control group. No toxicity or death was observed for all the compounds
on the administration of a dose of 2000 mg/kg. Hence, all those
compounds can be considered as safe (X-classify). A group of three
albino mice of either sex weighing 18-30 gm and of 90 d age selected
randomly and used for acute toxicity studies. The animals were kept
observed fasting overnight, prior to the experimental procedure. The
technique up and down or staircase was used to establish the dose. The
synthesised compounds were administered orally at the dose level of 5
mg/kg body weight to the animals and observed for 14 d. The
investigational protocol for the pharmacological selection was done in
accordance, with the guidelines prescribed by an Institutional Animal
Ethics Committee (CPCSEA No: 1292/ac/09/CPCSEA). Since no
mortality was observed, the procedure has been repeated for further
higher doses of 50, 300 and 2000 mg/kg body weight. The compounds
show no mortality at a dose up to 2000 mg/kg. Hence 1/10th (200
mg/kg) and 1/5th (400 mg/kg) of this dose were selected as the dose
levels for the study.
Computationally predicted toxicity, lipophilicity and drug score
profiles
The shredding of each molecule at every rotatable bond leads to a
set of nucleus fragments. These, in turn, were used to rebuild all
possible larger fragments which could be the substructure of the
original fragment. Afterwards, a search procedure for substructure
resolute the occurrence, frequency of every one of the fragment
(constructed and core fragments) surrounded by all traded drugs of
3300 in addition to 15,000 commercially available chemicals (Fluka)
to predict toxicity, C Log P, and drug score [33, 34].
In vitro antimicrobial activity
Antibacterial activity
In vitro antibacterial activity of the newly synthesized compounds were
tested against the standard cultures of gram-positive organisms, such as
Staphylococcus aureus and Klebsiella pneumoniae and gram-negative
organisms like Escherichia coli and Pseudomonas aeruginosa by cup plate
agar diffusion method. Bacteria were cultured in nutrient agar medium,
and the solutions of the synthesized compounds were dissolved in
dimethyl sulfoxide (DMSO 1 ml) at 150 µg/ml concentration and the
compounds incubated at 37 °C for 24 hr. After the incubation period, the
inhibition zones were measured in mm, and the known antibiotics like
ciprofloxacin at a concentration of 10 μg/ml as a standard drug were
used for the comparison at the same concentration [35, 36]. The results
are tabulated in the table 2.
Pentylenetetrazole (PTZ) induced seizure model
General procedure
Adult male mice with a body weight between 18 g and 22 g were used.
The test compounds and the standard drug, diphenyl hydantain (30
mg/kg) were given orally to a group of 6 mice. Another group of 6 mice
served as control, after 60 min, oral administration, 80 mg/kg PTZ was
injected through intra-peritoneal route. Each animal was placed into an
individual plastic cage, and the animals were observed for 30 min for
Table 2: Antimicrobial activity of the compounds on bacterial and fungal strains
Antimicrobial activity in terms of zone of inhibition in millimeter (mm)
compounds
S. aureus
15±0.12
14±0.64
13±1.72
16±0.51
15±0.42
14±0.41
12±0.83
13±1.62
15±0.64
16±1.14
14±1.53
16±0.91
22±0.64
-----------
K. pneamoniae
14±1.21
13±0.82
15±0.34
15±0.11
16±1.54
14±0.03
13±0.12
11±0.04
16±1.61
15±0.81
12±0.19
13±1.02
25±0.03
----------
E. coli
P. aeruginosa
14±0.85
13±0.16
15±0.88
14±1.59
16±0.07
15±0.46
12±0.19
14±1.16
16±1.52
18±0.72
13±0.18
14±0.71
25±0.64
-----------
C. albicans
15±0.31
16±0.54
15±1.06
17±0.53
16±0.64
14±0.13
14±0.37
13±0.68
12±1.86
15±0.47
12±0.79
14±0.67
----------
24±1.89
A. niger
12±0.65
13±1.76
14±0.86
15±0.64
16±0.56
12±0.25
14±1.73
13±0.54
16±0.46
13±0.41
15±0.08
15±0.53
-----------
23±0.85
TB1
TB2
TB3
TB4
TB5
TB6
TB7
TB8
TB9
TB10
TB11
TB12
Ciprofloxacin
Ketaconazole
16±0.15
15±0.66
14±1.58
15±0.60
16±0.02
15±1.72
13±0.13
13±0.95
15±0.67
17±0.01
14±0.86
13±1.52
22±0.17
----------
Diameter of zone of inhibition results are expressed as mean±SD. Data compared against positive standard group and each test group.
236

Bairam et al.
Int J Pharm Pharm Sci, Vol 9, Issue 3, 233-242
synthesized compounds are to be had in table 3. All the tested
compounds have showed optimum antimicrobial activity with minor
differences in their zone of inhibitions when compared with the
standard drugs.
Antifungal activity
The antifungal activity of the synthesized compounds was evaluated
against two fungal organisms Candida albicans and Asperigillus niger
by using cup plate agar diffusion method and inoculated at 28±1 °C
for seven days. After seven days, inhibition in fungal growth was
resolute as a difference in growth between control plates and those
treated with test compound and compared with the standard drug
ketaconazole at a concentration of 20 μg/ml and the results were
tabulated in the table 2. The observed zone of inhibition and the
minimum inhibitory concentration (MIC) values for all the
Minimum inhibitory concentration (MIC)
Minimum inhibitory concentration (MIC), anti-microbial activity of
each compound was evaluated at the concentration of 150 µg/ml;
values are expressed as mean±SD. Data compared against the
positive standard group.
Table 3: Minimum inhibitory concentration (MIC) data of the synthesized compounds
Diameter of zone of inhibition in millimeter (MIC) µg/ml
Entry
S. aureus
21±0.12**
22±0.03**
19±0.11
21±0.13
24±0.17 ***
19±0.61
18±1.02
21±0.41**
19±0.53
19±0.74
21±1.21**
19±0.95
K. pneamoniae
20±0.42
19±0.64
19±0.72
20±0.83
23±0.12**
20±1.84
22±0.73**
20±0.92
16±0.71
18±1.32
14±1.71
21±0.81**
26±0.79***
-----------------
E. coli
P. aeruginosa
18±0.65
17±0.88
16±1.45
17±1.84
22±0.54**
16±0.17
17±0.64
16±0.42
15±0.78
16±0.53
16±0.17
18±0.64
24±1.21***
---------------
C. albicans
23±0.18**
22±0.82*
22±0.48*
22±0.51*
25±0.01**
21±0.50
23±1.63
22±0.45
21±0.14
24±1.20**
22±1.64
A. niger
22±0.75*
21±0.36
23±1.75*
22±0.59*
26±0.64***
18±0.18
22±0.86*
24±0.61**
19±0.45
21±1.65
20±1.57
21±0.43
---------------
28±0.04***
TB1
TB2
TB3
TB4
TB5
TB6
TB7
TB8
TB9
TB10
TB11
TB12
Ciprofloxacin
Ketaconazole
18±0.11
16±0.63
18±0.52
18±0.71
21±0.42**
19±0.67
16±0.91
18±0.12
14±0.50
17±1.81
16±1.49
18±0.62
24±0.99***
--------------
23±0.36**
---------------
28±0.28***
26±0.65***
----------------
Diameter of the zone of inhibition for minimum inhibitory concentration results are expressed as mean±standard deviation of triplicates. The
diameter of well plates was 8 mm, Ciprofloxacin 10µg/ml used as standard against Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli,
and Pseudomonas aeruginosa, Ketaconazole at a concentration of 20 μg/ml was used as standard against Candida albicans and Asperigillus niger
RESULTS AND DISCUSSION
Chemistry
The results of elemental analysis were also in close agreement
within±0.4 % of the calculated values.
Anticonvulsant activity
Twelve novel 1, 3-thiazine derivatives (TB1-TB12) were synthesized
by the condensation of different 2, 6-dibenzylidene-4-tert-butyl-
cyclohexanones with thiourea in the presence of ethanol by
refluxation. The yields of the compounds were in between 65-94%.
All the compounds were purified by column chromatography and
characterized by spectral methods including IR, 1H NMR, 13C NMR,
and Mass. Formation of 1,3-thiazine scaffold is confirmed by the
characteristic IR absorption bands in the ranges of 3250-3450 cm-1
(imine NH-), 2950-3200 (cyclic NH-), 1590-1680 (C=N) and 1020-
1120 (C-N) respectively.
1, 3-thiazine derivatives were tested for their anticonvulsant activity
by pentylenetetrazole (PTZ) induced seizures. The results are
summarized in table 4. From the results it can be clearly observed
that 1, 3-thiazines possess significant anticonvulsant activity, but
less than the standard diphenyl hydantain. Compound TB7
containing 3, 4, 5-trimethoxyphenyl moiety was the most potent of
the sequence with the onset of convulsions by 18.7 min. This is
followed by TB5 with 4-isopropylphenyl substitution with 14.1 min.
The third and fourth in the activity are seen, in TB6 with 3, 4-
dimethoxyphenyl with 11.7 min and TB4 with 4-methoxyphenyl with
onset 11.3 min scaffolds respectively. Compound TB10 with 4-
ethylphenyl moiety with 10.7 min also possess significant
anticonvulsant activity. Halogenated thiazines were also exhibited
superior activity, and other compounds have shown moderate to
mild antiepileptic activity. However, none of these compounds has
greater activity than the standard diphenyl hydantain.
Two diagnostic singlet peaks in the 1H NMR spectrums around δ 6.4-
7.2 ppm helped to unravel the structures of the compounds. The 13C
NMR spectrum of compounds exhibited the characteristic signals in
the range of δ 170-190 ppm which corresponds to C=N, apart from
the peaks corresponding to the other carbons. The mass spectra
obtained by positive mode of ionization method revealed that the
[M+H]+ions are representing the molecular weight of the compound.
Table 4: Hind limb tonic extension seizure (HLTE)
Latency of onset of convulsion (in min)
Groups
Control (Normal saline)
Time of death* (in min)
5.72±0.3116
1.0 71±0.048
Standard (Diphenyl hydantain)
TB3
TB4
TB1
TB5
TB7
TB6
TB10
28.31±0.341
Prevented
5.122±0.187*
11.36±0.3411**
1.375±0.1661
14.15±0.321***
18.73±0.1241***
11.71±0.182**
10.76±0.192**
10.62±2.668*
25.48±2.857***
9.77±1.058
25.27±0.523***
30.87±0.506***
15.82±0.512*
16.62±0.612*
Stastical standard: * P<0.1, **P<0.01; ***P<0.001, Time of death*: 30 min was taken as the cut off time all values are mean±SEM values using n = 6
animals in each group.
237

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Int J Pharm Pharm Sci, Vol 9, Issue 3, 233-242
Statistics
(Schrodinger-Maestro) that applies a two stage scoring process to
sort out the best conformations and orientations of the ligand
(defined as pose), based on its interaction pattern with the receptor,
docked at its active site using a standard docking protocol. The
newly synthesised novel compounds TB1 to TB12 were selected for
performing molecular docking studies. Molecules were built using
Maestro build panel and prepared by LigPrep 2.0 application. Crystal
structures of S. aureus gyrase complex with ciprofloxacin and
deoxyribonucleic acid (DNA), protein data bank (PDB id: 2XCT) [37],
and structures of cytochrome P450 family 51 subfamily A member 1
[CYP51] from the pathogens Candida glabrata (PDB id: 5JLC) were
downloaded from protein data bank (www. rcsb. org). GLIDE 5.6
was used for molecular docking. The proteins were prepared using
protein preparation module applying the default parameters. The
grid was generated around the active site of the protein by selecting
the cocrystalized ligand. Receptor vander Waals scaling for the
nonpolar atoms was kept 0.9 [38], the Low-energy conformation of
the ligands was selected and docked into the grid using standard
precision (SP) docking mode. Dock pose of each ligand was analyzed
for interactions with the receptor.
The statistical analysis of the obtained results from diphenyl
hydantain and the synthesized compounds were made. The
significance of differences between the different dosing groups were
calculated by the Steel test (seizure score), by one-way analysis of
variance (ANOVA) followed by post hoc comparison using Dunnett’s
test, p<0.05 was considered statistically significant.
In vitro antimicrobial activity
All the newly synthesized compounds were tested for their
antimicrobial activity against two gram-positive (Staphylococcus
aures and Klebisiella pneamoniae), two gram negative (Escherichia
coli and Pseudomonas aeruginosa) bacterial and two fungal strains
(Candida albicans and Asperigillus niger) at a concentration of 150
μg/ml using cup plate method and minimum inhibitory
concentration (MIC) was determined by agar streak dilution
method. From the results, we have observed that TB5 have been
shown best antimicrobial activity in all the bacterial and fungal
strains, TB2 also shown better activity, the rest of the compounds
have been shown good antimicrobial activity. TB3 substituted moiety
(fig. 2) have been shown potent antifungal activity.
Computer-assisted drug design (CADD) approach has contributed to
the discovery of several novel drugs. Molecular docking continues to
hold great promise in the field of computer-based drug design. In
silico docking, scores are provided in table 5. Sources from protein
data bank: 2XCT, 5JLC both are IDs for docking of antimicrobial
activity. 2XCT: The twinned 3.35 a structure of s. aureus gyrase
complex with ciprofloxacin and DNA, classification: Isomerase/DNA/
antibiotic. 5JLC: Structure of CYP51 from the pathogen Candida
glabrata, classification: oxidoreductase/ oxidoreductase inhibitor.
Molecular docking and scoring function
Docking protocol and their validation
Molecular modeling studies were performed on workstation
running Red Hat enterprise and Linux 4.0 and selection of the
compounds depends on the compounds which are obeying Lipinsky
rule of five and used an automated docking software Glide 5.6
Table 5: Docking score of TB1-TB12 molecules from SP docking protocol in Glide 5.6
S. No.
1
2
3
4
5
6
7
8
Molecule
TB1
TB2
TB3
TB4
TB5
TB6
TB7
TB8
DNA gyrase PDB ID: 2XCT
CYP51A1 PDB ID: 5JLC
-9.05
-8.42
-8.622
-8.15
-7.98
-8.22
-4.66
-7.85
-8.12
-8.17
-8.74
-8.12
-12.21
---
-8.72
-9.76
-8.92
-9.24
-10.79
-7.98
-3.86
-9.81
-9.61
-10.63
-7.69
-9.77
---
9
TB9
10
11
12
13
14
TB10
TB11
TB12
Ciproflaxin
Ketaconazole
-9.76
Molecular docking of the drug molecule into the binding site of target receptor gives important information about drug–receptor interactions and is
frequently used to find out the binding mode of drug candidates to their protein targets in order to predict the affinity. Molecular docking studies of
TB1-TB12 were carried out on DNA gyrase and CYP51A1 protein targets.
DNA gyrase
CYP51 A1 (Lanosterol 14 α-demethylase) is a cytochrome P450
enzyme and converts Lanosterol to 4, 4-dimethylcholesta-8(9), 14,
24-trien-3β-ol. CYP51 catalyzes the demethylation of lanosterol to
create a key precursor that is converted into ergosterol in fungi
[40]. Antifungal azoles like ketaconazole target CYP51 activity and
prevent the production of this key compound [41]. Molecular
docking and dock pose analysis of TB1-TB12 molecules into CYP51A1
(PDB id: 5JLC) showed good dock score indicating better binding.
TB5 had the highest binding affinity in terms of dockscore-10.79
kcal/mol. The molecule showed hydrogen bond interaction with Met
512 amino acid, hydrophobic interactions with Heme group and Tyr
73, Tyr121, Tyr 141, Met 512 and Phe 242 amino acid residues. Figs.
3 and 4 have shown the binding pose of TB5 in CYP51A1 along with
intermolecular interactions.
DNA gyrase is an enzyme that relieves strain, while double-strand
DNA is being unwound by helicase. This causes negative supercoiling
of the DNA. Bacterial DNA gyrase supercoils into DNA by looping the
template so as to form a crossing, then cutting one of the double
helices and passing the other through it before releasing the break,
changing the linking number by two in each enzymatic step [39].
Bacterial DNA gyrase is the target of many antibiotics, including
ciprofloxacin that binds to this enzyme and prevents it from
decatenation replicating DNA.
Molecular docking and dock pose analysis of TB1-TB12 molecules
into DNA gyrase (PDB id: 2XCT) showed similar interaction as that
of standard drug ciprofloxacin. TB1 had the highest binding affinity
in terms of dockscore-9.05 kcal/mol. The molecule showed
hydrogen bond interaction with Ser1084 amino acid and G8
nucleotide from DNA, hydrophobic interactions with G8, C12, C13
nucleotides and Arg 458 amino acid residues. Fig. 3 shows the
binding pose of TB1 in DNA gyrase along with intermolecular
interactions.
Assessment of toxicity, lipophilicity and drug score profiles
Osiris program was used for the prophecy of the toxicity of the
synthesized compounds. The prediction relies on a substructure
look for route determining the occurrence frequency of any
fragment (constructed and core fragments) within any of toxicity
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Bairam et al.
Int J Pharm Pharm Sci, Vol 9, Issue 3, 233-242
classes. The drug score combines C log P, molecular weight and
toxicity risks in one handy value that may be used to judge the
compounds overall potential to meet the requirements for a drug.
Osiris program was used for the prophecy of the C log P of
compounds. C log P is a well-established parameter to determine the
hydrophilicity of the synthesised compounds. Compounds show a
reasonable probability of being well absorbed when they have C log
P value around 5.0. All synthesized 1, 3-thiazin-2-imine derivatives
have showed low Insilco possible toxicity risks. From the table, it
was observed that all compounds had revealed C log P around 5.0
indicating that the synthesized compounds could be potential drug
candidates. Prophecy of C log P, drug score and toxicity for 1, 3-
thiazin-2-imine derivatives are prearranged in table 6, and almost
all the compounds possess good values of drug score, C log P, and
low probable toxicity risks as revealed by computational in silico
studies and the values are tabulated in table 6.
3 Dimensional (3D) structure image of TB1 in DNA gyrase [a]
3 Dimensional (3D) structure image dockpose of TB1 showing hydrogen bond [b]
Graphical (2 Dimensional) image of TB1 showing ligand-receptor interaction[c]
Fig. 3: a) Dockpose TB1 shown in yellow tube form in the binding site of DNA gyrase, b) Dockpose of TB1 showing hydrogen bond [green
line] and hydrophobic pi-pi and pi-alkyl interaction [pink and light pink lines], c) Two dimensional Ligplot obtained from PDBsum
[www.ebi.ac.uk] of TB1 showing ligand-receptor interaction CYP51A1
239

Bairam et al.
Int J Pharm Pharm Sci, Vol 9, Issue 3, 233-242
3 Dimensional (3D) structure image of TB5 in CYP51A1 [a]
3 Dimensional (3D) structure image dockpose of TB5 showing hydrogen bond [b]
Graphical 2 Dimensional (2D) image of TB5 showing ligand-receptor interaction [c]
Fig. 4: a) Dockpose TB5 shown in yellow tube form in the binding site of CYP51A1, b) Dockpose of TB5 showing hydrogen bond [green line]
and hydrophobic pi-pi and pi-alkyl interaction [pink and light pink lines], c) Two dimensional ligplot obtained from PD Bsum
[www.ebi.ac.uk] of TB5 showing the ligand-receptor interaction
240

Bairam et al.
Int J Pharm Pharm Sci, Vol 9, Issue 3, 233-242
Table 6: Computationally predicted toxicity risks, lipophilicity drug scores
Entry
TB1
TB2
TB3
TB4
TB5
TB6
TB7
TB8
TB9
TB10
Clog P*
6.12
7.35
6.24
5.91
8.31
5.38
5.49
5.53
4.93
7.47
Drug score range
Toxicity risks**
0.27
0.25
0.21
0.37
0.08
0.33
0.31
0.37
0.42
0.21
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
* Indicating Clog P values calculated for the lipophilicity, ** Indicating the mutagenicity, tumorigenicity, irritancy and reproductive effects
CONCLUSION
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In conclusion, the results of the present study indicated that the
synthesized compounds have striking anticonvulsant as well as
antimicrobial activities. In the case of antimicrobial activity, among
all the compounds from TB1-TB12 isopropyl derivative have shown
better activity, whereas the other compounds were shown potent
activity, in the case of antifungal activity, along with that ethyl and
dihydroxy derivative shown high antifungal activity. From
pentylene-tetrazole (PTZ) induced model it can be clearly notified
that 1,3-thiazines possess significant anticonvulsant activity but less
than the standard diphenyl hydantain, moreover anticonvulsant
activity in pentylenetetrazole (PTZ) induced seizures, identifies
compound that can raise seizure threshold in the brain [42],
pentylenetetrazole (PTZ) has been shown to act together with
gamma-amino-butyric acid (GABA) neurotransmitters and the GABA
receptor complex. The compound TB7 containing 3, 4, 5-
trimethoxyphenyl substituents on the thiazine moiety was more
potent as it has prolonged the onset of convulsions by 18.7 min. In
particularly it has been found that if 4-substituted-aryl-8-substituted
arylidene-2-imino-5,6-dihydro-4H,7H-(3,1)-benzothiazines with an
increase in the number of hydrophobic electrons releasing or a
combination of electron releasing and electron donating groups at
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ACKNOWLEDGEMENT
The authors express their sincere gratitude to the management
Vignan Institute of Pharmaceutical Sciences Hyderabad, for
encouragement and for providing the essential requirements for
carrying out this research work, and we also express our sincere
thanks to Mr. Kadiri Sunil Kumar, Associate Professor, Department
of Pharmacology, Vijaya College of Pharmacy, for help in
pharmacological screening. We are extending our sincere and
humble thanks to IICT Hyderabad, for helping in spectral analysis.
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CONFLICT OF INTERESTS
The authors declare that they have no conflict of interest
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How to cite this article
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Ravindar Bairam, Srinivasa Murthy Muppavarapu, Sivan
Sreekanth. Synthesis, characterization, biological evaluation
and docking of some novel substituted 1, 3-thiazine
derivatives. Int J Pharm Pharm Sci 2017;9(3):233-242.
242