You are on page 1of 20

molecules

Review
Bioactive Thiazine and Benzothiazine Derivatives:
Green Synthesis Methods and Their
Medicinal Importance
Syed Lal Badshah 1,2,3, * and Abdul Naeem 1, *
1 National Center of Excellence in Physical Chemistry, Peshawar University, Peshawar,
Khyber Pukhtoonkhwa 25120, Pakistan
2 Department of Biochemistry, Abdul Wali Khan University Mardan, Khyber Pukhtoonkhwa 25120, Pakistan
3 Department of Chemistry, Islamia College University Peshawar, Peshawar,
Khyber Pukhtoonkhwa 25120, Pakistan
* Correspondence: shahbiochemist@gmail.com (S.L.B.); naeeem64@yahoo.com (A.N.);
Tel.: +92-331-931-6672 (S.L.B. & A.N.)

Academic Editor: Derek J. McPhee


Received: 11 July 2016; Accepted: 6 August 2016; Published: 15 August 2016

Abstract: Thiazines are a group of heterocyclic organic compounds that are still largely unexplored
for their pharmacological activities. There are different available methods for the synthesis of thiazine
derivatives in the literature. In this review, we discuss available methods of thiazine preparation
through green synthesis methods. Beside their synthesis, many thiazine derivatives are biologically
active and play an important role in the treatment of various diseases and show promising results of
varying degrees, where they act as antibacterial, antifungal, antitumor, antimalarial, antineoplastic,
antiviral, anti-inflammatory, analgesic and anticancer agents and thus they represent an interesting
class of heterocyclic medicinal compounds worthy of further exploration.

Keywords: thiazine; green synthesis; biologically active; antibacterial activity; anticancer agents

1. Introduction
Heterocyclic chemistry research encompasses almost half of the organic chemistry research
throughout the world. A huge amount of bioactive organic compounds that contain heterocyclic
frameworks play a vital part in the medicinal field. It is commonly reported that heterocycles having
sulphur or nitrogen atoms or both of them are the general features present in the structures of most of
the pharmaceutical and natural compounds [1,2]. They also act as multidentate ligands for different
metals due to the presence of nitrogen and sulfur atoms and are thus used extensively in coordination
chemistry to obtain new frameworks with potential bioactivity [2]. According to Joshi et al., it has also
been identified that several heterocyclic compounds in the developmental phase have the potential to be
part of new drugs and also play an important role in modern drug discovery [3]. Heterocyclic thiazine
derivatives are important because they are biological constituents of many biomolecules and drugs [3].
The thiazines possess a nitrogen and sulphur atoms in a six member ring (Figure 1), that is believed
to be important for their antifungal, anticonvulsant, and antiviral activities. The uniqueness and
resourcefulness of the simple thiazine chemical structure and easy availability make thiazines and
their derivatives amongst the most gifted sources of bioactive compounds [4,5]. There are a few review
articles [6–9] available on thiazine compounds, but they are either focused mostly on 1,3-thiazines or
lack comprehensiveness and there was a perceived need to discuss current green synthesis methods
and their biological importance, with the aim of showing the importance of the data published to
date on the synthesis and biological activities of different thiazines and their analogues. The present
work clearly establishes the importance of thiazine and its derivatives for the synthesis of a wide

Molecules 2016, 21, 1054; doi:10.3390/molecules21081054 www.mdpi.com/journal/molecules


Molecules
Molecules 2016,
Molecules 2016, 21,
2016, 21, 1054
21, 1054
1054 222 of
of 19
of 20
19

work
work clearly
clearly establishes
establishes the
the importance
importance of of thiazine
thiazine and
and its
its derivatives
derivatives for for the
the synthesis
synthesis of of aa wide
wide variety
variety
variety
of of heterocyclic compounds through environmentally friendly methods thatofare of academic
of heterocyclic compounds through environmentally friendly methods that are of academic and
heterocyclic compounds through environmentally friendly methods that are academic and
and pharmaceutical
pharmaceutical industry
industry interest
interest [4]. [4]. Moreover,
Moreover, during
during these
these syntheses
syntheses theyield
the yieldofof the
the desired
desired
pharmaceutical industry interest [4]. Moreover, during these syntheses the yield of the desired
compounds It has been
been noticed that that structural
compounds is is often
often high
high and
and they
they may
may bebe obtained
obtained in in aa single
single step.
step. It
It has
has been noticed
noticed that structural
structural
modifications in the thiazine and its derivatives result in valuable medicinal properties that should be
modifications in the thiazine and its derivatives result in valuable medicinal properties that should be
further explored through structure activity relationship (SAR) methods for the development of highly
further explored through structure activity relationship (SAR) methods for the development of highly
potent and other research
potent compounds
compounds against
against multi-drug
multi-drug resistant
resistant microorganisms
microorganisms and other diseases. diseases. Thus,
Thus, the
the research
research
to explore different avenues of chemical modifications of thiazine and its available available derivatives
derivatives to to obtain
obtain
to explore different avenues of chemical modifications of thiazine and its available derivatives to obtain
novel compounds should
should continued.
continued. Therefore, itit is is of utmost
utmost timeliness to to
novel active
active compounds
compounds should be be continued. Therefore,
Therefore, it is of of utmost timeliness
timeliness to briefly
briefly review
review
the synthetic methodologies and biological activities of thiazine and their derivatives.
the novel green, synthetic methodologies and biological activities of thiazine and their derivatives.
novel green, and their derivatives.
The current
The current collected data for the preparationbiochemical
and biochemical applications of thiazines
The current collected
collected data
data for
for the
the preparation
preparation and and biochemical applications
applications of of thiazines
thiazines and and their
their
and their derivatives
derivatives relate approach,
to the green approach, i.e.,microwave
reactions irradiation,
using microwave irradiation,
derivatives relate to the green approach, i.e., reactions using microwave irradiation, sonication, grinding
relate to the green i.e., reactions using sonication, grinding
sonication, grinding
techniques, techniques, solvent-free conditions, liquids,
nanoparticles, ionic liquids,inetc. are presented
techniques, solvent-free
solvent-free conditions,
conditions, nanoparticles,
nanoparticles, ionic
ionic liquids, etc. etc. are
are presented
presented in this this review.
review. The
The
in this
reagents review. The reagents used for the synthesis are ferric chloride, cesium carbonates,
reagents used for the synthesis are ferric chloride, cesium carbonates, tetraphenyl phosphine, thiourea,
used for the synthesis are ferric chloride, cesium carbonates, tetraphenyl phosphine, thiourea,
tetraphenyl phosphine,
ptolylsulphonic thiourea, ptolylsulphonic acid, palladium catalyst, perchloric acid,
ptolylsulphonic acid,acid, palladium
palladium catalyst,
catalyst, perchloric
perchloric acid,
acid, phosphomolybdic
phosphomolybdic acid, acid, 1-benzyl-3-methyl
1-benzyl-3-methyl
phosphomolybdic
imidazolium acid, 1-benzyl-3-methyl imidazolium hydrogen sulphate, etc. [9].
imidazolium hydrogen
hydrogen sulphate,
sulphate, etc.
etc. [9].
[9].

Figure
Figure 1.
1. Structures
Structures of
of 1,4-,
1,4-, 1,3-
1,3- and
and 1,2-thiazine.
1,2-thiazine.

2.
2. Green
GreenSyntheses
Green Synthesesof
Syntheses ofThiazines
of Thiazinesand
Thiazines andtheir
and theirDerivatives
their Derivatives
Derivatives
Edayadulla
Edayadulla and and Ramesh
Ramesh [10][10] synthesized
synthesized
synthesized aaa derivative
derivative of
derivative of 1,4-thiazine,
of1,4-thiazine, namely
1,4-thiazine, namely 2,6-dicarbethoxy-3,5-
namely 2,6-dicarbethoxy-3,5-
2,6-dicarbethoxy-3,5-
diphenyltetrahydro-1,4-thiazine-1,1-dioxide
diphenyltetrahydro-1,4-thiazine-1,1-dioxide by taking diethyl 2,2-sulfonyldiacetate and
by taking diethyl 2,2-sulfonyldiacetate and benzaldehyde
benzaldehyde
in water, to which ammonium acetate was added at room temperature
in water, to which ammonium acetate was added at room temperature [10]. The reactants [10]. The reactants
reactants were
were gently
gently
stirred for 3 h at 80
stirred for 3 h at 80 °C°C
◦ and after that
C and after that they
that they were
were cooled down to room temperature, and the product was
they were cooled down to room temperature, and the product was
extracted
extracted with
with ethyl
ethyl acetate.
acetate. The
The upper
upper organic
organic layer
layer was
was dehydrated
dehydrated completely
completely using
using the
the anhydrous
anhydrous
Na
Na222SO
SO444and
SO andconcentrated
and concentratedat
concentrated atatreduced
reducedpressure
reduced pressureto
pressure toobtain
to obtainthe
obtain the crude
the crude product,
crude product, which
product, which was
which was purified
purified and
and
recrystallized
recrystallized using
recrystallized using ethanol
usingethanol as a solvent
ethanolasasa asolvent
solventto give
totogive the pure
thethe
give pure target
target
pure compound
compound
target compound in excellent
in excellent yield [10].
yieldyield
in excellent The
[10]. [10].
The
chemical
chemical structure
structure of
of the
the compound
compound was
was determined
determined by
by different
different spectroscopic
spectroscopic
The chemical structure of the compound was determined by different spectroscopic and analytical and
and analytical
analytical
techniques
techniques (Scheme
(Scheme 1) 1) [10].
[10]. Test
Test results
Test results of
of these
these compounds
compounds on on mice
mice models
models showed
showed that
that they
they effective
effective
anticonvulsants
anticonvulsants [10].[10].

Scheme
Scheme 1.1. Eco-compatible
1. Eco-compatible preparation
preparationofof
Eco-compatiblepreparation the
ofthe
the 2,6-dicarbethoxy-3,5-diphenylltetrahydro-1,4-thiazine-
2,6-dicarbethoxy-3,5-diphenylltetrahydro-1,4-thiazine-
Scheme 2,6-dicarbethoxy-3,5-diphenylltetrahydro-1,4-thiazine-1,1-
1,1-dioxides
1,1-dioxides [10].
[10].
dioxides [10].

Kadhim
Kadhim reported
reported aa novel
novel azachalcone
azachalcone compound
compound that that was
was prepared
prepared through
through the
the reaction
reaction ofof
Kadhim
acetylated reported
pyridine witha novel azachalcone
4-hydroxybenzaldehyde compound
[11]. that
Later thewas prepared
azachalcone through
was the
treated reaction
with of
thiourea
acetylated pyridine with 4-hydroxybenzaldehyde [11]. Later the azachalcone was treated with thiourea
acetylated
to pyridineofwith 4-hydroxybenzaldehyde [11]. Later the azachalcone was treated with
to give
give aa high
high yield
yield of the
the thiazine
thiazine derivative
derivative ((E)-3-(4-hydroxyphenyl)-1-(pyridin-3-yl)
((E)-3-(4-hydroxyphenyl)-1-(pyridin-3-yl) prop-2-en-1-
prop-2-en-1-
thiourea
one) to give a high yield of the thiazine derivative ((E)-3-(4-hydroxyphenyl)-1-(pyridin-3-yl)
one) (Scheme
(Scheme 2) 2) [11].
[11]. The
The synthesized
synthesized compound
compound was was characterized
characterized byby infrared,
infrared, ultra-violet,
ultra-violet, 1H-NMR
1
H-NMR
prop-2-en-1-one)
spectroscopy (Scheme 2) [11]. The synthesized compound was characterized by infrared,
spectroscopy and elemental analysis. The obtained compound were tested for anti-bacterial and anti-
and elemental analysis. The obtained compound were tested for anti-bacterial and anti-
fungal
fungal properties
properties and
and showed
showed good
good activities
activities (Scheme
(Scheme 2) 2) [11].
[11].
Molecules 2016, 21, 1054 3 of 20

ultra-violet, 1 H-NMR spectroscopy and elemental analysis. The obtained compound were tested
for anti-bacterial
Molecules and anti-fungal properties and showed good activities (Scheme 2) [11].
2016, 21, 1054 3 of 19
Molecules 2016, 21, 1054 3 of 19

Scheme
Scheme 2.
2. Formation
Formation of of azachalcone
azachalcone compound
compound from
from acetylated
acetylated pyridine
pyridine and
and benzaldehyde
benzaldehyde and
and its
its
Scheme 2. Formation of azachalcone compound from acetylated pyridine and benzaldehyde and its
subsequent
subsequent use
use for
for the
the synthesis
synthesis of
of aa thiazine
thiazine derivative;
derivative; R
R represents
represents m-NO
m-NO22,, p-OH,
p-OH, m-Br,
m-Br, m-OCH
m-OCH33,,
subsequent use for the synthesis of a thiazine derivative; R represents m-NO2, p-OH, m-Br, m-OCH3,
p-N(CH
p-N(CH33)2
)2[11].
[11].
p-N(CH3)2 [11].
According to Elarfi et al., chalcone derivatives can be synthesized by reacting benzaldehyde
According
AccordingtotoElarfi
Elarfietetal.,
al.,chalcone
chalconederivatives
derivativescan
canbebesynthesized
synthesizedby byreacting
reactingbenzaldehyde
benzaldehyde
derivatives with acetophenone [12]. In the second step of this reaction, the product obtained was
derivatives
derivatives with acetophenone [12]. In the second step of this reaction, the product obtainedwas
with acetophenone [12]. In the second step of this reaction, the product obtained was
allowed to react with thiourea to form thiazines and other related compounds. The products obtained
allowed
allowedtotoreact
reactwith
withthiourea
thioureatotoform
formthiazines
thiazinesand
andother
otherrelated
relatedcompounds.
compounds.TheTheproducts
productsobtained
obtained
were characterized by elemental analysis, electromagnetic induction spectroscopy (EMIS), proton NMR
were
werecharacterized
characterizedby
byelemental
elementalanalysis,
analysis,electromagnetic
electromagneticinduction
inductionspectroscopy
spectroscopy(EMIS),
(EMIS),proton
protonNMR
NMR
and infrared spectroscopy [12]. The thiazine and its related derivatives were checked for bioactivity
and
andinfrared
infraredspectroscopy
spectroscopy[12].
[12].The
Thethiazine
thiazineand
andits
itsrelated
relatedderivatives
derivativeswere
werechecked
checkedfor
forbioactivity
bioactivity
using some antibacterial tests (Scheme 3) [12].
using
usingsome
someantibacterial
antibacterialtests
tests(Scheme
(Scheme3)3)[12].
[12].

Scheme 3. Preparation of thiazine derivatives from benzaldehyde and acetophenone through chalcones.
Scheme3.3.Preparation
Scheme Preparationof
ofthiazine
thiazinederivatives
derivativesfrom
frombenzaldehyde
benzaldehydeand
andacetophenone
acetophenonethrough
throughchalcones.
chalcones.
Where X = o-OH; p-N(CH 3)2; m-OCH 3 [12].
WhereXX==o-OH;
Where o-OH;p-N(CH
p-N(CH)3)2;;m-OCH
m-OCH3 [12].
[12].
3 2 3
Gayathri et al. reported that thiazine derivatives containing fluorine, chlorine and benzimidazole
Gayathri et al. reported that thiazine derivatives containing fluorine, chlorine and benzimidazole
can be synthesized
Gayathri by microwave
et al. reported induced
that thiazine reactionscontaining
derivatives [13]. They fluorine,
took 1-(7-chloro-6-fluoro-1H-benzo
chlorine and benzimidazole
can be synthesized by microwave induced reactions [13]. They took 1-(7-chloro-6-fluoro-1H-benzo
[d]imidazol-2-yl)-3-arylprop-2-en-1-one
can be synthesized by microwave induced and cyclized
reactionsit [13].
with They
thiourea in1-(7-chloro-6-fluoro-1H-benzo
took a microwave induced reaction
[d]imidazol-2-yl)-3-arylprop-2-en-1-one and cyclized it with thiourea in a microwave induced reaction
producing the 1,3-thiazine derivative 6-(7-chloro-6-fluoro-1H-benzo-2-yl)-4-phenyl-6H-1,3-thiazine-2-
[d]imidazol-2-yl)-3-arylprop-2-en-1-one and cyclized it with thiourea in a microwave induced reaction
producing the 1,3-thiazine derivative 6-(7-chloro-6-fluoro-1H-benzo-2-yl)-4-phenyl-6H-1,3-thiazine-2-
amine
producing the synthesized
[13]. The 1,3-thiazinecompounds were confirmed and characterized by thin layer chromatography
derivative 6-(7-chloro-6-fluoro-1H-benzo-2-yl)-4-phenyl-6H-1,3-thiazine-
amine [13]. The synthesized compounds were confirmed and characterized by thin layer chromatography
(TLC), EMIS, elemental analysis, proton NMR and infrared spectroscopy. The manufactured compounds
(TLC), EMIS, elemental analysis, proton NMR and infrared spectroscopy. The manufactured compounds
were screened for analgesic and antibacterial activities showing potent activities in both areas
were screened for analgesic and antibacterial activities showing potent activities in both areas
(Scheme 4) [13].
(Scheme 4) [13].
Molecules 2016, 21, 1054 4 of 20

2-amine [13]. The synthesized compounds were confirmed and characterized by thin layer
chromatography (TLC), EMIS, elemental analysis, proton NMR and infrared spectroscopy.
The manufactured compounds were screened for analgesic and antibacterial activities showing
potent activities
Molecules in both areas (Scheme 4) [13].
2016, 21, 1054 4 of 19

NH2
Molecules 2016, 21, 1054 4 of 19
O
S N
N NH2
N
O thiourea
N S N
F N
H microwave N
F N
H
Cl thiourea
N Cl
F H microwave N
F
Scheme 4. H
Synthesis of 1,3-thiazine derivatives under microwave irradiation [13].
Scheme Cl
4. Synthesis of 1,3-thiazine derivatives underClmicrowave irradiation [13].

Scheme et
Zia-ur-Rehman 4. Synthesis of 1,3-thiazine
al. synthesized a seriesderivatives
of analogues under of microwave irradiation [13].
4-hydroxy-N-(benzylidene)-2H-benzo
Zia-ur-Rehman et al. synthesized a series of analogues of 4-hydroxy-N-(benzylidene)-2H-benzo
[e][1,2]thiazine-3 carbohydrazide 1,1-dioxides [14]. They performed N-alkylaton of sodium saccharin
[e][1,2]thiazine-3
with Zia-ur-Rehman carbohydrazide
methyl chloroacetate in the1,1-dioxides
et al. synthesized a seriesof[14].
presence They performed
ofultrasonic
analogues N-alkylaton
[14]. Bothofthe sodium
of 4-hydroxy-N-(benzylidene)-2H-benzo
irradiation saccharin
reagents were
with methyl
[e][1,2]thiazine-3chloroacetate
carbohydrazide in the presence
1,1-dioxides of ultrasonic
[14]. They irradiation
performed [14].
N-alkylaton
dissolved in dimethyformamide for the ultrasonic irradiation. The advantage of this process is that Both of the reagents
sodium were
saccharin it
dissolved
with methyl in dimethyformamide
chloroacetate in the for the
presence ultrasonic
of ultrasonicirradiation.
irradiation The advantage
[14].
can be done at lower temperatures and in a short period of time. In the next stage, the five membered Both the of this
reagents process
were
is that it in
dissolved
isothiazole can
ring bewas
done
dimethyformamideat lowerinto
converted temperatures
for the thiazineand
theultrasonic inunder
a short
irradiation.
ring The
inertperiod of time.
advantage
atmosphere Inprocess
the next
of conditions
this stage,
is that
and thenit
the
can five
be membered
done at lower isothiazole
temperatures ring was
and in converted
a short into
period ofthe thiazine
time. In
treated with hydrazine which was followed by reaction with benzaldehydes to give the desired the ring
next under
stage, inert
the five atmosphere
membered
conditions
isothiazole
products in and
highthen
ring yieldtreated
was converted
(Scheme with hydrazine
5)into
[14]. the
Some ofwhich
thiazine wasunder
ring
the derivativesfollowedinertby
have reaction
atmosphere
good with benzaldehydes
conditions
antibacterial andwhile
properties, to
then
give the
treated
most desired
with
of the products
hydrazine
products in high
which
possess yieldfollowed
was
antioxidant (Scheme 5) [14].
by
activities. Somethe
reaction
Recently of same
with the derivatives
benzaldehydes have
research group to good antibacterial
giveexpanded
has the desired the
synthesis of these 1,2-benzothiazine-3-carbohydrazide 1,1-dioxides using a microwave-assistedresearch
properties,
products in while
high most
yield of
(Scheme the products
5) [14]. Some possess
of the antioxidant
derivatives activities.
have good Recently
antibacterial the same
properties, while
method
group
most
that ofhas
gives expanded
thethe
products
products the
insynthesis
possess high yieldof[15].
antioxidant these 1,2-benzothiazine-3-carbohydrazide
activities. Recentlyet
Zia-ur-Rehman theal.same
haveresearch group1,1-dioxides
also performed has expanded using
crystallographic the
a microwave-assisted
synthesis of these method that gives the
1,2-benzothiazine-3-carbohydrazide products in high yield
1,1-dioxides [15].
using Zia-ur-Rehman
a microwave-assisted
studies of the 1,2-benzothiazine compounds to get better information about their molecular structure in et al. have also
method
performed
that
terms gives crystallographic
the
of bond productsbond
lengths, studies
in high yield
angles of [15].
and the 1,2-benzothiazine
Zia-ur-Rehman
various compounds
et al. have also
possible conformational to get better information
performed
states [16]. about
crystallographic
their molecular structure in terms of bond lengths, bond angles and various
studies of the 1,2-benzothiazine compounds to get better information about their molecular structure in possible conformational
states of
terms [16].
bond lengths, bond angles and various possible conformational states [16].

Scheme 5. General Scheme for the synthesis of different N-[(1E)-arylmethylidene]-4-hydroxy 2H-1,2-


benzothiazine-3-carbohydrazide 1,1-dioxides derivatives [14].
Scheme
Scheme 5.5.General Scheme
General for the
Scheme forsynthesis of different
the synthesis N-[(1E)-arylmethylidene]-4-hydroxy
of different 2H-1,2-
N-[(1E)-arylmethylidene]-4-hydroxy
benzothiazine-3-carbohydrazide
Dighade 1,1-dioxides
et al. synthesized different
2H-1,2-benzothiazine-3-carbohydrazide derivatives
chalcones
1,1-dioxides [14]. a condensation
through
derivatives [14]. process of 2-hydroxy-3-
iodo-5-methylacetophenone as a starting material with different aromatic aldehydes in ethanol using
40% Dighade
Dighade
et al. synthesized
sodium hydroxide
et al. solutiondifferent
synthesized
chalcones
as a different
catalyst through
[17]. a condensation
The chalcones
chalcones through produced
process
wereofcyclized
a condensation
2-hydroxy-3-
processwith
of
iodo-5-methylacetophenone
diphenylthiourea in ethanol as a
usingstarting
KOH material
and a fewwith different
drops of aromatic
piperidine asaldehydes
a catalyst. in ethanol
All the using
thiazine
2-hydroxy-3-iodo-5-methylacetophenone as a starting material with different aromatic aldehydes
40% sodium were
compounds hydroxide solution as
confirmed a catalystby[17]. The chalcones produced were cyclized with
sodiumand categorized
solution elemental analysis, EIMS, 1H-NMR and infrared
in ethanol using 40% hydroxide as a catalyst [17]. The chalcones produced were
diphenylthiourea
spectroscopies in ethanol using KOH and a few drops of piperidine as a catalyst. All
(Scheme 6) [17]. in ethanol using KOH and a few drops of piperidine as a catalyst.the thiazine
cyclized with diphenylthiourea
compounds were confirmed and categorized by elemental analysis, EIMS, 1H-NMR 1and infrared
All the thiazine compounds were confirmed and categorized by elemental analysis, EIMS, H-NMR and
spectroscopies (Scheme 6) [17].
infrared spectroscopies (Scheme 6) [17].
Bunker and colleagues synthesized and characterized a group of 1,2-benzothiazine analogues [18].
Methyl-2-(chlorosulfonyl)benzoate and 2-(trifluoromethyl)aniline were taken as starting materials and
the whole benzothiazine synthesis was completed in three steps [18]. It was claimed that these
1,2-benzothiazine derivatives are useful in treating hypertension and as endothelial antagonists
(Scheme 7) [18].
Dighade et al. synthesized different chalcones through a condensation process of 2-hydroxy-3-
iodo-5-methylacetophenone as a starting material with different aromatic aldehydes in ethanol using
40% sodium hydroxide solution as a catalyst [17]. The chalcones produced were cyclized with
diphenylthiourea in ethanol using KOH and a few drops of piperidine as a catalyst. All the thiazine
compounds
Molecules were
2016, 21, 1054 confirmed and categorized by elemental analysis, EIMS, 1H-NMR and infrared
5 of 20
spectroscopies (Scheme 6) [17].

Molecules 2016, 21, 1054 5 of 19

Bunker and colleagues synthesized and characterized a group of 1,2-benzothiazine analogues [18].
Methyl-2-(chlorosulfonyl)benzoate and 2-(trifluoromethyl)aniline were taken as starting materials
and the whole benzothiazine synthesis was completed in three steps [18]. It was claimed that these
Scheme 6.
Scheme 6. Formation
Formation of
of chalcones
chalcones and
and their
their cyclization
cyclization with
with diphenylthiourea
diphenylthiourea in
in ethanol
ethanol using
using KOH
KOH
1,2-benzothiazine derivatives are useful in treating hypertension and as endothelial antagonists
and few
and few drops of piperidine as a catalyst [17].
drops of piperidine as a catalyst [17].
(Scheme 7) [18].

Scheme 7.
Scheme 7. Formation
Formation of
of 1,2-benzothiazine
1,2-benzothiazine derivatives
derivatives using
using methyl-2-(chlorosulfonyl)
methyl-2-(chlorosulfonyl) benzoate
benzoate and
and
2-(trifluoromethyl)aniline [18].
2-(trifluoromethyl)aniline [18].

Yadav et al. developed a new, expeditious, three-component method for the synthesis of 3,6-diaryl-
Yadav et al. developed a new, expeditious, three-component method for the synthesis
5-mercaptoperhydro-2-thioxo-1,3-thiazin-5-ones 1,3-thiazine analogues from 2-methyl-2-phenyl-1,3-
of 3,6-diaryl-5-mercaptoperhydro-2-thioxo-1,3-thiazin-5-ones 1,3-thiazine analogues from
oxathiolan-5-one under solvent-free conditions [19]. They synthesized 2-methyl-2-phenyl-1,3-oxathiolan-
2-methyl-2-phenyl-1,3-oxathiolan-5-one under solvent-free conditions [19]. They synthesized
5-one [20] from 2-mercaptoacetic acid and acetophenone using lithium bromide as a catalyst [19]. This
2-methyl-2-phenyl-1,3-oxathiolan-5-one [20] from 2-mercaptoacetic acid and acetophenone using
intermediate was treated with a benzaldehyde and N-aryldithio carbamic acid to synthesize the desired
lithium bromide as a catalyst [19]. This intermediate was treated with a benzaldehyde and N-aryldithio
product in a one-pot synthesis method using microwaves [19]. It is diastereoselective process and involves
carbamic acid to synthesize the desired product in a one-pot synthesis method using microwaves [19].
tandem Knoevenagel, Michael and ring transformation steps, as presented in Scheme 8 [19,20].
It is diastereoselective process and involves tandem Knoevenagel, Michael and ring transformation
steps, as presented in Scheme 8 [19,20].
Torres-García et al. reported zinc complexes of a new ligand 2-(3,5-diphenyl-1-pyrazolyl)-
1,3-thiazine (DPhPzTz) [21]. They treated a methanol solution of DPhPzTz with a methanol solution
of zinc chloride [21]. After completion of the reaction and gentle dehydration of the solution at
room temperature, colorless crystal of the complex ZnCl2 (DPhPzTz) were obtained [21]. The product
obtained was confirmed and characterized through elemental analysis and spectroscopic techniques,
Molecules 2016, 21, 1054 6 of 20

while the
Molecules crystal
2016, structure was also determined. In addition, Torres-García and coworkers investigated
21, x 6 of 20
the phagocytosis process of human neutrophils that was increased when treated with the Zn (II)
complexes [21] and similar observations were reported for cadmium complexes with other ligands [22].

Scheme
Scheme8.8.Three-component
Three-componentexpeditious
expeditiousmethod
methodfor
forthe
thesynthesis
synthesisof
of1,3-thiazine
1,3-thiazinederivatives
derivatives[19].
[19].

Torres-García et al. reported zinc complexes of a new ligand 2-(3,5-diphenyl-1-pyrazolyl)-1,3-


Tozkoparan and coworkers synthesized a series of 5-carbomethoxy-2-substituted-7H-
thiazine (DPhPzTz) [21]. They treated a methanol solution of DPhPzTz with a methanol solution of
1,2,4-triazolo(3,2-b)-1,3-thiazine-7-one 1,3-thiazine derivatives [23]. According to their reaction
zinc chloride [21]. After completion of the reaction and gentle dehydration of the solution at room
(Scheme 9), these compounds can be made by reacting 1,2,4-triazole-5-thiones with dimethyl
temperature, colorless crystal of the complex ZnCl2(DPhPzTz) were obtained [21]. The product
acetylene dicarboxylate using toluene as a solvent under reflux conditions. They purified and
obtained was confirmed and characterized through elemental analysis and spectroscopic techniques,
characterized their thiazine compounds by different spectroscopic methods and elemental analysis.
while the crystal structure was also determined. In addition, Torres-García and coworkers
The synthesized thiazine analogues exhibit analgesic, anti-inflammatory activities and other interesting
investigated the phagocytosis process of human neutrophils that was increased when treated with
characteristics [23]. Most of the derivatives showed remarkable anti-inflammatory activity against
the Zn (II) complexes [21] and similar observations were reported for cadmium complexes with other
edema caused by serotonin, carrageenan and in the inhibition of diarrhea tests [23], thus these novel
ligands [22].
1,3-thiazines could be used in the future for the treatment of inflammatory pain after further laboratory
Tozkoparan and coworkers synthesized a series of 5-carbomethoxy-2-substituted-7H-1,2,4-
trials. These compounds were also found safe for gastric ulcer treatment [23].
triazolo(3,2-b)-1,3-thiazine-7-one 1,3-thiazine derivatives [23]. According to their reaction (Scheme 9),
Singh and colleagues developed an innovative, easy to use, inexpensive and highly efficient
these compounds can be made by reacting 1,2,4-triazole-5-thiones with dimethyl acetylene
one pot, multi-component ceric ammonium nitrate (CAN)-catalyzed preparation of 1,3-thiazine
dicarboxylate using toluene as a solvent under reflux conditions. They purified and characterized
derivatives in polyethylene glycol (PEG) 400 by mixing substituted acetophenones, aromatic aldehydes
their thiazine compounds by different spectroscopic methods and elemental analysis. The
and thiourea in PEG-400 in specific amounts [24]. The reaction mixture was gently stirred while
synthesized thiazine analogues exhibit analgesic, anti-inflammatory activities and other interesting
maintaining a uniform temperature of 45 ◦ C until the formation of product was confirmed through
characteristics [23]. Most of the derivatives showed remarkable anti-inflammatory activity against
TLC (Scheme 10). The desired 1,3-thiazines were isolated through a mixture of ether and PEG-400
edema caused by serotonin, carrageenan and in the inhibition of diarrhea tests [23], thus these novel
that forms two separate layers as PEG is insoluble in ether and their structures were confirmed by
1,3-thiazines could be used in the future for the treatment of inflammatory pain after further
elemental analysis and spectroscopic analysis [24]. These thiazine derivatives act as potent inhibitors
laboratory trials. These compounds were also found safe for gastric ulcer treatment [23].
of Gram-negative bacteria by targeting 4-diphosphocytidyl-2-C-methyl-D-erythritol (IspE) kinase [24].
Il’inykh and coworkers made S-alkenyl forms of 5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol
compounds by treating various alkenyl halides with 2,4-triazoles conjugated with trifluoromethyl and
thiol groups [25]. Furthermore the chemical process between the S-alkenyl derivatives and iodine
molecules occurs regiospecifically producing new fused halogenated (1,2,4)triazole(3,4-b)(1,3)thiazine
compounds (Scheme 11) [25]. The chemical structures of these products were confirmed by elemental
analysis, IR and mass spectroscopy and different isotopic (1 H-, 13 C- and 19 F-) NMR spectroscopies,
including state of the art 2D 1 H-13 C-HSQC, 1 H- 1 H-COSY, 1 H-13 C-HMBC correlations, and also by
R = 1–8
single-crystal XRD technique
R1 = CHfor
3 better results [25].
R2 =
compounds by different spectroscopic methods and elemental analysis. The synthesized thiazine
analogues exhibit analgesic, anti-inflammatory activities and other interesting characteristics [23]. Most
of the derivatives showed remarkable anti-inflammatory activity against edema caused by serotonin,
carrageenan and in the inhibition of diarrhea tests [23], thus these novel 1,3-thiazines could be used
in the future
Molecules for1054
2016, 21, the treatment of inflammatory pain after further laboratory trials. These compounds
7 of 20
were also found safe for gastric ulcer treatment [23].

R = 1–8

R1 = CH3
R2 =

Cl
R4 =
R3 = Cl

O2N
R7 =
R5= NO2
CH3
H3C CH3
C CH
H
H3C
R7 =
R8 = H3CO
Scheme 9.
Scheme 9. Synthesis of thiazine
Synthesis of thiazine derivatives
derivatives using
using 1,2,4-triazole-5-thiones
1,2,4-triazole-5-thiones as
as aa starting
starting material
material [23].
[23].
Molecules 2016, 21, 1054 7 of 19
Singh and colleagues developed an innovative, easy to use, inexpensive and highly efficient one
pot, multi-component ceric ammonium
O nitrate (CAN)-catalyzed preparation
CHO O of 1,3-thiazine derivatives
in polyethylene glycol (PEG) 400 by mixing substituted acetophenones, aromatic aldehydes and
thiourea in PEG-400 in specific amounts CAN [24]. The reaction mixture was gently stirred while
maintaining a uniform temperature of 45 °C until450C the formation of product was confirmed through TLC
R2
R1
(Scheme 10). The desired 1,3-thiazines were isolated throughR1 a mixture of ether
R2 and PEG-400 that forms
S
two separate layers as PEG is insoluble in ether and their structures were confirmed by elemental
R2
analysis and spectroscopic analysis [24]. These thiazine derivatives act as potent inhibitors of
HN NH
2 2
Gram-negative bacteria by targeting 4-diphosphocytidyl-2-C-methyl-D-erythritol (IspE) kinase [24].

S PEG-400

450C
N NH2

R1

Scheme 10. Ceric ammonium nitrate catalyzed preparation of 1,3-thiazines in polyethylene glycol [24].
Scheme 10. Ceric ammonium nitrate catalyzed preparation of 1,3-thiazines in polyethylene glycol [24].

Il’inykh and coworkers made S-alkenyl forms of 5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol


According
compounds by to Baharfar
treating et al. pyrimido(2,1-b)(1,3)thiazine
various derivatives
alkenyl halides with 2,4-triazoles can be synthesized
conjugated initially by
with trifluoromethyl
the combination of an isocyanide and a dialkyl acetylenedicarboxylate that forms an active
and thiol groups [25]. Furthermore the chemical process between the S-alkenyl derivatives and iodine zwitterionic
intermediate.
molecules occurs Thisregiospecifically
zwitterionic formproducing
of the intermediate
new fused is treated with thiouracil
halogenated that forms ketenimine
(1,2,4)triazole(3,4-b)(1,3)thiazine
as
compounds (Scheme 11) [25]. The chemical structures of these products were confirmed bytoelemental
an intermediate. This ketenimine undergoes chemical cyclization and rearrangement form the
desired product in high yield (Scheme 12) [26]. During the course of the reaction,
analysis, IR and mass spectroscopy and different isotopic (1H-, 13C- and 19F-) NMR spectroscopies, the contents are
stirred for astate
day at ◦
including of25theC.art
Baharfar
2D 1H-and colleagues
13C-HSQC, 1H- observed
1H-COSY, the1H-
formation
13C-HMBC of intermediates
correlations, byandanalyzing
also by
them on TLC, and after completion of the whole
single-crystal XRD technique for better results [25]. process, the solvent was removed and the thiazines
were purified by silica gel column chromatography using n-hexane and ethyl acetate as a solvents in
a three to one volumetric ratio [26].
compounds by treating various alkenyl halides with 2,4-triazoles conjugated with trifluoromethyl
and thiol groups [25]. Furthermore the chemical process between the S-alkenyl derivatives and iodine
molecules occurs regiospecifically producing new fused halogenated (1,2,4)triazole(3,4-b)(1,3)thiazine
compounds (Scheme 11) [25]. The chemical structures of these products were confirmed by elemental
analysis, IR and mass spectroscopy and different isotopic (1H-, 13C- and 19F-) NMR spectroscopies,
including
Molecules 2016, 21, state
1054 of the art 2D 1H-13C-HSQC, 1H-1H-COSY, 1H-13C-HMBC correlations, and also by8 of 20
single-crystal XRD technique for better results [25].

Scheme 11. Alkenation reaction for the synthesis of triazole-based thiazine heterocyclic compounds [25].
Scheme 11. Alkenation reaction for the synthesis of triazole-based thiazine heterocyclic compounds [25].
Molecules 2016, 21,
According to1054
Baharfar et al. 8 of 19
pyrimido(2,1-b)(1,3)thiazine derivatives can be synthesized initially
Molecules 2016, 21, 1054 of an isocyanide and a dialkyl acetylenedicarboxylate that forms an active zwitterionic
by the combination 8 of 19

intermediate. This zwitterionic form of the intermediate is treated with thiouracil that forms ketenimine
as an intermediate. This ketenimine undergoes chemical cyclization and rearrangement to form the
desired product in high yield (Scheme12) [26]. During the course of the reaction, the contents are stirred
for a day at 25 °C. Baharfar and colleagues observed the formation of intermediates by analyzing them
on TLC, and after completion of the whole process, the solvent was removed and the thiazines were
purified by silica gel column chromatography using n-hexane and ethyl acetate as a solvents in a three
to one volumetric ratio [26].

Scheme 12. Chemical preparation of pyrimido (2,1-b)(1,3)thiazine derivatives [26].


Scheme 12. Chemical preparation of pyrimido (2,1-b)(1,3)thiazine derivatives [26].
Scheme 12. Chemical preparation of pyrimido (2,1-b)(1,3)thiazine derivatives [26].
Wang et al. made a series of novel multithioether derivatives using the reaction of thiazinethiones
Wang
withetalkyl
Wang al.etmade
al. a series
made ofof
a series
dibromides novel
novel
following multithioether
multithioether
Scheme derivatives
13 [27]. derivatives
The chemical using
using thethe reaction
reaction
properties of thiazinethiones
andofstructures
thiazinethiones
of these
with with
alkylalkyl
thiazine dibromides
dibromides following
analoguesfollowing
were studiedScheme
Schemethrough13 [27].
13 [27]. The
EIMS, chemical
elemental
The properties
analysis,
chemical andand
IR, and
properties structures
1H-NMR of these
spectroscopy.
structures of these
thiazine
The analogues
synthesized were studied
compounds through
were tested EIMS,
for elemental
antitumor analysis,
activity and IR,
showedand 1H-NMR
good
thiazine analogues were studied through EIMS, elemental analysis, IR, and H-NMR spectroscopy. 1 resultsspectroscopy.
[27].
The synthesized
The synthesized compoundswere
compounds weretested
tested for
forantitumor
antitumor activity and and
activity showed good results
showed [27].
good results [27].

R= -CH2CH2- , -CH2CH2CH2- , -CH2CH2CH2CH2-


R= -CH2CH2- , -CH2CH2CH2- , -CH2CH2CH2CH2-
Scheme 13. Formation of multithioether derivatives of thiazine [27].
Scheme Formation
13.13.
Scheme Formationof
ofmultithioether derivatives
multithioether derivatives of of thiazine
thiazine [27].[27].
El Shehry et al. reported that 1,4-thiazine derivatives can be synthesized by the reaction of
El Shehry et al. reported
α-bromopropenone that
derivatives 1,4-thiazine
with derivatives
2-aminothiophenol can be synthesized
in ethanolic solution of by the reaction
potassium of
hydroxide
El Shehry et al. reported that 1,4-thiazine derivatives can be synthesized by the reaction of
α-bromopropenone derivatives
(Scheme 14) [28]. These with
thiazine 2-aminothiophenol
derivatives infor
were tested ethanolic solution of activities
antimolluscicidal potassiumandhydroxide
the results
α-bromopropenone derivatives with 2-aminothiophenol in ethanolic solution of potassium hydroxide
(Scheme
showed 14)that
[28]. These
they thiazinemoderate
exhibited derivatives were tested
inhibitory for[28].
power antimolluscicidal activities and the results
(Scheme 14) [28].
showed These
that they thiazine
exhibited derivatives
moderate were power
inhibitory tested [28].
for antimolluscicidal activities and the results
showed that they exhibited moderate inhibitory power [28]. OH
Br
OH H
Zhao et al. described a resourceful H2N
one-pot cyclization reaction process N for the preparation
Br
O R H
of pyridazino(4,5-b)(1,4)thiazine-dione
H2N analogues following
KOH, Ethanol
the famous
N Smiles rearrangement
O R
method [29]. They obtained a number of ideal compounds in high yields without any side
KOH, Ethanol
reaction products. Moreover, R S
thisHSis a transition metal-free, economical, environmentally compatible,
R HS the production of complex heterocyclicS moieties with thiazines as
and highly Scheme
efficient 14.method
Synthesisfor
of 1,4-thiazine derivatives from α-bromopropenone derivative and 2-amino-
constituent thiophenol
Scheme
parts 14.
[29]. inThey
ethanolic
Synthesis of potassium hydroxide
1,4-thiazine
synthesized derivativessolution [28].
from α-bromopropenone
their complex 1,4-thiazine derivative
analogues and 2-amino-
(Scheme 15) by treating
thiophenol in ethanolic potassium hydroxide solution [28].
Zhao et al. described a resourceful one-pot cyclization reaction process for the preparation of
Zhao et al. described a resourceful
pyridazino(4,5-b)(1,4)thiazine-dione one-potfollowing
analogues cyclization
the reaction process
famous Smiles for the preparation
rearrangement methodof [29].
pyridazino(4,5-b)(1,4)thiazine-dione
They obtained a number of ideal analogues following
compounds the famous
in high Smiles rearrangement
yields without method
any side reaction [29].
products.
They obtained
Moreover, thisa is
number of ideal
a transition compounds
metal-free, in highenvironmentally
economical, yields without compatible,
any side reaction products.
and highly efficient
Moreover,
method this is aproduction
for the transition metal-free,
of complexeconomical,
heterocyclic environmentally compatible,
moieties with thiazines and highly efficient
as constituent parts [29].
Scheme 12. Chemical preparation of pyrimido (2,1-b)(1,3)thiazine derivatives [26].

Wang et al. made a series of novel multithioether derivatives using the reaction of thiazinethiones
with alkyl dibromides following Scheme 13 [27]. The chemical properties and structures of these
Molecules 2016,
thiazine 21, 1054 were studied through EIMS, elemental analysis, IR, and 1H-NMR spectroscopy.
analogues 9 of 20

The synthesized compounds were tested for antitumor activity and showed good results [27].
4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one with N-benzyl-2-mercaptoacetamide
using Cs2 CO3 as catalyst in DMF [29]. The one-pot Smiles rearrangement process is quite useful in
organic chemistry [30] and it should be fully explored for the synthesis of other complex thiazine
derivatives that are important from medicinal point of view.
Konstantinova and coworkers synthesized the bis(1,2)dithiolo derivative of 1,4-thiazine class
(Scheme 16) by treating 4-isopropylamino-5-chloro-1,2-dithiole-3-ones with sulfuryl chloride in
acetonitrile as a solvent thatR= resulted
-CH2CHin 2- the formation
, -CH2CH2CH2- ,of an2CH
-CH intermediate
2CH2CH2- salt of bis(1,2)dithiolo(1,4)
thiazine chloride [31,32]. When this intermediate salt is further treated with triethylamine (Scheme 16),
it resulted in the desired
Schemeproduct [31]. of
13. Formation The product formed
multithioether was of
derivatives further confirmed
thiazine [27]. and analyzed
by various techniques. These thiazine derivatives were also checked for their antiviral properties
usingElthe
Shehry et al. reported
nucleocapsid protein of that
the1,4-thiazine derivatives can
feline immunodeficiency virusbe(FIV)
synthesized by the
[33] in vitro reactionthat
cell culture of
α-bromopropenone derivativesconcentration
showed activity in nanomolar with 2-aminothiophenol in ethanolic
and low toxicity solution
[34]. Thus these of potassium
thiazine hydroxide
analogues may
(Scheme
be suitable14)candidates
[28]. Thesefor
thiazine derivatives
HIV treatment andwere
couldtested for antimolluscicidal
be tested further to checkactivities
for potencyandinthe results
mice and
showed that they exhibited
human HIV infected tissues. moderate inhibitory power [28].
Molecules 2016, 21, 1054 9 of 19
OH
Br
H
H2N N
O R
KOH, Ethanol

R HS S

Scheme 14. Synthesis of 1,4-thiazine derivatives from α-bromopropenone derivative and 2-amino-
Scheme 14. Synthesis of 1,4-thiazine derivatives from α-bromopropenone derivative and
thiophenol in ethanolic potassium hydroxide solution [28].
2-amino-thiophenol in ethanolic potassium hydroxide solution [28].
Molecules 2016, 21, 1054 9 of 19
Zhao et al.
Scheme 15.described a resourceful
One-pot synthesis one-pot cyclization reaction
of pyridazino[4,5-b][1,4]thiazine-diones process
involving forrearrangement
a Smiles the preparation of
pyridazino(4,5-b)(1,4)thiazine-dione
process [29]. analogues following the famous Smiles rearrangement method [29].
They obtained a number of ideal compounds in high yields without any side reaction products.
Konstantinova
Moreover, and coworkers
this is a transition metal-free, synthesized
economical, theenvironmentally
bis(1,2)dithiolo derivative
compatible, of and
1,4-thiazine class
highly efficient
(Scheme 16) by treating 4-isopropylamino-5-chloro-1,2-dithiole-3-ones
method for the production of complex heterocyclic moieties with thiazines as constituent parts [29]. with sulfuryl chloride in
acetonitrile
They as a solvent
synthesized theirthat resulted1,4-thiazine
complex in the formation of an intermediate
analogues (Schemesalt 15)of bis(1,2)dithiolo(1,4)thiazine
by treating 4,5-dichloro-2-
chloride [31,32]. When this intermediate salt is further
(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one with N-benzyl-2-mercaptoacetamide treated with triethylamine (Scheme
using Cs16), it
2CO3 as
resulted in the desired product [31]. The product formed was further confirmed and analyzed by
catalyst in DMF [29]. The one-pot Smiles rearrangement process is quite useful in organic chemistry
various techniques. These thiazine derivatives were also checked for their antiviral properties using
[30] and it should be fully explored for the synthesis of other complex thiazine derivatives that are
the nucleocapsid protein of the feline immunodeficiency virus (FIV) [33] in vitro cell culture that
important
Schemefrom medicinal
15. One-pot pointof ofpyridazino[4,5-b][1,4]thiazine-diones
of view.
pyridazino[4,5-b][1,4]thiazine-diones
synthesisconcentration involving
involving a Smiles
Smiles rearrangement
rearrangement
Scheme
showed 15.
activity in nanomolar and low toxicity [34]. Thus these athiazine analogues may
process
process [29].
[29].
be suitable candidates for HIV treatment and could be tested further to check for potency in mice and
human HIV infected tissues.
Konstantinova and coworkers synthesized the bis(1,2)dithiolo derivative of 1,4-thiazine class
R
(Scheme 16) by treating R
O
4-isopropylamino-5-chloro-1,2-dithiole-3-ones
Cl O with sulfuryl chloride in
acetonitrile as a solvent
N that resulted in the formation of an intermediate N salt of bis(1,2)dithiolo(1,4)thiazine
chloride [31,32]. When thisS intermediate MeCN salt is further treated with triethylamine (Scheme 16), it
S2Cl2 Cl S S

resulted in the desired product S


[31]. The product formed
S
S
was further
S confirmed and analyzed by
Cl Et3N
various techniques. These thiazine derivatives were also checked for their antiviral properties using
R Ranging from 1-8
the nucleocapsid protein of the feline immunodeficiency virus (FIV) [33] in vitro cell culture that
%yield
showed activity in nanomolarR1= concentration
CH2CH2Cl
and
40
low toxicity [34]. Thus these thiazine analogues may
be suitable candidates for HIV treatmentR2= CH 2CH2N 3 and could be tested further to check for
65
R
potency in mice and
R3= CH2CH2CO2Et 73 S O
human HIV infected tissues. R4= CH2CH2SPh 54
R5= CH2CH2CN 49 N
R6= CH2CH2SO2Ph 44
R R7= CH2CH2OC(O)H 78 R S S
Cl O
O R8= CH2Ph 62
S S
N N S

Scheme16.
16. Synthesis MeCN
of bis(1,2)dithiolo
Scheme S Synthesis Cl S derivatives
S2Cl2 of bis(1,2)dithiolo derivativesofof1,4-thiazine
S
1,4-thiazine[31].
[31].
S S
S S
3. Biological Activities
Cl of Thiazine and Benzothiazine Derivatives Et3N
R Ranging from 1-8
Heterocyclic thiazine and benzothiazine compounds are a crucial part of medicinal organic
%yield
chemistry due to their useful medicinal properties. The largely unexplored heterocyclic compounds
R1= CH2CH2Cl 40
like thiazines possess a variety of pharmacological
R2= CH2CH2N3 65 activities, ranging from antitumor, antipsychotic and
R3= CH2CH2CO2Et 73 R
S
anti-inflammatory propertiesR4= onCHtheCHone hand, while on the pathogenic side, they are equallyOimportant
2 2SPh 54
N
due to their antibacterial, R5= CH2CH2CN
antitubercular, 49
antifungal, antiviral and antiprotozoal activities. Thus
Molecules 2016, 21, 1054 10 of 20

3. Biological Activities of Thiazine and Benzothiazine Derivatives


Heterocyclic thiazine and benzothiazine compounds are a crucial part of medicinal organic
chemistry due to their useful medicinal properties. The largely unexplored heterocyclic compounds
like thiazines possess a variety of pharmacological activities, ranging from antitumor, antipsychotic
and anti-inflammatory properties on the one hand, while on the pathogenic side, they are equally
important due to their antibacterial, antitubercular, antifungal, antiviral and antiprotozoal activities.
Thus thiazine compounds display a wide range of beneficial properties [6]. These activities are
discussed one by one in the following paragraphs.

3.1. Antimicrobial Activities


Phenothiazines and their novel derivatives exhibit valuable biological activities both in vivo
and in vitro. These compounds show good results against various diseases caused by bacteria,
viruses, fungi, mollusca, or protozoa. The activities of these compounds were examined by
applying them on various organisms such as mammals infected with pathogenic bacteria and
viruses, cell lines, etc. [35]. The 1,3-thiazine moiety is the functional part of cephalosporins that
are the β-lactam antibiotics, active against most Gram positive and a number of Gram negative
Molecules 2016, 21, 1054 10 of 19
pathogenic bacteria [36]. Cephalosporins have a similar mode of action like penicillins and have
an
have identical
a similarβ-lactam
mode of ring, however,
action there are more
like penicillins atoms
and have anatidentical
the side rings as presented
β-lactam in Figure
ring, however, 2 [37].
there are
Most of the at
more atoms penicillin-resistant bacteria are
the side rings as presented sensitive
in Figure to Most
2 [37]. cephalosporins, although there
of the penicillin-resistant are some
bacteria are
exceptions [37]. Bacterial resistance is a common problem to cephalosporins,
sensitive to cephalosporins, although there are some exceptions [37]. Bacterial resistance is a common for example the
enteric
problembacteria are resistantfor
to cephalosporins, toexample
almost all theofenteric
the third and are
bacteria fourth generation
resistant to almostdrugs [38].
all of theThere are
third and
several strains of Staphylococcus
fourth generation drugs [38]. There aureus
are that are strains
several even resistant to the fifthaureus
of Staphylococcus generation
that are cephalosporins
even resistant
like
to theceftobiprole and cephalosporins
fifth generation ceftaroline [39].likeTherefore,
ceftobiprolenovel strategies are
and ceftaroline [39].being devised
Therefore, novel to strategies
generate
future
are being generation
devised to cephalosporins
generate future [38]. In addition
generation to broad spectrum
cephalosporins activities,to1,3-thiazine
[38]. In addition broad spectrum and
its derivatives contains wonderful properties like antitumor, insecticide, and fungicidal
activities, 1,3-thiazine and its derivatives contains wonderful properties like antitumor, insecticide, [19,20,40,41].
Further, these can
and fungicidal be used as Further,
[19,20,40,41]. anti-radiation
these canagents in radiation-sickness
be used as anti-radiation[19,20,40,41]. The 4-hydroxy-
agents in radiation-sickness
N 0 -(benzylidene)-2H-benzo(e)(1,2) thiazine-3-carbohydrazidethiazine-3-carbohydrazide
1,1-dioxides [10] compounds possess
[19,20,40,41]. The 4-hydroxy-N′-(benzylidene)-2H-benzo(e)(1,2) 1,1-dioxides
not
[10] compounds possess not only antibacterial but also has radical scavenging activities and when
only antibacterial but also has radical scavenging activities and these properties are raised these
more lipophilic
properties is the when
are raised compound
more [14,15].
lipophilicThus, such
is the thiazine derivatives
compound [14,15]. Thus, aresuch
useful chemical
thiazine tools in
derivatives
biochemistry
are useful chemicalresearch and
tools incan be used inresearch
biochemistry respiratory
and and photosynthetic
can be electron
used in respiratory andtransfer research
photosynthetic
where the free radicals are produced during normal activity as well as malfunction
electron transfer research where the free radicals are produced during normal activity as well as of some pathways.
Patel et al. made
malfunction of some around fortyPatel
pathways. different 1,2-benzothiazine
et al. made around forty derivatives, among which derivatives,
different 1,2-benzothiazine some only
exhibited antibacterial activity against Gram positive bacteria [42].
among which some only exhibited antibacterial activity against Gram positive bacteria [42].

Figure 2.
Figure 2. Chemical
Chemical structure
structure of
of the
the cephalosporin
cephalosporin nucleus.
nucleus.

A number of 1,4-thiazine analogues that were modified form of their parent thiazine compounds
A number of 1,4-thiazine analogues that were modified form of their parent thiazine compounds
displayed broad spectrum antibacterial action in vitro. They were active against several types of both
displayed broad spectrum antibacterial action in vitro. They were active against several types of both
Gram positive and Gram negative pathogenic bacteria [43]. The imides and N-carboxymethyl imides
Gram positive and Gram negative pathogenic bacteria [43]. The imides and N-carboxymethyl imides
based 2-substituted N-acylphenothiazines also have antimicrobial activity [44].
based 2-substituted N-acylphenothiazines also have antimicrobial activity [44].
Thiazine compounds are also useful as reactants in the preparation of several other important
Thiazine compounds are also useful as reactants in the preparation of several other important
classes of synthetic antibiotics like quinolones that are used for the treatment of several pathogenic
classes of synthetic antibiotics like quinolones that are used for the treatment of several pathogenic
bacterial diseases [45]. For example Parai and colleagues prepared several 1,4-thiazine analogues and
bacterial diseases [45]. For example Parai and colleagues prepared several 1,4-thiazine analogues
(S)-3-methyl-1,4-benzoxazine [46]. These thiazine derivatives can be made using copper as a catalyst
and (S)-3-methyl-1,4-benzoxazine [46]. These thiazine derivatives can be made using copper
through the intramolecular N-aryl amination reaction mechanism on substituted 2-(2-bromo-phenylthio)
ethanamines [47] that can be prepared by treating 2-bromobenzenethiol with Boc-protected amino
alcohol compounds [46]. The (S)-3-methyl-1,4-benzoxazine can be used as a reactant for the synthesis
of levofloxacin which is a common quinolone antibiotic [46]. There are several green synthesis methods
in which thiazine derivatives and quinolones can be synthesized in the same reaction step [48,49].
Molecules 2016, 21, 1054 11 of 20

as a catalyst through the intramolecular N-aryl amination reaction mechanism on substituted


2-(2-bromo-phenylthio)ethanamines [47] that can be prepared by treating 2-bromobenzenethiol with
Boc-protected amino alcohol compounds [46]. The (S)-3-methyl-1,4-benzoxazine can be used as
a reactant for the synthesis of levofloxacin which is a common quinolone antibiotic [46]. There are
several green synthesis methods in which thiazine derivatives and quinolones can be synthesized in
the same reaction step [48,49].
Jeleń et al. explored the possible antimicrobial role of 44 other phenothiazine analogues that
contained the quinobenzothiazine nucleus in their structure. Most of these phenothiazines exhibited
different levels of inhibitory action on the growth of common pathogenic bacteria and fungi [50]. It is
also important to mention that 6-(1-methyl-2-piperidylethyl) quinobenzothiazine was highly toxic for
common pathogenic Staphylococcus and E. coli while a multi-substituted thiazine like 6-methane
sulfonylaminobutyl-9-methylthioquinobenzothiazine was lethal for all the tested microbes [50].
The hybrid forms of pyrazine-1,3-thiazine derivatives displayed antiviral activities in micromolar
concentration against HIV, influenza A virus, Enterovirus 71 and Coxsackievirus B3 [51]. These hybrid
derivatives were active against HIV reverse transcriptase, influenza A neuraminidase enzyme in
enzyme based assays [51]. The Enterovirus 71 and Coxsackievirus B3 infection was cured with the
respective pyrazine-1,3-thiazine derivatives with high specificity [51]. Heavy metals with their ligands
prepared using the Schiff base obtained from 5-acetyl-4-hydroxy-2H-1,3-thiazine-2,6(3H)-dione and
2-aminophenol have broad spectrum antibacterial and antifungal activities [52]. The heavy metals
with thiazine compounds in different assays exhibit variable results of antibacterial and antifungal
activities [52].

3.2. Antitubercular Activities


Mycobacterium tuberculosis is a highly resistant pathogenic bacterium which is almost resistant
to a number of the drugs and there is always a requirement to develop new drugs to
control the resistant pathogen challenges. Koketsu et al. synthesized around eight different
5,6-dihydro-4H-1,3-thiazine analogues and they were tested on mycobacterium species, where several
of them have inhibitory activities [53]. Most of these compounds have high antitubercular
activity and are effective in microgram concentration, thus 1,3-thiazine derivatives have potential
antimycobacterial activities [53]. The ethyl 6-(4-chlorobenzoyl)-1,1-dioxo-3,5-diaryl derivatives
of the 1,4-thiazinane-2-carboxylates are also highly active compound against different species of
mycobacterium that are highly resistant to other drugs [54]. They can be obtained very easily by
treating ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetates with various branched aromatic aldehydes and
amines and the reaction is catalyzed by L-proline [54]. The advantages of this method are that the
products (1,4-thiazines) are obtained in good yield and it is a green synthesis method [54].

3.3. Antimalarial Activities


The search for thiazine-based antimalarial drugs are quite old and it dates back to 1891
when Guttmann and Ehrlich used thiazine dyes for the treatment of malaria [55]. The thiazine
dyes are quite potent and selective for the inhibition of plasmodium growth [55]. In the past
it was observed that the 2,4-diamino-1-(p-chlorophenyl)-1,6-dihydro-6,6-dimethyl derivative of
1,3,5-triazine [56] which is a chloroguanidine metabolite has some activity against plasmodium
while the 3,5-dichlorophenyl analogue which is a metabolite of dichloroguanide, is more potent
against plasmodium [57]. The Australian marine sponge Plakortis lita contained four thiazine-based
alkaloids called thiaplakortones, among which thiaplakortone A is the most active against both
chloroquine-sensitive and -resistant strains of Plasmodium falciparum with IC50 values in the range
of 51 to 6.6 nM [58]. A total synthesis of thiaplakortone is also available and several different
derivatives for drug resistant plasmodium species can now easily be synthesized through this
established method [59]. A number of amide and urea containing groups of thiaplakortone has
Molecules 2016, 21, 1054 12 of 20

also been synthesized and checked for their antiplasmodial activity [60,61]. It was also observed that
several of these analogues have IC50 values of less than 500 nM, with good aqueous solubility [60,61].

3.4. Antifungal Activities


Some thiazine have antifungal properties, for example Vicentini et al. synthesized pyrazole
forms of 1,3-thiazine and 1,3,5-thiadiazines derivatives [62]. They tested them on rice blast caused by
Magnaporthe grisea [63]. Both the thiazine derivatives inhibit the growth of the fungus when used in the
concentration range of 10 to 200 µg·mL−1 while in some cases, they can stop the growth of mycelium
when used at concentration of 10 µg·mL−1 . Thus, these thiazine derivatives have quite impressive
mycotoxic activities [62,63]. The substituted forms of 1,4-benzothiazines and 1,5-benzothiazepines
and their annelated derivatives are pharmacologically very important as some of them can be used
as antimicrobials, antiviral, antibacterial and antifungal drugs [64]. The 1,4-thiazines are toxic to the
two fungal species of Aspergillus niger and Aspergillus fumigatus [43].

3.5. Anticancer Activities


The thiazinediones (Figure 3), prepared by Ferreira and colleagues showed anticancer activity
against leukemia cells [65]. It was observed that the DNA fragmentation (cell death) was produced
by various aromatic groups attached to the 1,3-thiazine-2,4-diones that possibly intercalate with
the targeted DNA resulting in DNA fragmentation and ultimate cell death [65]. It was also
proposed that the caspase cascade activation occurs, along with the disparity in intracellular calcium
ion, disturbance in basic cell functional organelles [65,66]. The newly synthesized compound
2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-one (BChTT) can be used to stop lung, colon and12other
Molecules 2016, 21, 1054 of 19
types of progressing cancers and it is non-toxic to normal body cells and organs [66]. These thiazine
derivatives
DNA stop the
and ceased thesynthesis
different of DNA
cell andstages
growth ceasedbythe different cell
decreasing the growth
activity stages
of p38 by decreasing
kinase the
and cyclin
activity of p38
D1 enzymes [66]. kinase and cyclin D1 enzymes [66].

O
O

NH NH

S O S O

Figure
Figure 3.
3. Chemical
Chemical structure
structure of
of bicyclic
bicyclic and
and tricyclic
tricyclic thiazinediones that have
thiazinediones that have anticancer
anticancer activity
activity [65].
[65].

Jeleń and coworkers have prepared novel tetracyclic azaphenothiazines from 6-substituted
Jeleń and coworkers have prepared novel tetracyclic azaphenothiazines from 6-substituted
9-fluoroquinobenzothiazines (Figure 4) which showed inhibition of different types of blood cancer
9-fluoroquinobenzothiazines (Figure 4) which showed inhibition of different types of blood cancer
cells and are also having antitumor, antiproliferative and anti-inflammatory properties. Substitution
cells and are also having antitumor, antiproliferative and anti-inflammatory properties. Substitution at
at the thiazine nitrogen of 9-fluoroquinobenzothiazine decreased its toxicity [67]. Some of the thiazine
the thiazine nitrogen of 9-fluoroquinobenzothiazine decreased its toxicity [67]. Some of the thiazine
derivatives are close to cisplatin for cancer and cyclosporine A for anti-inflammation in terms of
derivatives are close to cisplatin for cancer and cyclosporine A for anti-inflammation in terms of
activity [67]. Thus the promising low cost of thiazine based anticancer and anti-inflammatory drugs
activity [67]. Thus the promising low cost of thiazine based anticancer and anti-inflammatory drugs
should be considered and further trials need to be done on them so that they can come early to the
should be considered and further trials need to be done on them so that they can come early to the
market and we can control the plight of cancer in our society.
market and we can control the plight of cancer in our society.
Ha et al. reported a skin depigmenting agent made from synthetic R1,3-thiazine compounds [68].
F
These thiazine Fanalogues S inhibit the activity of Styrosinase enzymes 2 CH3 in different kinds of cells
RX 3 CH
and blocking the melanin biosynthesis base pathway, thus they possess 2CH=CH2
anti-melanogenesis effects [68].
4 CH2CCH
N N N N
The 1,2-thiazine 1-oxides are very useful for the synthesis of several 5 CH2CH2different
N(C2H5)2 conjugated forms
H
of pyrrole and benzodiazepines or R
benzothiadiazepines that have
6 CH antitumor
CH CH N(CH ) properties [69,70].
1 2-10 2 2 2 3 2

The monoterpene-fused 2-imino-1,3-thiazines also exhibit anticancer7 CH 2CH(CH3)CH 2and


properties N(CH3)2
they can be made
in a few steps using green synthesis methods [71]. A combination of ruthenium II-arene fragments with
10 CH2 CH 2 9 CH 2CH 2 N
oxicams showed that they are useful in the N treatment of colon, breast8 cancers
CH 2CH2 N
and carcinogenesis-based
H3C
inflammations [72].
Figure 4. Synthesis of tetracyclic azaphenothiazine derivatives.

Ha et al. reported a skin depigmenting agent made from synthetic 1,3-thiazine compounds [68].
These thiazine analogues inhibit the activity of tyrosinase enzymes in different kinds of cells and
blocking the melanin biosynthesis pathway, thus they possess anti-melanogenesis effects [68]. The
1,2-thiazine 1-oxides are very useful for the synthesis of several different conjugated forms of pyrrole
cells and are also having antitumor, antiproliferative and anti-inflammatory properties. Substitution
at the thiazine nitrogen of 9-fluoroquinobenzothiazine decreased its toxicity [67]. Some of the thiazine
derivatives are close to cisplatin for cancer and cyclosporine A for anti-inflammation in terms of
activity [67]. Thus the promising low cost of thiazine based anticancer and anti-inflammatory drugs
should be
Molecules considered
2016, 21, 1054 and further trials need to be done on them so that they can come early 13toofthe
20
market and we can control the plight of cancer in our society.

R
F
F S S 2 CH3
RX 3 CH2CH=CH2
base
4 CH2CCH
N N N N
5 CH2CH2N(C2H5)2
H R 6 CH2CH2CH2N(CH3) 2
1 2-10
7 CH2CH(CH3)CH2N(CH3)2

10 CH2 CH 2 9 CH 2 CH 2 N
8 CH 2CH2 N
N
H3C

Figure 4.
Figure 4. Synthesis
Synthesis of
of tetracyclic azaphenothiazine derivatives.
tetracyclic azaphenothiazine derivatives.

Ha et al. reported a skin depigmenting agent made from synthetic 1,3-thiazine compounds [68].
3.6. Anti-Inflammatory Activities
These thiazine analogues inhibit the activity of tyrosinase enzymes in different kinds of cells and
The the
blocking thiazine
melanin alkaloids present
biosynthesis in the
pathway, thusNewthey Zealand Aplidium ascidianeffects
possess anti-melanogenesis species
[68].have
The
anti-inflammatory activity as they have proved to inhibit neutrophil-based superoxide production
1,2-thiazine 1-oxides are very useful for the synthesis of several different conjugated forms of pyrrole [73].
Chia and colleagues or
and benzodiazepines made different thiazinethat
benzothiadiazepines analogues conjugated
have antitumor with quinolones
properties [69,70]. The and quinones
monoterpene-
that suppress the free radical production by neutrophils in vitro when used in small concentrations.
fused 2-imino-1,3-thiazines also exhibit anticancer properties and they can be made in a few steps using
Thus, they can methods
green synthesis be future NSAID
[71]. alternatives
A combination [74]. Several
of ruthenium thiazine
II-arene derivatives
fragments mentioned
with oxicams showedabove
that
have both
they are anti-inflammatory
useful in the treatmentand analgesic
of colon, breastactivities at lower
cancers and doses and are inflammations
carcinogenesis-based also safe at lower
[72].
doses in gastrointestinal irritation [23]. Derivatives of 2-arylimino-5,6-dihydro-4H-1,3-thiazine act as
cannabinoid receptor agonists
3.6. Anti-Inflammatory Activitiesfor CB1 and CB2 receptors and were found to have analgesic activity.
In these medicinal compounds the oxazine moiety has been merged as an isosteric alternative for the
The thiazine alkaloids present in the New Zealand Aplidium ascidian species have anti-inflammatory
thiazine ring of actual compound and one of the compounds possess oral bioavailability as well as
activity as they have proved to inhibit neutrophil-based superoxide production [73]. Chia and colleagues
analgesic properties [75–77]. The benzothiazepines conjugated with other thiazines were tested on
made different thiazine analogues conjugated with quinolones and quinones that suppress the free radical
neuronal receptors, where only one derivative showed inhibitory effects on the central nervous system
production by neutrophils in vitro when used in small concentrations. Thus, they can be future
while most of the others exhibited anti-inflammatory properties [78]. Benzothiazines are quite bioactive
NSAID alternatives [74]. Several thiazine derivatives mentioned above have both anti-inflammatory
and this activity, mostly depends on the attached side groups [79,80]. The current oxicam medicines
and analgesic activities at lower doses and are also safe at lower doses in gastrointestinal irritation
are chemically benzothiazines in nature (Figure 5) and they are second generation non-steroidal drugs
[23]. Derivatives of 2-arylimino-5,6-dihydro-4H-1,3-thiazine act as cannabinoid receptor agonists for
that act as an anti-inflammatory agent [79,80]. The current medicinal use of oxicams is restricted due to
CB1 and CB2 receptors and were found to have analgesic activity. In these medicinal compounds the
their adverse effects, although a number of research efforts were done to increase their potency against
oxazine moiety has been merged as an isosteric alternative for the thiazine ring of actual compound
inflammatory conditions with lower side effects [79,80]. Xu et al. resolved the crystal structure of
and one of the compounds possess oral bioavailability as well as analgesic properties [75–77]. The
cyclooxygenases in binding mode with oxicam compounds at 2–2.45 Å resolution [81,82]. The oxicam
benzothiazepines conjugated with other thiazines were tested on neuronal receptors, where only one
compounds bind inside the active site of cyclooxygenases through two water-mediated hydrogen
derivative showed inhibitory effects on the central nervous system while most of the others exhibited
bonds and this mode of interaction is different from that of other NSAIDs [81,82]. There is a hydrogen
anti-inflammatory properties [78]. Benzothiazines are quite bioactive and this activity, mostly depends
bonding interaction between the 4-OH group of thiazine and serine-530 of the cyclooxygenase while
on the attached side groups [79,80]. The current oxicam medicines are chemically benzothiazines in
the heteroatom of carboxamide ring interacts with tyrosine-385 and serine-530 via water-mediated
hydrogen bonding interaction [81]. The second water-based H-bond is formed between the nitrogen
atom of thiazine and oxygen atom of carboxamide to the arginine-120 and tyrosine-355 [81].
The oxicams also possess free radical scavenging properties [83–86]. Eleftheriou et al. reported that
imbalanced cyclooxygenase-1 and 2 functions resulted in inflammation and these enzymes can be
blocked with benzo/benzisothiazolimino-5-aryliden-4-thiazolidinones using a balanced selection
of several enzymes involved in inflammation mechanism [87]. The benzothiazolyl basic unit with
other groups attached can be explored further as active inhibitors for the whole cyclooxygenase
enzyme family [87]. They can provide a scaffold on which full fragment-based drug ligands (FBDL)
as inhibitors can be made for different enzymes [87]. In this report a chemoinformatics method was
used and a fragment library of the above mentioned drugs were created [87]. These fragments were
docked with the cyclooxygenases and along with this computation study; these drugs were also tested
both in vitro and in vivo in biological samples [87]. These fragment based ligands can also be used as
possible covalent inhibitors and should be studied on different enzymes involved in various diseases.
which full fragment-based drug ligands (FBDL) as inhibitors can be made for different enzymes [87].
In this report a chemoinformatics method was used and a fragment library of the above mentioned
drugs were created [87]. These fragments were docked with the cyclooxygenases and along with this
computation study; these drugs were also tested both in vitro and in vivo in biological samples [87].
These fragment
Molecules based ligands can also be used as possible covalent inhibitors and should be studied
2016, 21, 1054 14 of 20
on different enzymes involved in various diseases.

Figure
Figure 5.
5. Chemical
Chemical structure
structure of
of the
the oxicam
oxicam nucleus.
nucleus.

3.7. Antiarrhythmic Activities


3.7. Antiarrhythmic Activities
Some thiazine derivatives are also useful for the treatment of heart diseases, for example
Some thiazine derivatives are also useful for the treatment of heart diseases, for example Galanski
Galanski and coworkers made several position 6-substituents of 1,4-thiazine derivatives like 6-ethyl
and coworkers made several position 6-substituents of 1,4-thiazine derivatives like 6-ethyl and
and 6-benzylthieno(2,3-b)(1,4)thiazine analogues that relax the vascular smooth muscle and terminal
6-benzylthieno(2,3-b)(1,4)thiazine analogues that relax the vascular smooth muscle and terminal
ileum [88,89]. They observed that the thieno(3,2-b)(1,4)thiazines [88] are better vasopressin antagonists
ileum [88,89]. They observed that the thieno(3,2-b)(1,4)thiazines [88] are better vasopressin antagonists
as compared to the thieno(2,3-b)derivatives of the 1,4-thiazine and 1,4-thiazepine compounds [88]. The
as compared to the thieno(2,3-b)derivatives of the 1,4-thiazine and 1,4-thiazepine compounds [88].
same compounds were further analyzed as non-peptide vasopressin antagonists on different heart
The same compounds were further analyzed as non-peptide vasopressin antagonists on different heart
muscles and it was concluded that they are useful for the cure of cardiac arrest due to congestion of
muscles and it was concluded that they are useful for the cure of cardiac arrest due to congestion of
valves, hypertension or peripheral vascular diseases and renal malfunctions [88,89].
valves, hypertension or peripheral vascular diseases and renal malfunctions [88,89].

3.8.
3.8. Antidiabetic
Antidiabetic Activities
Activities
Aldose
Aldose reductase
reductaseis considered
is considered to betoonebeof the
onekey
of enzymes
the keyinvolved
enzymes in diabetic
involvedcomplications
in diabetic
[90–93] and that
complications is whyand
[90–93] it isthat
a suitable
is why drug
it is atarget fordrug
suitable diabetic treatment
target [94].treatment
for diabetic For this purpose
[94]. Forsome
this
1,2-benzothiazine 1,1-dioxide acetic acid derivatives were synthesized and tested
purpose some 1,2-benzothiazine 1,1-dioxide acetic acid derivatives were synthesized and tested against aldose
reductase, among
against aldose them theamong
reductase, double halogenated
them the double benzene analoguesbenzene
halogenated showed the most promising
analogues showedinhibition
the most
capacity [94,95]. The structure activity relationship and molecular docking of these
promising inhibition capacity [94,95]. The structure activity relationship and molecular docking compounds with
of
aldose reductase showed that saturated carboxylic acid have a higher binding affinity
these compounds with aldose reductase showed that saturated carboxylic acid have a higher binding for the enzyme
as compared
affinity for thetoenzyme
the unsaturated
as compared carboxylic acid [94,95]. carboxylic acid [94,95].
to the unsaturated

3.9. Anti-Alzheimer Activities


Recently it is also discovered that the bicyclic thiazines can be used for controlling Alzheimer’s
disease (AD). The bicyclic thiazine targets the beta-secretase 1 (BACE1) enzyme which is an important
target protein in the fight against this disease [96]. This work is still in progress in designing more
effective thiazine derivatives that can bind strongly in different pockets of the BACE1 enzyme.
The spiro-analogues of 1,3-thiazine that are potential neuroprotectors have the ability to inhibit
the amino acid-induced calcium ion uptake into rats’ brain cortex special functional parts like
synaptosomes. The blocking activity of such drugs is due to the specified chemical structure of
the side chain attached to the exocyclic nitrogen atoms [97,98]. Another useful activity of thiazine in
AD is that the Thiazine Red+ dye is used for the identification of Alzheimer affected areas in the rat
brain in laboratories [99].
It was also recorded that the 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide
analogues work better in maximal electroshock, subcutaneous pentylenetetrazole methods for finding
anticonvulsant properties [10]. The experimental evidence proved their anticonvulsant properties
that are mostly attributed to the kind and position of side chain present on the phenyl ring [10].
It is also an advantage that some structurally close compounds had no toxicity in the neurotoxic
experiments [12].
Beside the above mentioned bioactivity of thiazine against various diseases, other active chemical
compounds can also be synthesized from them that have medicinal importance in the fight against
different types of viral and cancerous diseases.
Molecules 2016, 21, 1054 15 of 20

4. Conclusions and Future Perspectives


The available data in the literature reveal that thiazines are a considerably vital group of
heterocyclic compounds and their applications in the treatment of different infectious and inflammatory
diseases are promising. This review summarized the design and synthesis of different thiazine
derivatives by various methods, including microwave irradiation, solvent free reactions, one pot
synthesis and other environmentally friendly methods which should be adapted easily in different
biomedical and pharmaceutical research. Moreover, the study of thiazine has attracted the interest
of medicinal chemists and biochemists up to a great extent and showed that this potent molecule
possess capabilities for designing potential bioactive agents. This review provides a preliminary
information and its references will greatly help medicinal chemists in making better and highly
efficient, cost effective and easily available thiazine derivatives. Further, we can conclude that many
other derivatives of thiazine, their nanoparticles as well as their complexes with transition metals can
be synthesized that may possess effective pharmacological activities.

Acknowledgments: A.N. acknowledges the financial support of National Center of Excellence in Physical
Chemistry, University of Peshawar, Pakistan.
Author Contributions: S.L.B. and A.N. contributed equally in providing the concept and design of this review
manuscript. Both the authors contributed equally in writing and discussion of this manuscript. The authors read
and approved the final manuscript of this review.
Conflicts of Interest: Both the authors declare that they have no conflict of interest.

Abbreviations

IR Infra-red spectroscopy
EMIS Electromagnetic induction spectroscopy
CAN Ceric ammonium nitrate
CB Cannabinoid receptors
AVP Arginine vasopressin
PBTDs Pyrrolobenzothiadiazepines
ALR2 Aldose reductase 2
NSAIDs Nonsteroidal anti-inflammatory drugs
FBDL Fragment based drug ligands
AD Alzheimer’s disease
BACE1 beta-secretase 1

References
1. Deepika, G.; Gopinath, P.; Kranthi, G.; Nagamani, C.; Jayasree, Y.V.; Naidu, N.V.; Enaganti, S. Synthesis and
antibacterial activity of some new thiazine derivatives. J. Pharm. Res. 2012, 5, 1105–1107.
2. Chaviara, A.T.; Cox, P.J.; Repana, K.H.; Papi, R.M.; Papazisis, K.T.; Zambouli, D.; Kortsaris, A.H.;
Kyriakidis, D.A.; Bolos, C.A. Copper(II) Schiff base coordination compounds of dien with heterocyclic
aldehydes and 2-amino-5-methyl-thiazole: Synthesis, characterization, antiproliferative and antibacterial
studies. Crystal structure of CudienOOCl2 . J. Inorg. Biochem. 2004, 98, 1271–1283. [CrossRef] [PubMed]
3. Joshi, H.; Upadhyay, P.; Baxi, A.J. Studies on 4-thiazolidinones. Synthesis and antimicrobial activity
of 1,4-bis(20 -aryl-50 (H)-40 -thiazolidinone-30 -ylamino)phthalazine. J. Indian Chem. Soc. 1990, 67, 779–780.
[CrossRef]
4. Al-Khamees, H.A.; Bayomi, S.M.; Kandil, H.A.; El-Tahir, K.E.H. Synthesis and pharmacological screening of
a new series of 3-(4-antipyryl)-2-arylthiazolidin-4-ones. Eur. J. Med. Chem. 1990, 25, 103–106. [CrossRef]
5. Bano, M.; Barot, K.P.; Jain, S.V.; Ghate, M.D. Identification of 3-hydroxy-4(3,4-dihydro-3-oxo-2H-
1,4-benzoxazin-4-yl)-2,2-dimethyldihydro-2H-benzopyran derivatives as potassium channel activators and
anti-inflammatory agents. Med. Chem. Res. 2015, 24, 3008–3020. [CrossRef]
6. Vincent, G.; Mathew, B.V.; Joseph, J.; Chandran, M.; Bhat, A.R.; Kumar, K.K. A Review on Biological Activities
of Thiazine Derivatives. Int. J. Pharm. Chem. Sci. 2014, 3, 341–348.
Molecules 2016, 21, 1054 16 of 20

7. Preet, S.; Damanjit., C.S. Synthesis and biological evaluation of 1,3-thiazines—A review. Pharmacophore 2013,
4, 70–88.
8. Asif, M. Chemical and Pharmacological Potential of Various Substituted Thiazine Derivatives. J. Pharm.
Appl. Chem. 2015, 1, 49–64.
9. Didwagh, S.S.; Piste, P.B. Green synthesis of thiazine and oxazine derivatives—A short review. Int. J. Pharm.
Sci. Res. 2013, 4, 2045–2061.
10. Edayadulla, N.; Ramesh, P. Synthesis of 2,6-dicarbethoxy-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxide
derivatives as potent anticonvulsant agents. Eur. J. Med. Chem. 2015, 106, 44–49. [CrossRef] [PubMed]
11. Kadhim, M.A. Synthesis and chemical characterization of some novel azachalcones compounds and
evaluation of their biological activity. J. Univ. Anbar Pure Sci. 2010, 4, 40–43.
12. Elarfi, M.J.; Al-Difar, H. A Synthesis of some heterocyclic compounds derived from chalcones. Elix. Online J.
2012, 2, 6243–6245.
13. Banda, G.; Hipparagi, S.M.; Ramjith, U.S. Microwave Assisted Synthesis of Fluoro, Chloro 2-Substituted
Benzimidazole Thiazine derivatives for antimicrobial activities. Int. J. Res. Pharm. Sci. 2012, 2, 146–158.
14. Zia-ur-Rehman, M.; Choudary, J.A.; Elsegood, M.R.J.; Siddiqui, H.L.; Khan, K.M. A facile synthesis of novel
biologically active 4-hydroxy-N 0 -(benzylidene)-2H-benzo(e)(1,2)thiazine-3-carbohydrazide 1,1-dioxides.
Eur. J. Med. Chem. 2009, 44, 1311–1316. [CrossRef] [PubMed]
15. Ahmad, N.; Zia-ur-Rehman, M.; Siddiqui, H.L.; Ullah, M.F.; Parvez, M. Microwave assisted synthesis
and structure-activity relationship of 4-hydroxy-N 0 -(1-phenylethylidene)-2H/2-methyl-1,2-benzothiazine-
3-carbohydrazide 1,1-dioxides as anti-microbial agents. Eur. J. Med. Chem. 2011, 46, 2368–2377. [CrossRef]
[PubMed]
16. Arshad, M.N.; Sahin, O.; Zia-ur-Rehman, M.; Shafiq, M.; Khan, I.U.; Asiri, A.M.; Khan, S.B.;
Alamry, K.A. Crystallographic studies of dehydration phenomenon in methyl 3-hydroxy-2-methyl-
1,1,4-trioxo-1,2,3,4-tetrahydro-1λ6 -benzo(e)(1,2)thiazine-3-carboxylate. J. Chem. Crystallogr. 2013, 43, 671–676.
[CrossRef]
17. Dighade, A.S.; Dighade, S.R. Synthesis of substituted-4,6-diaryl-2-imino-6H-2,3-dihydro-1,3-thiazine. Int. J.
Chem. Sci. 2012, 10, 291–296.
18. Bunker, A.M.; Cheng, X.-M.; Doherty, A.M.; Lee, C.; Repine, J.T.; Skeean, R.; Edmunds, J.J.;
Kanter, G.D. Certain Benzothiazine Dioxide Endothelin Antagonists and Processes for Their Preparation.
U.S. Patent 6,545,150 B2, 8 April 2003.
19. Yadav, L.D.S.; Yadav, S.; Rai, V.K. Mercaptoacetic acid based expeditious synthesis of polyfunctionalised
1,3-thiazines. Tetrahedron 2005, 61, 10013–10017. [CrossRef]
20. Yadav, L.D.S.; Rai, V.K.; Yadav, B.S. The first ionic liquid-promoted one-pot diastereoselective synthesis of
2,5-diamino-/2-amino-5-mercapto-1,3-thiazin-4-ones using masked amino/mercapto acids. Tetrahedron 2009,
65, 1306–1315. [CrossRef]
21. Torres-García, P.; Viñuelas-Zahínos, E.; Luna-Giles, F.; Espino, J.; Barros-García, F.J. Zinc(II) complexes
with novel 1,3-thiazine/pyrazole derivative ligands: Synthesis, structural characterization and effect of
coordination on the phagocytic activity of human neutrophils. Polyhedron 2011, 30, 2627–2636. [CrossRef]
22. Viñuelas-Zahínos, E.; Luna-Giles, F.; Torres-García, P.; Rodríguez, A.B.; Bernalte-García, A. Effects of
a derivative thiazoline/thiazolidine azine ligand and its cadmium complexes on phagocytic activity by
human neutrophils. Inorg. Chim. Acta 2011, 366, 373–379. [CrossRef]
23. Tozkoparan, B.; Aktay, G.; Yeşilada, E. Synthesis of some 1,2,4-triazolo(3,2-b)-1,3-thiazine-7-ones with
potential analgesic and antiinflammatory activities. II Farmaco 2002, 57, 145–152. [CrossRef]
24. Singh, U.P.; Bhat, H.R.; Singh, R.K. Ceric ammonium nitrate (CAN) catalysed expeditious one-pot synthesis
of 1,3-thiazine as IspE kinase inhibitor of Gram-negative bacteria using polyethylene glycol (PEG-400) as
an efficient recyclable reaction medium. C. R. Chim. 2013, 16, 462–468. [CrossRef]
25. Il’inykh, E.S.; Kim, D.G.; Kodess, M.I.; Matochkina, E.G.; Slepukhin, P.A. Synthesis of novel fluorine-
and iodine-containing (1,2,4)triazolo(3,4-b)(1,3)thiazines based 3-(alkenylthio)-5-(trifluoromethyl)-4H-1,2,4-
triazole-3-thiols. J. Fluor. Chem. 2013, 149, 24–29. [CrossRef]
26. Baharfar, R.; Baghbanian, S.M.; Vahdat, S.M. An efficient one-pot synthesis of pyrimido(2,1-b)(1,3)thiazine
derivatives by reaction of activated acetylenes, thiouracils, and isocyanides. Tetrahedron Lett. 2011, 52,
6018–6020. [CrossRef]
Molecules 2016, 21, 1054 17 of 20

27. Wang, W.; Zhao, B.; Xu, C.; Wu, W. Synthesis and Antitumor Activity of the Thiazoline and Thiazine
Multithioether. Int. J. Org. Chem. 2012, 2012, 117–120. [CrossRef]
28. El Shehry, M.F.; Swellem, R.H.; Abu-Bakr, S.M.; El-Telbani, E.M. Synthesis and molluscicidal evaluation
of some new pyrazole, isoxazole, pyridine, pyrimidine, 1,4-thiazine and 1,3,4-thiadiazine derivatives
incorporating benzofuran moiety. Eur. J. Med. Chem. 2010, 45, 4783–4787. [CrossRef] [PubMed]
29. Zhao, Y.; Bai, Y.; Zhang, Q.; Chen, Z.; Dai, Q.; Ma, C. A facile method for the synthesis of pyridazino
(4,5-b)(1,4)thiazine-diones via Smiles rearrangement. Tetrahedron Lett. 2013, 54, 3253–3255. [CrossRef]
30. Liu, Y.; Ma, Y.; Zhan, C.; Huang, A.; Ma, C. One-Pot Synthesis of Fused Pyridazino(4,5-b)(1,4)oxazepine-
diones via Smiles Rearrangement. Synlett 2012, 2012, 255–258. [CrossRef]
31. Konstantinova, L.S.; Berezin, A.A.; Lysov, K.A.; Rakitin, O.A. Selective synthesis of bis(1,2)dithiolo(1,4)
thiazines from 4-isopropylamino-5-chloro-1,2-dithiole-3-ones. Tetrahedron Lett. 2007, 48, 5851–5854.
[CrossRef]
32. Amelichev, S.A.; Barriga, S.; Konstantinova, L.S.; Markova, T.B.; Rakitin, O.A.; Rees, C.W.; Torroba, T.
Synthesis of bis(1,2)dithiolo(1,4)thiazine imines from Hünig’s base. J. Chem. Soc. Perkin 1 2001, 2409–2412.
[CrossRef]
33. Asquith, C.R.M.; Meli, M.L.; Konstantinova, L.S.; Laitinen, T.; Poso, A.; Rakitin, O.A.; Hofmann-Lehmann, R.;
Allenspach, K.; Hilton, S.T. Novel fused tetrathiocines as antivirals that target the nucleocapsid zinc finger
containing protein of the feline immunodeficiency virus (FIV) as a model of HIV infection. Bioorg. Med.
Chem. Lett. 2015, 25, 1352–1355. [CrossRef] [PubMed]
34. Asquith, C.R.M.; Meli, M.L.; Konstantinova, L.S.; Laitinen, T.; Peräkyläd, M.; Poso, A.; Rakitin, O.A.;
Allenspach, K.; Hofmann-Lehmann, R.; Hilton, S.T. Evaluation of the antiviral efficacy of
bis(1,2)dithiolo(1,4)thiazines and bis(1,2)dithiolopyrrole derivatives against the nucelocapsid protein of
the Feline Immunodeficiency Virus (FIV) as a model for HIV infection. Bioorg. Med. Chem. Lett. 2014, 24,
2640–2644. [CrossRef] [PubMed]
35. Pluta, K.; Morak-Młodawska, B.; Jeleń, M. Recent progress in biological activities of synthesized
phenothiazines. Eur. J. Med. Chem. 2011, 46, 3179–3189. [CrossRef] [PubMed]
36. Yadav, L.D.S.; Singh, A. Microwave activated solvent-free cascade reactions yielding highly functionalised
1,3-thiazines. Tetrahedron Lett. 2003, 44, 5637–5640. [CrossRef]
37. Harrison, C.J.; Bratcher, D. Cephalosporins: A Review. Pediatr. Rev. 2008, 29, 264–273. [CrossRef] [PubMed]
38. Pfeifer, Y.; Cullik, A.; Witte, W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial
pathogens. Int. J. Med. Microbiol. 2010, 300, 371–379. [CrossRef] [PubMed]
39. Greninger, A.L.; Chatterjee, S.S.; Chan, L.C.; Hamilton, S.M.; Chambers, H.F.; Chiu, C.Y.
Whole-genome sequencing of methicillin-resistant staphylococcus aureus resistant to fifth-generation
cephalosporins reveals potential non-meca mechanisms of resistance. PLoS ONE 2016, 11, e0149541.
[CrossRef] [PubMed]
40. Yadav, L.D.S.; Awasthi, C.; Rai, V.K.; Rai, A. Biorenewable and mercaptoacetylating building blocks in
the Biginelli reaction: Synthesis of thiosugar-annulated dihydropyrimidines. Tetrahedron Lett. 2007, 48,
4899–4902. [CrossRef]
41. Rai, V.K.; Rai, P.; Thakur, Y. Masked mercapto acid-driven MCR in task-specific ionic liquid: A new
sterocontrolled entry into bicyclic 1,3-thiazines. Tetrahedron Lett. 2013, 54, 6469–6473. [CrossRef]
42. Patel, C.; Jatinder, P.; Bassin, M.S.; Flye, J.; Ann, P.; Lee, H.; Martin, G.M. Synthesis and Antimicrobial Activity
of 1,2-Benzothiazine Derivatives. Molecules 2016, 21. [CrossRef] [PubMed]
43. Govindan, S.; Valliappan, R.; Chakravarthy, J.; Vanitha, P.; Sundari, V. Synthesis, characterization and
biological studies of some 3,5-diaryl-tetrahydro-N-formyl-1,4-thiazine-1,1-dioxide. J. Chem. Pharm. Res. 2013,
5, 99–103.
44. Bansode, T.N.; Shelke, J.V.; Dongre, V.G. Synthesis and antimicrobial activity of some new N-acyl substituted
phenothiazines. Eur. J. Med. Chem. 2009, 44, 5094–5098. [CrossRef] [PubMed]
45. Naeem, A.; Badshah, S.L.; Ahmad, N.; Khan, K. The Current Case of Quinolones: Synthetic Approaches and
Antibacterial Activity. Molecules 2016, 21. [CrossRef] [PubMed]
46. Parai, M.K.; Panda, G. A convenient synthesis of chiral amino acid derived 3,4-dihydro-2H-benzo(b)(1,4)
thiazines and antibiotic levofloxacin. Tetrahedron Lett. 2009, 50, 4703–4705. [CrossRef]
47. Ajani, O.O. Functionalized 1,4-benzothiazine: A versatile scaffold with diverse biological properties.
Arch. Pharm. 2012, 345, 841–851. [CrossRef] [PubMed]
Molecules 2016, 21, 1054 18 of 20

48. Charris, J.; Barazarte, A.; Domínguez, J.; Gamboa, N. Microwave-assisted synthesis of quinolones and
4H-1,4-benzo-thiazine 1,1-dioxides. J. Chem. Res. 2005, 2005, 27–28. [CrossRef]
49. Harmata, M.; Hong, X. Benzothiazine appl enantiomeric pure 4-sub quinolone. Org. Lett. 2007, 9, 2701–2704.
[CrossRef] [PubMed]
50. Czarny, A.; Zaczyńska, E.; Jeleń, M.; Zimecki, M.; Pluta, K.; Morak-Młodawska, B.; Artym, J.; Koci˛eba, M.
Antimicrobial properties of substituted quino(3,2-b)benzo(1,4)thiazines. Pol. J. Microbiol. 2014, 63, 335–339.
[PubMed]
51. Wu, H.-M.; Zhou, K.; Wu, T.; Cao, Y.-G. Synthesis of Pyrazine-1,3-thiazine hybrid analogues as antiviral
agent against HIV-1, influenza A (H1N1), enterovirus 71 (EV71) and coxsackievirus B3 (CVB3). Chem. Biol.
Drug Des. 2016, 88. [CrossRef] [PubMed]
52. Adly, O.M.I. Characterization, molecular modeling and antimicrobial activity of metal complexes of
tridentate Schiff base derived from 5-acetyl-4-hydroxy-2H-1,3-thiazine-2,6(3H)-dione and 2-aminophenol.
Spectrochim. Acta A Mol. Biomol. Spectrosc. 2012, 95, 483–490. [CrossRef] [PubMed]
53. Koketsu, M.; Tanaka, K.; Takenaka, Y.; Kwong, C.D.; Ishihara, H. Synthesis of 1,3-thiazine derivatives and
their evaluation as potential antimycobacterial agents. Eur. J. Pharm. Sci. 2002, 15, 307–310. [CrossRef]
54. Indumathi, S.; Perumal, S.; Banerjee, D.; Yogeeswari, P.; Sriram, D. l-Proline-catalysed facile green protocol
for the synthesis and antimycobacterial evaluation of (1,4)-thiazines. Eur. J. Med. Chem. 2009, 44, 4978–4984.
[CrossRef] [PubMed]
55. Vennerstrom, J.L.; Makler, M.T.; Angerhofer, C.K.; Williams, J.A. Antimalarial dyes revisited:
Xanthenes, azines, oxazines and thiazines. Antimicrob. Agents Chemother. 1995, 39, 2671–2677. [CrossRef]
[PubMed]
56. Ryley, F. The mode of action of proguanil and related antimalarial drugs. Br. J. Pharmacol. Chemother. 1953, 8,
424–430.
57. Schmidt, L.H.; Loo, T.L.; Fradkin, R.; Hughes, H.B. Antimalarial activities of thiazine metabolites of
chloroguanide and dichloroguanide. Proc. Soc. Exp. Biol. Med. 1952, 80, 367–370. [CrossRef] [PubMed]
58. Davis, R.A.; Duffy, S.; Fletcher, S.; Avery, V.M.; Quinn, R.J. Thiaplakortones A–D: Antimalarial thiazine
alkaloids from the Australian marine sponge plakortis lita. J. Org. Chem. 2013, 78, 9608–9613. [CrossRef]
[PubMed]
59. Pouwer, R.H.; Deydier, S.M.; le van, P.; Schwartz, B.D.; Franken, N.C.; Davis, R.A.; Coster, M.J.; Charman, S.A.;
Edstein, M.D.; Skinner-Adams, T.S.; et al. Total synthesis of thiaplakortone A: Derivatives as metabolically
stable leads for the treatment of malaria. ACS Med. Chem. Lett. 2014, 5, 178–182. [CrossRef] [PubMed]
60. Schwartz, B.D.; Skinner-Adams, T.S.; Andrews, K.T.; Coster, M.J.; Edstein, M.D.; MacKenzie, D.;
Charman, S.A.; Koltun, M.; Blundell, S.; Campbell, A.; et al. Synthesis and antimalarial evaluation of
amide and urea derivatives based on the thiaplakortone A natural product scaffold. Org. Biomol. Chem. 2015,
13, 1558–1570. [CrossRef] [PubMed]
61. Schwartz, B.D.; Coster, M.J.; Skinner-Adams, T.S.; Andrews, K.T.; White, J.M.; Davis, R.A. Synthesis and
antiplasmodial evaluation of analogues based on the tricyclic core of thiaplakortones A–D. Mar. Drugs 2015,
13, 5784–5795. [CrossRef] [PubMed]
62. Vicentini, C.B.; Forlani, G.; Manfrini, M.; Romagnoli, C.; Mares, D. Development of new fungicides
against Magnaporthe grisea: Synthesis and biological activity of pyrazolo(3,4-d)(1,3)thiazine, pyrazolo(1,5-c)
(1,3,5)thiadiazine, and pyrazolo(3,4-d)pyrimidine derivatives. J. Agric. Food Chem. 2002, 50, 4839–4845.
[CrossRef] [PubMed]
63. Mares, D.; Romagnoli, C.; Andreotti, E.; Forlani, G.; Guccione, S.; Vicentini, C.B. Emerging antifungal azoles
and effects on Magnaporthe grisea. Mycol. Res. 2006, 110, 686–696. [CrossRef] [PubMed]
64. Ambrogi, V.; Grandolini, G.; Perioli, L.; Ricci, M.; Rossi, C.; Tuttobello, L. Synthesis, antibacterial
and antifungal activities of several new benzo- naphtho- and quinolino-1,4-thiazine and 1,5-thiazepine
derivatives. Eur. J. Med. Chem. 1990, 25, 403–411. [CrossRef]
65. Ferreira, M.; Assunção, L.S.; Filippin-Monteiro, F.B.; Creczynski-Pasa, T.B.; Sa, M.M. Synthesis of
1,3-thiazine-2,4-diones with potential anticancer activity. Eur. J. Med. Chem. 2013, 70, 411–418. [CrossRef]
[PubMed]
Molecules 2016, 21, 1054 19 of 20

66. Juszczak, M.; Walczak, K.; Matysiak, J.; Lemieszek, M.K.; Langner, E.; Karpińska, M.M.; Pożarowski, P.;
Niewiadomy, A.; Rzeski, W. New derivative of 2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-one (BChTT)
elicits antiproliferative effect via p38-mediated cell cycle arrest in cancer cells. Bioorg. Med. Chem. 2016, 24,
1356–1361. [CrossRef] [PubMed]
67. Jeleń, M.; Pluta, K.; Zimecki, M.; Morak-Młodawska, B.; Artym, J.; Koci˛eba, M. 6-Substituted 9-Fluoroquino
(3,2-b)Benzo(1,4)Thiazines Display Strong Antiproliferative and Antitumor Properties. Eur. J. Med. Chem.
2015, 89, 411–420. [CrossRef] [PubMed]
68. Ha, S.K.; Koketsu, M.; Lee, M.; Moon, E.; Kim, S.H.; Yoon, T.J.; Kim, S.Y. Inhibitory effects of 1,3-thiazine
derivatives on melanogenesis. J. Pharm Pharmacol 2009, 61, 1657–1663. [CrossRef] [PubMed]
69. Hemming, K.; Patel, N. The synthesis of pyrrolo(1,2-b)(1,2,5)benzothiadiazepines from 1,2-thiazine
1-oxides—Sulfonamide analogues of the pyrrolobenzodiazepine antitumour natural products.
Tetrahedron Lett. 2004, 45, 7553–7556. [CrossRef]
70. Loukou, C.; Patel, N.; Foucher, V.; Hemming, K. The synthesis of 1,2,5-benzothiadiazepine 1,1-dioxides from
1,2-thiazine 1-oxides. J. Sulfur Chem. 2005, 26, 455–479. [CrossRef]
71. Szakonyi, Z.; Zupk, I.; Zupkó, I.; Sillanpää, R.; Fülöp, F. Stereoselective synthesis and Cytoselective toxicity
of Monoterpene-fused 2-Imino-1,3-Thiazines. Molecules 2014, 19, 15918–15937. [CrossRef] [PubMed]
72. Aman, F.; Hanif, M.; Siddiqui, W.A.; Ashraf, A.; Filak, L.K.; Reynisson, J.; Söhnel, T.; Jamieson, S.M.F.;
Hartinger, C.G. Anticancer Ruthenium(n6 -p-cymene) complexes of nonsteroidal anti-inflammatory drug
derivatives. Organometallics 2014, 33, 5546–5553. [CrossRef]
73. Pearce, A.N.; Chia, E.W.; Berridge, M.V.; Clark, G.R.; Harper, J.L.; Larsen, L.; Maas, E.W.; Page, M.J.;
Perry, N.B.; Webb, V.L.; et al. Anti-inflammatory thiazine alkaloids isolated from the New Zealand ascidian
Aplidium sp.: Inhibitors of the neutrophil respiratory burst in a model of gouty arthritis. J. Nat. Prod. 2007,
70, 936–940. [CrossRef] [PubMed]
74. Chia, E.W.; Pearce, A.N.; Berridge, M.V.; Larsen, L.; Perry, N.B.; Sansom, C.E.; Godfrey, C.A.; Hanton, L.R.;
Lu, G.L.; Walton, M.; et al. Synthesis and anti-inflammatory structure-activity relationships of
thiazine-quinoline-quinones: Inhibitors of the neutrophil respiratory burst in a model of acute gouty
arthritis. Bioorg. Med. Chem. 2008, 16, 9432–9442. [CrossRef] [PubMed]
75. Kai, H.; Morioka, Y.; Murashi, T.; Morita, K.; Shinonome, S.; Nakazato, H.; Kawamoto, K.; Hanasaki, K.;
Takahashi, F.; Mihara, S.; et al. 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid
receptor agonists. Part 1: Discovery of CB2 receptor selective compounds. Bioorg. Med. Chem. Lett. 2007, 17,
4030–4034. [CrossRef] [PubMed]
76. Kai, H.; Morioka, Y.; Tomida, M.; Takahashi, T.; Hattori, M.; Hanasaki, K.; Koike, K.; Chiba, H.; Shinohara, S.;
Kanemasa, T.; et al. 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists.
Part 2: Orally bioavailable compounds. Bioorg. Med. Chem. Lett. 2007, 17, 3925–3929. [CrossRef] [PubMed]
77. Kai, H.; Morioka, Y.; Koriyama, Y.; Okamoto, K.; Hasegawa, Y.; Hattori, M.; Koike, K.; Chiba, H.; Shinohara, S.;
Iwamoto, Y.; et al. 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists.
Part 3: Synthesis and activity of isosteric analogs. Bioorg. Med. Chem. Lett. 2008, 18, 6444–6447. [CrossRef]
[PubMed]
78. Grandolini, G.; Ambrogi, V.; Perioli, L.; DEramo, D.; Bernardini, C.; Giampietri, A. Studies on annelated
1,4-benzothiazines and 1,5-benzothiazepines. XI. Synthesis and biological activity of several naphtho- and
quinolino-1,4-thiazine and -1,4-thiazepine derivatives containing the imidazole ring. Farmaco 1997, 52,
379–384. [PubMed]
79. Volovenko, J.; Volovnenko, T.; Popov, K. Novel benzo(e)(1,2)thiazine derivatives, synthesis and reactions.
Tetrahedron Lett. 2009, 50, 1171–1172. [CrossRef]
80. Popov, K.; Volovnenko, T.; Volovenko, J. On the functionalization of benzo(e)(2,1)thiazine. Beilstein J.
Org. Chem. 2009, 5. [CrossRef] [PubMed]
81. Xu, S.; Hermanson, D.J.; Banerjee, S.; Ghebreselasie, K.; Clayton, G.M.; Garavito, R.M.; Marnett, L.J.
Oxicams bind in a novel mode to the cyclooxygenase active site via a two-water-mediated H-bonding
network. J. Biol. Chem. 2014, 289, 6799–6808. [CrossRef] [PubMed]
82. Xu, S.; Rouzer, C.A.; Marnett, L.J. Oxicams, a class of nonsteroidal anti-inflammatory drugs and beyond.
IUBMB Life 2014, 66, 803–811. [CrossRef] [PubMed]
Molecules 2016, 21, 1054 20 of 20

83. Ferrari, G.V.; Natera, J.; Paulina Montaña, M.; Muñoz, V.; Gutiérrez, E.L.; Massad, W.; Miskoski, S.;
García, N.A. Scavenging of photogenerated ROS by Oxicams. Possible biological and environmental
implications. J. Photochem. Photobiol. B Biol. 2015, 153, 233–239. [CrossRef] [PubMed]
84. Van Antwerpen, P.; Nève, J. In vitro comparative assessment of the scavenging activity against three
reactive oxygen species of non-steroidal anti-inflammatory drugs from the oxicam and sulfoanilide families.
Eur. J. Pharmacol. 2004, 496, 55–61. [CrossRef] [PubMed]
85. Tsopelas, F.; Ochsenkühn-Petropoulou, M.; Zikos, N.; Spyropoulou, E.; Andreadou, I.; Tsantili-Kakoulidou, A.
Electrochemical study of some non-steroidal anti-inflammatory drugs: Solvent effect and antioxidant activity.
J. Solid State Electrochem. 2010, 15, 1099–1108. [CrossRef]
86. Ghaempanah, A.; Darvishpour, M.; Fekri, M.H. Electrochemical Calculations of Some Non-Steroidal
Anti-Inflammatory Drugs: Solvent Effect and Antioxidant Activity. Int. J. Electrochem. Sci. 2012, 7, 6127–6133.
87. Eleftheriou, P.; Geronikaki, A.; Hadjipavlou-Litina, D.; Vicini, P.; Filz, O.; Filimonov, D.; Poroikov, V.;
Chaudhaery, S.S.; Roy, K.K.; Saxena, A.K. Fragment-based design, docking, synthesis, biological
evaluation and structure-activity relationships of 2-benzo/benzisothiazolimino-5-aryliden-4-thiazolidinones
as cycloxygenase/lipoxygenase inhibitors. Eur. J. Med. Chem. 2012, 47, 111–124. [CrossRef] [PubMed]
88. Galanski, M.E.; Erker, T.; Studenik, C.R.; Kamyar, M.; Rawnduzi, P.; Pabstova, M.; Lemmens-Gruber, R.
Synthesis and pharmacological profile of non-peptide vasopressin antagonists. Eur. J. Pharm. Sci. 2005, 24,
421–431. [CrossRef] [PubMed]
89. Galanski, M.E.; Erker, T.; Handler, N.; Lemmens-Gruber, R.; Kamyar, M.; Studenik, C.R. Studies on
the chemistry of thienoanellated O,N- and S,N-containing heterocycles. Part 30: Synthesis and
pharmacological properties of thieno(2,3-b)(1,4)thiazines with potential vasopressin receptor antagonistic
activity. Bioorg. Med. Chem. 2006, 14, 826–836. [CrossRef] [PubMed]
90. Yabe-Nishimura, C. Aldose Reductase in Glucose Toxicity: A Potential Target for the Prevention of Diabetic
Complications. Pharmacol. Rev. 1998, 50, 21–34. [PubMed]
91. Tang, W.H.; Martin, K.A.; Hwa, J. Aldose reductase, oxidative stress, and diabetic mellitus. Front. Pharmacol.
2012, 3. [CrossRef] [PubMed]
92. Zentgraf, M.; Steuber, H.; Koch, C.; la Motta, C.; Sartini, S.; Sotriffer, C.A.; Klebe, G. How reliable are current
docking approaches for structure-based drug design? Lessons from aldose reductase. Angew. Chem. Int. Ed.
2007, 46, 3575–3578. [CrossRef] [PubMed]
93. Saraswat, M.; Muthenna, P.; Suryanarayana, P.; Petrash, J.M.; Reddy, G.B. Dietary sources of aldose reductase
inhibitors: prospects for alleviating diabetic complications. Asia Pac. J. Clin. Nutr. 2008, 17, 558–565.
[PubMed]
94. Chen, X.; Zhang, S.; Yang, Y.; Hussain, S.; He, M.; Gui, D.; Ma, B.; Jing, C.; Qiao, Z.; Zhu, C.; et al.
1,2-Benzothiazine 1,1-dioxide carboxylate derivatives as novel potent inhibitors of aldose reductase.
Bioorg. Med. Chem. 2011, 19, 7262–7269. [CrossRef] [PubMed]
95. Chen, X.; Zhu, C.; Guo, F.; Qiu, X.; Yang, Y.; Zhang, S.; He, M.; Parveen, S.; Jing, C.; Li, Y.; et al.
Acetic Acid Derivatives of 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide as a Novel Class of Potent
Aldose Reductase Inhibitors. J. Med. Chem. 2010, 53, 8330–8344. [CrossRef] [PubMed]
96. Winneroski, L.L.; Schiffler, M.A.; Erickson, J.A.; May, P.C.; Monk, S.A.; Timm, D.E.; Audia, J.E.; Beck, J.P.;
Boggs, L.N.; Borders, A.R.; et al. Preparation and biological evaluation of conformationally constrained
BACE1 inhibitors. Bioorg. Med. Chem. 2015, 23, 3260–3268. [CrossRef] [PubMed]
97. Blokhina, S.V.; Volkova, T.V.; Ol’Khovich, M.V.; Sharapova, A.V.; Proshin, A.N.; Bachurin, S.O.; Perlovich, G.L.
Synthesis, biological activity, distribution and membrane permeability of novel spiro-thiazines as potent
neuroprotectors. Eur. J. Med. Chem. 2014, 77, 8–17. [CrossRef] [PubMed]
98. Menna, M.; Imperatore, C.; D’Aniello, F.; Aiello, A. Meroterpenes from marine invertebrates:
Structures, occurrence, and ecological implications. Mar. Drugs 2013, 11, 1602–1643. [CrossRef] [PubMed]
99. Kniewallner, K.M.; Wenzel, D.; Humpel, C. Thiazine Red+ platelet inclusions in Cerebral Blood Vessels are
first signs in an Alzheimer0 s Disease mouse model. Sci. Rep. 2016, 6. [CrossRef] [PubMed]

© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).