Bioactive Thiazine and Benzothiazine Derivatives: Green Synthesis Methods and Their Medicinal Importance

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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: [email protected] (S.L.B.); [email protected] (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 (Figure1), 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 2016,, 21,, 1054 1054 2 of 19 20 work clearly establishes the importance of thiazine and its derivatives for the synthesis of a wide variety variety of heterocyclic compounds through environmentally friendly methods that are of academic of heterocyclic compounds through environmentally friendlyfriendly methodsmethods thatthat areare ofof academicacademic andand and pharmaceutical industry interest [4]. Moreover, during these syntheses the yield of the desired pharmaceutical industry interest [4]. Moreover, during these syntheses the yield of the desired compounds is often high and they may be obtained in a single step. It has been noticed that structural compounds is often high and they may be obtained in a single step. It has been noticed that structural modifications in the thiazine and its derivatives result in valuable medicinal properties that should be modifications in the thiazine and its derivatives result inin valuablevaluable medicinalmedicinal propertiesproperties thatthat shouldshould bebe 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 compounds against multi-drug resistant microorganisms and other diseases. Thus, the research potent compounds against multi-drug resistantresistant microorganismsmicroorganisms andand otherother diseases.diseases. Thus,Thus, thethe researchresearch to explore different avenues of chemical modifications of thiazine and its available derivatives to obtain to explore different avenues of chemicalical modificationsmodifications ofof thiazinethiazine andand itsits availableavailable derivativesderivatives toto obtainobtain novel active compounds should be continued. Therefore, it is of utmost timeliness to briefly review novel active compounds should be continued. Therefore, it is of utmost timeliness to briefly review the novel green, synthetic methodologies and biological activities of thiazine and their derivatives. the novel green, synthetic methodologies and biological activities of thiazine and their derivatives. The current collected data for the preparation and biochemical applications of thiazines The current collected data for the preparation and biochemical applications of thiazines and their and their derivatives relate to the green approach, i.e., reactions using microwave irradiation, derivatives relate to the green approach, i.e., reactions using microwave irradiation, sonication, grinding sonication, grinding techniques, solvent-free conditions, nanoparticles, ionic liquids, etc. are presented techniques, solvent-free conditions, nanoparticles, ionic liquids, etc. are presented in this review. The in this 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, tetraphenyl phosphine, thiourea, ptolylsulphonic acid, palladium catalyst, perchloric acid, ptolylsulphonic acid, palladium catalyst, perchloric acid, phosphomolybdic acid, 1-benzyl-3-methyl phosphomolybdic acid, 1-benzyl-3-methyl imidazolium hydrogen sulphate, etc. [9]. imidazoliumimidazolium hydrogenhydrogen sulphate,sulphate, etc.etc. [9].[9].

Figure 1. StructuresStructures ofof 1,4-,1,4-, 1,3- 1,3- and and 1,2-thiazine. 1,2-thiazine.

2. Green Green Syntheses Syntheses of of Thia Thiazineszines and and their their Derivatives Derivatives Edayadulla and Ramesh [[10]10] synthesizedsynthesized a derivativederivative ofof 1,4-thiazine,1,4-thiazine, namelynamely 2,6-dicarbethoxy-3,5-2,6-dicarbethoxy-3,5- diphenyltetrahydro-1,4-thiazine-1,1-dioxide by taki takingng diethyl 2,2-sulfonyldiacetate and benzaldehyde in water,water, to to which which ammoniumammonium acetate acetate was was addedadded atat roomroom room temperaturetemperature [10]. [[10].10]. TheThe The reactantsreactants reactants werewere were gentlygently gently stirred for 3 h at 80 °C◦C and and after after that that they they were were cooled cooled down down to to room room temperature, temperature, and the product was extracted with ethyl acetate. The The upper upper organic organic la layeryer was was dehydrated dehydrated completely using the anhydrous Na2SO4 and concentrated at reduced pressure to obtain the crude product, which was purified and Na2SOSO44 andand concentrated concentrated at at reduced reduced pressure pressure to to obtain obtain the the crude product, which was puriﬁedpurified and recrystallized using using ethanol ethanol as as a asolvent solvent to togive give the the pure pure target target compound compound in excellent in excellent yield yield [10]. [The10]. chemicalThe chemical structure structure of the of thecompound compound was was determin determineded by by different different spectroscopic spectroscopic and and analyticalanalytical techniques (Scheme 11))[ [10].10]. Test Test re resultssults of these these compounds compounds on mice mice mo modelsdels showed that they effective anticonvulsants [10]. [10].

Scheme 1. Eco-compatible preparation of the 2,6-dicarbethoxy-3,5-diphenylltetrahydro-1,4-thiazine- Scheme 1.1. Eco-compatible preparationpreparation of of the the 2,6-dicarbethoxy-3,5-diphenylltetrahydro-1,4-thiazine-1,1- 2,6-dicarbethoxy-3,5-diphenylltetrahydro-1,4-thiazine- 1,1-dioxides [10]. dioxides1,1-dioxides [10]. [10].

Kadhim reported a novel azachalcone compound that was prepared through the reaction of Kadhim reported a novel azachalcone compound that was prepared through the reaction of acetylated pyridine with 4-hydroxybenzaldehyde [11]. Later the azachalcone was treated with thiourea acetylated pyridine with 4-hydroxybenzaldehyde [11]. Later the azachalcone was treated with to give a high yield of the thiazine derivative ((E)-3-(4-hydroxyphenyl)-1-(pyridin-3-yl) prop-2-en-1- thiourea to give a high yield of the thiazine derivative ((E)-3-(4-hydroxyphenyl)-1-(pyridin-3-yl)1 one) (Scheme 2) [11]. The synthesized compound was characterized by infrared, ultra-violet, 1H-NMR prop-2-en-1-one) (Scheme2)[ 11]. The synthesized compound was characterized by infrared, spectroscopy and elemental analysis. The obtained compound were tested for anti-bacterial and antifungal properties and showed good activities (Scheme 2) [11].

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ultra-violet, 1H-NMR spectroscopy and elemental analysis. The obtained compound were tested Moleculesfor anti-bacterial 2016, 21, 1054 and anti-fungal properties and showed good activities (Scheme2)[11]. 3 of 19 Molecules 2016, 21, 1054 3 of 19

SchemeScheme 2. FormationFormation of of azachalcone azachalcone compound compound from from acet acetylatedylated pyridine pyridine and and benzaldehyde benzaldehyde and and its its Scheme 2. Formation of azachalcone compound from acetylated pyridine and benzaldehyde and its subsequent use for the synthesis of a thiazine derivative; R represents m-NO2, p-OH, m-Br, m-OCH3, subsequent use for the synthesis of a thiazine derivative; R represents m-NO2, p-OH, m-Br, m-OCH3, subsequent use for the synthesis of a thiazine derivative; R represents m-NO2, p-OH, m-Br, m-OCH3, p-N(CH3)2 [11]. p-N(CH3)2 [11]. p-N(CH3)2 [11]. According to Elarfi et al., chalcone derivatives can be synthesized by reacting benzaldehyde AccordingAccording toto ElarﬁElarfi et et al., al., chalcone chalcone derivatives derivatives can can be be synthesized synthesized by by reacting reacting benzaldehyde benzaldehyde derivatives with acetophenone [12]. In the second step of this reaction, the product obtained was derivativesderivatives withwith acetophenoneacetophenone [12[12].]. InIn thethe secondsecond stepstep ofof thisthis reaction,reaction, thethe productproduct obtained obtained was was allowed to react with thiourea to form thiazines and other related compounds. The products obtained allowedallowed to to react react with with thiourea thiourea to to form form thiazines thiazines and and other other related related compounds. compounds. The The products products obtained obtained were characterized by elemental analysis, electromagnetic induction spectroscopy (EMIS), proton NMR werewere characterized characterized by by elemental elemental analysis, analysis, electromagnetic electromagnetic induction induction spectroscopy spectroscopy (EMIS), (EMIS), proton proton NMR NMR and infrared spectroscopy [12]. The thiazine and its related derivatives were checked for bioactivity andand infrared infrared spectroscopy spectroscopy [ 12[12].]. The The thiazine thiazine and and its its related related derivatives derivatives were were checked checked for for bioactivity bioactivity using some antibacterial tests (Scheme 3) [12]. usingusing some some antibacterial antibacterial tests tests (Scheme (Scheme3)[ 3)12 [12].].

Scheme 3. Preparation of thiazine derivatives from benzaldehyde and acetophenone through chalcones. Scheme 3. Preparation of thiazine derivatives from benzaldehyde and acetophenone through chalcones. WhereScheme X 3.= oPreparation-OH; p-N(CH of thiazine3)2; m-OCH derivatives3 [12]. from benzaldehyde and acetophenone through chalcones. Where X = o-OH; p-N(CH3)2; m-OCH3 [12]. Where X = o-OH; p-N(CH3)2; m-OCH3 [12]. 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 beGayathri synthesized et al. reportedby microwave that thiazine induced derivatives reactions containing[13]. They fluorine,took 1-(7-chloro-6-fluoro-1 chlorine and benzimidazoleH-benzo can be synthesized by microwave induced reactions [13]. They took 1-(7-chloro-6-fluoro-1H-benzo [cand]imidazol-2-yl)-3-arylprop-2-en-1-one be synthesized by microwave induced and cyclized reactions it [with13]. Theythiourea took in 1-(7-chloro-6-fluoro-1a microwave inducedH reaction-benzo [d]imidazol-2-yl)-3-arylprop-2-en-1-one and cyclized it with thiourea in a microwave induced reaction producing[d]imidazol-2-yl)-3-arylprop-2-en-1-one the 1,3-thiazine derivative 6-(7-chloro-6-fluoro-1 and cyclized it with thioureaH-benzo-2-yl)-4-phenyl-6 in a microwave inducedH-1,3-thiazine-2- reaction producing the 1,3-thiazine derivative 6-(7-chloro-6-fluoro-1H-benzo-2-yl)-4-phenyl-6H-1,3-thiazine-2- amineproducing [13]. The the synthesized 1,3-thiazine compounds derivative 6-(7-chloro-6-fluoro-1were confirmed and characterizedH-benzo-2-yl)-4-phenyl-6 by thin layer chromatographyH-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].

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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 Moleculespotent activities 2016, 21, 1054 in both areas (Scheme4)[13]. 4 of 19

Molecules 2016, 21, 1054 NH2 4 of 19 O S N N NH2 N O thiourea N S N F NH microwave F N NH Cl thiourea N Cl F H microwave F N H Scheme 4.Cl Synthesis of 1,3-thiazine derivatives under microwave irradiation [13]. Scheme 4. Synthesis of 1,3-thiazine derivatives underC microwavel irradiation [13 ]. Zia-ur-RehmanScheme et4. Synthesisal. synthesized of 1,3-thiazine a series derivati of analoguesves under of microwave4-hydroxy- irradiationN-(benzylidene)-2 [13]. H-benzo [e][1,2]thiazine-3Zia-ur-Rehman carbohydrazide et al. synthesized 1,1-dioxides a series [14]. of analogues They performed of 4-hydroxy- N-alkylatonN-(benzylidene)-2 of sodium saccharinH-benzo with[e][1,2]thiazine-3 Zia-ur-Rehmanmethyl chloroacetate carbohydrazide et al. synthesized in the 1,1-dioxides presence a series of [of14 ultrasonic analogues]. They performed irradiation of 4-hydroxy-N -alkylaton[14].N- (benzylidene)-2Both of the sodium reagents saccharinH-benzo were [dissolvedwithe][1,2]thiazine-3 methyl in dimethyformamide chloroacetate carbohydrazide in the for 1, presence1-dioxides the ultrasonic of [14]. ultrasonic irradiation.They performed irradiation The advantage N-alkylaton [14]. Both of thisof the sodium process reagents saccharin is that were it withcandissolved be methyl done in at chloroacetate dimethyformamidelower temperatures in the andpresence for thein a ultrasonicshort of ultrasonic period irradiation. of time.irradiation In the The next[14]. advantage stage,Both the offivereagents this membered process were dissolvedisothiazoleis that it in can ring dimethyformamide be was done converted at lower intofor temperatures the the ultrasonic thiazine and ringirradiation. in under a short inertThe period advantageatmosphere of time. of conditionsthis In process the next and is that stage, then it cantreatedthe ﬁvebe done with membered at hydrazine lowerisothiazole temperatures which ringwas and wasfollowed in a converted short by period reac intotion of the time.with thiazine Inbenzaldehydes the next ring stage, under to the inertgive five atmospherethe membered desired isothiazoleproductsconditions in andringhigh then wasyield treatedconverted (Scheme with 5) into [14]. hydrazine the Some thiazine of which the derivativesring was under followed have inert bygood atmosphere reaction antibacterial with conditions benzaldehydes properties, and while then to treatedmostgive theof thewith desired products hydrazine products possess which in highantioxidant was yield followed (Scheme activities. 5by)[ Recentlyreac14].tion Some thewith of same the benzaldehydes derivatives research group have to goodhasgive expanded antibacterialthe desired the productssynthesisproperties, in of high these while yield 1,2-benzothiazine-3-carbohydrazide most (Scheme of the 5) products [14]. Some possess of the antioxidantderivatives 1,1-dioxides have activities. usinggood antia Recentlymicrowave-assistedbacterial the properties, same research method while mostthatgroup gives of hasthe the expandedproducts products possess the in synthesishigh antioxidant yield of [15]. these activities. Zia-ur-R 1,2-benzothiazine-3-carbohydrazide Recentlyehman et the al. same have research also performed group 1,1-dioxides has crystallographic expanded using the synthesisstudiesa microwave-assisted of of the these 1,2-benzothiazine 1,2-benzothiazine-3-carbohydrazide method that compounds gives the to products get better in1,1-dioxides highinformation yield using [15 about]. Zia-ur-Rehman a microwave-assisted their molecular et al.structure have method also in thattermsperformed gives of bond the crystallographic lengths,products bond in high studiesangles yield and of [15]. the va 1,2-benzothiazinerious Zia-ur-R possibleehman conformational et compounds al. have also states to getperformed [16]. better information crystallographic about studiestheir molecular of the 1,2-benzothiazine structure in terms compounds of bond lengths,to get better bond information angles and about various their possible molecular conformational structure in termsstates of [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]. SchemeScheme 5. 5. GeneralGeneral Scheme Scheme for the for synthesis the synthesis of different of different N-[(1E)-arylmethylidene]-4-hydroxyN-[(1E)-arylmethylidene]-4-hydroxy 2H-1,2- benzothiazine-3-carbohydrazideDighade2H-1,2-benzothiazine-3-carbohydrazide et al. synthesized different 1,1-dioxides 1,1-dioxideschalcones derivatives through derivatives [14]. a condensation [14]. process of 2-hydroxy-3- iodo-5-methylacetophenone as a starting material with different aromatic aldehydes in ethanol using Dighade et al. synthesized different chalcones through a condensation process of 2-hydroxy-3- 40% Dighadesodium hydroxide et al. synthesizedsolution as a differentcatalyst [1 chalcones7]. The chalcones through produced a condensation were cyclized process with of iodo-5-methylacetophenone as a starting material with different aromatic aldehydes in ethanol using diphenylthiourea2-hydroxy-3-iodo-5-methylacetophenone in ethanol using KOH and as a a few starting drops material of piperidine with differentas a catalyst. aromatic All the aldehydes thiazine 40% sodium hydroxide solution as a catalyst [17]. The chalcones produced1 were cyclized with compoundsin ethanol using were 40% confirmed sodium and hydroxide categorized solution by elemental as a catalyst analysis, [17]. TheEIMS, chalcones H-NMR produced and infrared were diphenylthiourea in ethanol using KOH and a few drops of piperidine as a catalyst. All the thiazine spectroscopiescyclized with diphenylthiourea(Scheme 6) [17]. in ethanol using KOH and a few drops of piperidine as a catalyst. compounds were confirmed and categorized by elemental analysis, EIMS, 1H-NMR and infrared All the thiazine compounds were conﬁrmed and categorized by elemental analysis, EIMS, 1H-NMR and spectroscopies (Scheme 6) [17]. infrared spectroscopies (Scheme6)[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 (Scheme7)[18].

Scheme 6. Formation of chalcones and their cyclization with diphenylthiourea in ethanol using KOH and few drops of piperidine as a catalyst [17]. Scheme 6. Formation of chalcones and their cyclization with diphenylthiourea in ethanol using KOH and few drops of piperidine as a catalyst [17].

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NH2

O S N N N thiourea N F H microwave F N H Cl Cl Scheme 4. Synthesis of 1,3-thiazine derivatives under microwave irradiation [13].

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 with methyl chloroacetate in the presence of ultrasonic irradiation [14]. Both the reagents were dissolved in dimethyformamide for the ultrasonic irradiation. The advantage of this process is that it can be done at lower temperatures and in a short period of time. In the next stage, the five membered isothiazole ring was converted into the thiazine ring under inert atmosphere conditions and then treated with hydrazine which was followed by reaction with benzaldehydes to give the desired products in high yield (Scheme 5) [14]. Some of the derivatives have good antibacterial properties, while most of the products possess antioxidant activities. Recently the same research group has expanded the synthesis of these 1,2-benzothiazine-3-carbohydrazide 1,1-dioxides using a microwave-assisted method that gives the products in high yield [15]. Zia-ur-Rehman et al. have also performed crystallographic studies of the 1,2-benzothiazine compounds to get better information about their molecular structure in terms of 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].

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 Moleculescompounds2016, 21were, 1054 confirmed and categorized by elemental analysis, EIMS, 1H-NMR and infrared5 of 20 spectroscopies (Scheme 6) [17].

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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. Formation of chalcones and their cyclization with diphenylthiourea in ethanol using KOH 1,2-benzothiazineScheme 6. Formation derivatives of chalcones are useful and their in cyclizationtreating hypertension with diphenylthiourea and as inendothelial ethanol using antagonists KOH and few drops of piperidine as a catalyst [17]. (Schemeand few7) [18]. drops of piperidine as a catalyst [17].

Scheme 7. Formation of 1,2-benzothiazine derivatives using methyl-2-(chlorosulfonyl) benzoate and 2-(triﬂuoromethyl)aniline2-(trifluoromethyl)aniline [[18].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 Scheme8[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,

Scheme 8. Three-component expeditious method for the synthesis of 1,3-thiazine derivatives [19].

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Moleculeswhile the 2016 crystal, 21, x structure was also determined. In addition, Torres-García and coworkers investigated6 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].

SchemeScheme 8. 8. ThreeThree-component-component expeditious expeditious method method for for the the synthesis synthesis of of 1,3 1,3-thiazine-thiazine derivatives 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 (Scheme9), 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 (1H-, 13C- and 19F-) NMR spectroscopies, 1 13 1 1 1 13 including state of the art 2D H- C-HSQC, H-R = 1H-COSY,–8 H- C-HMBC correlations, and also by single-crystal XRD techniqueR1 = CH for3 better results [25]. R2 =

Molecules 2016, 21, 1054 6 of 19

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, while the crystal structure was also determined. In addition, Torres-García and coworkers investigated 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]. Tozkoparan and coworkers synthesized a series of 5-carbomethoxy-2-substituted-7H-1,2,4- triazolo(3,2-b)-1,3-thiazine-7-one 1,3-thiazine derivatives [23]. According to their reaction (Scheme 9), these compounds can be made by reacting 1,2,4-triazole-5-thiones with dimethyl acetylene dicarboxylate using toluene as a solvent under reflux conditions. They purified and characterized their thiazine 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 Moleculesin the future2016, 21 for, 1054 the treatment of inflammatory pain after further laboratory trials. These compounds7 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 H C R7 = 3 R8 = H3CO

Scheme 9. Synthesis of thiazine derivatives using 1,2,4-triazole-5-thiones1,2,4-triazole-5-thiones as a starting materialmaterial [[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 ammoniumO CHO nitrate (CAN)-catalyzed preparationO 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 (Scheme 10). The desiredR1 1,3-thiazines were isolated throughR1 a mixture of etherR2 and PEG-400 that forms two separate layers as PEG is insoluble in ether and their structuresS were confirmed by elemental analysis and spectroscopic analysis [24].R2 These thiazine derivatives act as potent inhibitors of H2N NH2 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 compoundsAccording by totreating Baharfar various et al.pyrimido(2,1- alkenyl halidesb)(1,3)thiazine with 2,4-triazoles derivatives conjugated can be synthesized with trifluoromethyl initially by theand combination thiol groups of[25]. an isocyanideFurthermore and the a dialkylchemical acetylenedicarboxylate process between the S that-alkenyl forms derivatives an active zwitterionic and iodine intermediate.molecules occurs This regiospecifically zwitterionic form producin of the intermediateg new fused is treatedhalogenated with thiouracil(1,2,4)triazole(3,4- that formsb)(1,3)thiazine ketenimine ascompounds an intermediate. (Scheme This 11) [25]. ketenimine The chemical undergoes structures chemical of these cyclization products and were rearrangement confirmed by to elemental form the desiredanalysis, product IR and inmass high spectroscopy yield (Scheme and 12 different)[26]. During isotopic the (1 courseH-, 13C- of and the 19 reaction,F-) NMR the spectroscopies, contents are ◦ stirredincluding for astate day atof 25theC. art Baharfar 2D 1H- and13C-HSQC, colleagues 1H- observed1H-COSY, the 1H- formation13C-HMBC of intermediatescorrelations, byand analyzing also by themsingle-crystal on TLC, XRD and aftertechnique completion for better of the results whole [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].

Scheme 11. Alkenation reaction for the synthesis of triazole-based thiazine heterocyclic compounds [25].

According to Baharfar et al. pyrimido(2,1-b)(1,3)thiazine derivatives can be synthesized initially by the combination of an isocyanide and a dialkyl acetylenedicarboxylate that forms an active zwitterionic 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].

Molecules 2016, 21, 1054 7 of 19

O CHO O

CAN 450C R2 R1 R1 R2 S

H2N NH2

S PEG-400

450C

N NH2

R1 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 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, Moleculesincluding2016, 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].

SchemeScheme 11. 11.Alkenation Alkenation reaction reaction for for the thesynthesis synthesis of triazo triazole-basedle-based thiazine thiazine hetero heterocycliccyclic compounds compounds [25]. [25 ].

MoleculesAccording 2016, 21 to, 1054 Baharfar et al. pyrimido(2,1-b)(1,3)thiazine derivatives can be synthesized initially8 of 19 Moleculesby the combination 2016, 21, 1054 of an isocyanide and a dialkyl acetylenedicarboxylate that forms an active zwitterionic8 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 WangwithWang et alkyl al. et made al.dibromides made a series a series following of of novel novel Scheme multithioether multithioether 13 [27]. derivatives derivativesThe chemical using using properties the the reaction reaction and of structures thiazinethiones of thiazinethiones of these withwith alkylthiazine alkyl dibromides dibromidesanalogues following were following studied Scheme Scheme through 13 13[ EIMS,[27].27]. Th Theelementale chemical chemical analysis, properties properties IR, and and and1 H-NMRstructures structures spectroscopy. of these of these thiazinethiazineThe analogues synthesized analogues were compounds were studied studied were through through tested EIMS, forEIMS, anti elementaltumorelemental activity analysis, analysis, and showed IR, IR, and andgood 1H-NMR1 resultsH-NMR spectroscopy. [27]. spectroscopy. The synthesizedThe synthesized compounds compounds were were testedtested for for anti antitumortumor activity activity and andshowed showed good results good results[27]. [27].

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

R= -CH2CH2- , -CH2CH2CH2- , -CH2CH2CH2CH2- Scheme 13. Formation of multithioether derivatives of thiazine [27]. SchemeScheme 13. 13.Formation Formation of ofmultithioether multithioether derivatives derivatives of ofthiazine thiazine [27]. [27 ]. El Shehry et al. reported that 1,4-thiazine derivatives can be synthesized by the reaction of α-bromopropenoneEl Shehry et al. reported derivatives that with 1,4-thiazine 2-aminothiopheno derivativesl in ethanoliccan be synthesized solution of bypotassium the reaction hydroxide of El Shehry et al. reported that 1,4-thiazine derivatives can be synthesized by the reaction of α-bromopropenone(Scheme 14) [28]. Thesederivatives thiazine with derivatives 2-aminothiopheno were testled in forethanolic antimolluscicidal solution of activitiespotassium and hydroxide the results α-bromopropenone derivatives with 2-aminothiophenol in ethanolic solution of potassium hydroxide (Schemeshowed 14) that [28]. they These exhibited thiazine moderate derivatives inhibitory were test powered for [28]. antimolluscicidal activities and the results (Schemeshowed 14)[ that28]. they These exhibited thiazine moderate derivatives inhibitory were power tested [28]. for antimolluscicidal activities and the results showed that they exhibited moderate inhibitory power [28]. OH Br Zhao et al. described a resourceful one-pot cyclization reactionOH processH for the preparation Br H2N N O R H of pyridazino(4,5-b)(1,4)thiazine-dioneH2N analoguesKOH, following Ethanol the famousN Smiles rearrangement O R method [29]. They obtained a number of idealKOH, Ethanol compounds in high yields without any side reaction products. Moreover,R thisHS is a transition metal-free, economical, environmentallyS compatible, R and highlyScheme efﬁcient 14. method Synthesisfor ofHS 1,4-thiazine the production derivatives of complexfrom α-bromopropenone heterocyclicS derivative moieties and with 2-amino- thiazines as constituentScheme partsthiophenol 14. [29 Synthesis]. in They ethanolic of synthesized 1,4-thiazine potassium hydroxidederivatives their complex solution from α 1,4-thiazine -bromopropenone[28]. analogues derivative (Scheme and 2-amino- 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 pyridazino(4,5-Zhao et al. describedb)(1,4)thiazine-dione a resourceful analogues one-pot following cyclization the reactionfamous Smiles process rearrangement for the preparation method of[29]. pyridazino(4,5-They obtainedb)(1,4)thiazine-dione a number of ideal analogues compounds following in hi thegh famousyields withoutSmiles rearrangement any side reaction method products. [29]. TheyMoreover, obtained this a isnumber a transition of ideal metal-free, compounds economic in hial,gh environmentally yields without compatibany sidele, reaction and highly products. efficient Moreover,method thisfor theis a productiontransition metal-free, of complex economic heterocyclical, environmentally moieties with thiazinescompatib le,as constituentand highly efficientparts [29]. methodThey forsynthesized the production their ofcomplex complex 1,4-thiazine heterocyclic analogues moieties with(Scheme thiazines 15) byas constituenttreating 4,5-dichloro-2- parts [29]. They(tetrahydro-2 synthesizedH-pyran-2-yl)pyridazin-3(2 their complex 1,4-thiazineH)-one analogues with N-benzyl-2-mercaptoacetamide (Scheme 15) by treating 4,5-dichloro-2- using Cs2CO3 as (tetrahydro-2catalyst in HDMF-pyran-2-yl)pyridazin-3(2 [29]. The one-pot SmilesH)-one rearrangem with N-benzyl-2-mercaptoacetamideent process is quite useful in using organic Cs 2chemistryCO3 as catalyst[30] and in DMF it should [29]. beThe fully one-pot explored Smiles for rearrangem the syntheentsis ofprocess other iscomplex quite useful thiazine in organic derivatives chemistry that are [30]important and it should from bemedicinal fully explored point of for view. the synthesis of other complex thiazine derivatives that are important from medicinal point of view.

Molecules 2016, 21, 1054 8 of 19

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 thiazineMolecules 2016 analogues, 21, 1054 were studied through EIMS, elemental analysis, IR, and 1H-NMR spectroscopy.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 Cs2CO3 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= -CH2CH in2- the, -CH formation2CH2CH2- , of -CH an2CH intermediate2CH2CH2- 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 desiredScheme product 13. Formation [31]. of The multithioether product formed derivatives was of further thiazine conﬁrmed [27]. and analyzed by various techniques. These thiazine derivatives were also checked for their antiviral properties usingEl the Shehry nucleocapsid et al. reported protein ofthat the 1,4-thiazine feline immunodeﬁciency derivatives ca virusn be (FIV) synthesized [33] in vitro by thecell culturereaction that of αshowed-bromopropenone activity in nanomolar derivatives concentration with 2-aminothiopheno and low toxicityl in ethanolic [34]. Thus solution these of thiazine potassium analogues hydroxide may (Schemebe suitable 14) candidates [28]. These for thiazine HIV treatment derivatives and were could test beed tested for antimolluscicidal further to check activities for potency and in the mice results and showedhuman HIVthat infectedthey exhibited 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 ZhaoScheme et al. 15. described One-pot synthesis a resourceful of pyridazino[4,5- one-potb][1,4]thiazine-diones cyclization reaction involving process a Smiles for rearrangement the preparation of pyridazino(4,5-process [29].b)(1,4)thiazine-dione analogues following the famous Smiles rearrangement method [29]. They obtained a number of ideal compounds in high yields without any side reaction products. Moreover,Konstantinova this is a transition and coworkers metal-free, synthesized economic theal, environmentally bis(1,2)dithiolo derivative compatib le,of and1,4-thiazine highly efficient class method(Scheme for 16)the productionby treating of4-isopropylamino-5-chloro- complex heterocyclic moieties1,2-dithiole-3-ones with thiazines with as sulfurylconstituent chloride parts [29].in Theyacetonitrile synthesized as a solvent their that complex resulted 1,4-thiazine in the formation analogues of an intermediate (Scheme salt 15) of bis(1,2)dithiolo(1,4)thiazineby treating 4,5-dichloro-2- chloride [31,32]. When this intermediate salt is further treated with triethylamine (Scheme 16), it (tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one with N-benzyl-2-mercaptoacetamide using Cs2CO3 as catalystresulted in DMFin the [29].desired The product one-pot [31]. Smiles The rearrangem product formedent process was further is quite confirmed useful in and organic analyzed chemistry by 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 from medicinal point of view. showedSchemeScheme activity 15.15. One-pot in nanomolar synthesis concentration of pyridazino[4,5-pyridazino[4,5- andbb ][1,4]thiazine-diones][1,4]thiazine-dioneslow toxicity [34]. Thus involvinginvolving these athiazinea SmilesSmiles rearrangement rearrangementanalogues may be processsuitableprocess [[29]. 29candidates]. 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 R Cl O (Scheme 16) by treatingO 4-isopropylamino-5-chloro-1,2-dithiole-3-ones with sulfuryl chloride in N acetonitrile as a solventN that resulted in the formation of an intermediate salt of bis(1,2)dithiolo(1,4)thiazine MeCN S S chloride [31,32]. When thisS intermediateS2Cl2 salt isCl further treated with triethylamine (Scheme 16), it S S resulted in the desired productS [31]. The product formedS was further confirmed and analyzed by various techniques.Cl These thiazine derivatives were also checked for their antiviralEt3N properties using the nucleocapsid protein of Rthe Ranging feline from 1-8immunodeficiency virus (FIV) [33] in vitro cell culture that showed activity in nanomolar concentration%yield and low toxicity [34]. Thus these thiazine analogues may R1 = CH2CH2Cl 40 R2 = CH2CH2N3 65 be suitable candidates for HIV treatment and could be tested further to check forR potency in mice and R3 = CH2CH2CO2Et 73 S O human HIV infected tissues. R4 = CH2CH2SPh 54 N R5 = CH2CH2CN 49 R6 = CH2CH2SO2Ph 44 R S S R R7 = CH2CH2OC(O)H 78 Cl O O R8 = CH Ph 62 2 S S N N S MeCN Scheme 16. Synthesis of bis(1,2)dithioloCl S derivatives of 1,4-thiazineS [31]. Scheme 16.S SynthesisS2Cl2 of bis(1,2)dithiolo derivatives of 1,4-thiazine [31]. S S S S 3. Biological ActivitiesCl of Thiazine and Benzothiazine Derivatives Et3N R Ranging from 1-8 Heterocyclic thiazine and benzothiazine compounds are a crucial part of medicinal organic chemistry due to their useful medicinal properties%yield . The largely unexplored heterocyclic compounds R1 = CH2CH2Cl 40 like thiazines possess a varietyR2 =of CH pharmacological2CH2N3 65 activities, ranging from antitumor, antipsychotic and R anti-inflammatory propertiesR3 on = CH th2eCH one2CO2 hand,Et while 73 on the pathogenic side,S they are equallyO important R4 = CH2CH2SPh 54 N due to their antibacterial, R5antitubercular, = CH2CH2CN antifu 49 ngal, antiviral and antiprotozoal activities. Thus R6 = CH2CH2SO2Ph 44 thiazine compounds displayR7 a = wide CH2CH 2rangeOC(O)H of 78beneficial properties [6]. TheseS activities are discussedS R8 = CH Ph 62 one by one in the following paragraphs.2 S S S 3.1. Antimicrobial SchemeActivities 16. Synthesis of bis(1,2)dithiolo derivatives of 1,4-thiazine [31].

3. BiologicalPhenothiazines Activities and of their Thiazine novel andderivatives Benzothiazine exhibit va Derivativesluable biological activities both in vivo and in vitro. These compounds show good results against various diseases caused by bacteria, viruses, fungi,Heterocyclic mollusca, orthiazine protozoa. and The benzothiazine activities of th compouese compoundsnds are were a crucial examined part by of applying medicinal them organic on chemistryvarious organisms due to their such useful as mammals medicinal infected properties with pathogenic. The largely bacteria unexplored and viruses, heterocyclic cell lines, compounds etc. [35]. likeThe thiazines 1,3-thiazine possess moiety a variety is the functionalof pharmacological part of cephalosporins activities, ranging that are from the βantitumor,-lactam antibiotics, antipsychotic active and anti-inflammatoryagainst most Gram properties positive and on tha numbere one hand, of Gram while negative on the pathogenic pathogenic side,bacteria they [36]. are Cephalosporins 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.

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 β areMolecules the 2016-lactam, 21, 1054 antibiotics, active against most Gram positive and a number of Gram negative10 of 19 pathogenic bacteria [36]. Cephalosporins have a similar mode of action like penicillins and have anhave identical a similarβ-lactam mode of ring, action however, like penicillins there are moreand have atoms an at identical the side ringsβ-lactam as presented ring, however, in Figure there2[ 37are]. Mostmore atoms of the at penicillin-resistant the side rings as presented bacteria arein Figure sensitive 2 [37]. to Most cephalosporins, of the penicil althoughlin-resistant there bacteria are some are exceptionssensitive to [cephalosporins,37]. Bacterial resistancealthough there is a are common some exceptions problem to[37]. cephalosporins, Bacterial resistance for exampleis a common the entericproblem bacteria to cephalosporins, are resistant for to exampl almoste allthe of enteric the third bacteria and are fourth resistant generation to almost drugs all of [38 the]. Therethird and are severalfourth generation strains of Staphylococcus drugs [38]. There aureus are thatseveral are strains even resistant of Staphylococcus to the ﬁfth aureus generation that are cephalosporins even resistant liketo the ceftobiprole fifth generation and cephalosporins ceftaroline [39 ].like Therefore, ceftobipro novelle and ceftaroline strategies are[39]. being Therefore, devised novel to strategies generate futureare being generation devised to cephalosporins generate future [38 generation]. In addition cephalosporins to broad spectrum [38]. In addition activities, to 1,3-thiazinebroad spectrum and itsactivities, derivatives 1,3-thiazine contains and wonderful its derivatives properties contains like antitumor, wonderful insecticide, properties and like fungicidalantitumor,[19 insecticide,,20,40,41]. Further,and fungicidal these can [19,20,40,41]. be used as Further, anti-radiation these can agents be us ined radiation-sickness as anti-radiation [ 19agents,20,40 in,41 radiation-sickness]. The 4-hydroxy- 0 N[19,20,40,41].-(benzylidene)-2 The 4-hydroxy-H-benzo(Ne)(1,2)′-(benzylidene)-2 thiazine-3-carbohydrazideH-benzo(e)(1,2) thiazine-3-carbohydrazide 1,1-dioxides [10] compounds 1,1-dioxides possess not[10] onlycompounds antibacterial possess but not also only has radicalantibacterial scavenging but al activitiesso has radical and these scavenging properties activities are raised and whenthese moreproperties lipophilic are raised is the when compound more [lipophilic14,15]. Thus, is the such compound thiazine derivatives[14,15]. Thus, are such useful thiazine chemical derivatives tools in biochemistryare useful chemical research tools and in canbiochemistry be used in research respiratory and andcan be photosynthetic used in respiratory electron and transfer photosynthetic research whereelectron the transfer free radicals research are producedwhere the during free radicals normal are activity produced as well during as malfunction normal activity of some as pathways. well as Patelmalfunction et al. madeof some around pathways. forty Patel different et al. made 1,2-benzothiazine around forty derivatives,different 1,2-benzothiazine among which derivatives, some only exhibitedamong which antibacterial some only activity exhibited against antibacterial Gram positive activity bacteriaagainst Gram [42]. positive bacteria [42].

Figure 2. Chemical structure of the 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]. 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].

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]. Jeleńet 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 (Figure3), 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

Molecules2-(2,4-dihydroxyphenyl)thieno-1,3-thiazin-4-one 2016, 21, 1054 (BChTT) can be used to stop lung, colon and12 other of 19 types of progressing cancers and it is non-toxic to normal body cells and organs [66]. These thiazine DNAderivatives and ceased stop the the synthesis different ofcell DNA growth and stages ceased by the decreasing different cellthe growthactivity stagesof p38 bykinase decreasing and cyclin the D1activity enzymes of p38 [66]. kinase and cyclin D1 enzymes [66].

O O

NH NH

S O S O

Figure 3. ChemicalChemical structure structure of bicyclic and tricyclic thi thiazinedionesazinediones that have anticancer activity [[65].65].

Jeleń and coworkers have prepared novel tetracyclic azaphenothiazines from 6-substituted Jeleńand coworkers have prepared novel tetracyclic azaphenothiazines from 6-substituted 9-fluoroquinobenzothiazines (Figure 4) which showed inhibition of different types of blood cancer 9-fluoroquinobenzothiazines (Figure4) 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 syntheticR 1,3-thiazine compounds [68]. F F S S These thiazine analogues inhibit the activity of tyrosinase enzymes2CH3 in different kinds of cells RX 3CH CH=CH and blocking the melanin biosynthesisbase pathway, thus they possess anti-melanogenesis2 2 effects [68]. 4CH2CCH The 1,2-thiazine 1-oxidesN areN very useful for theN synthesisN of several different conjugated forms 5CH2CH2N(C2H5)2 H R 6CH CH CH N(CH ) of pyrrole and benzodiazepines1 or benzothiadiazepines2-10 that have2 antitumor2 2 3 2 properties [69,70]. The monoterpene-fused 2-imino-1,3-thiazines also exhibit anticancer7CH properties2CH(CH3)CH2 andN(CH they3)2 can be made in a few steps using green synthesis methods [71]. A combination of ruthenium II-arene fragments with 10 CH2CH2 9 CH2CH2 N 8 CH2CH2 N oxicams showed that they are useful in theN treatment of colon, breast cancers and carcinogenesis-based H C inflammations [72]. 3 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 and benzodiazepines or benzothiadiazepines that have antitumor properties [69,70]. The monoterpene- fused 2-imino-1,3-thiazines also exhibit anticancer properties and they can be made in a few steps using green synthesis methods [71]. A combination of ruthenium II-arene fragments with oxicams showed that they are useful in the treatment of colon, breast cancers and carcinogenesis-based inflammations [72].

3.6. Anti-Inflammatory Activities The thiazine alkaloids present in the New Zealand Aplidium ascidian species have anti-inflammatory activity as they have proved to inhibit neutrophil-based superoxide production [73]. Chia and colleagues made different thiazine analogues conjugated with quinolones and quinones that suppress the free radical production by neutrophils in vitro when used in small concentrations. Thus, they can be future NSAID alternatives [74]. Several thiazine derivatives mentioned above have both anti-inflammatory and analgesic activities at lower doses and are also safe at lower doses in gastrointestinal irritation [23]. Derivatives of 2-arylimino-5,6-dihydro-4H-1,3-thiazine act as cannabinoid receptor agonists for 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 thiazine ring of actual compound and one of the compounds possess oral bioavailability as well as analgesic properties [75–77]. The benzothiazepines conjugated with other thiazines were tested on neuronal receptors, where only one derivative showed inhibitory effects on the central nervous system while most of the others exhibited anti-inflammatory properties [78]. Benzothiazines are quite bioactive and this activity, mostly depends on the attached side groups [79,80]. The current oxicam medicines are chemically benzothiazines in

Molecules 2016, 21, 1054 12 of 19

DNA and ceased the different cell growth stages by decreasing the activity of p38 kinase and cyclin D1 enzymes [66].

O O

NH NH

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

Jeleń and coworkers have prepared novel tetracyclic azaphenothiazines from 6-substituted 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 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

Moleculesshould be2016 considered, 21, 1054 and further trials need to be done on them so that they can come early 13to ofthe 20 market and we can control the plight of cancer in our society.

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

10 CH2CH2 9 CH2CH2 N 8 CH2CH2 N N H3C

Figure 4. Synthesis of tetracyclic azaphenothiazineazaphenothiazine 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 blockingThe the thiazine melanin alkaloids biosynthesis present pathway, in the thus New they Zealandpossess anti-melanogenesisAplidium ascidian effects species [68]. have The anti-inflammatory1,2-thiazine 1-oxides activity are very as theyuseful have for provedthe synthe to inhibitsis of several neutrophil-based different co superoxidenjugated forms production of pyrrole [73]. Chiaand benzodiazepines and colleagues or made benzothiadiazepines different thiazine that analogues have antitumor conjugated properties with quinolones[69,70]. The andmonoterpene- quinones thatfused suppress 2-imino-1,3-thiazines the free radical also production exhibit anticancer by neutrophils propertiesin vitroand theywhen can used be made in small in a concentrations.few steps using Thus,green synthesis they can methods be future [71]. NSAID A comb alternativesination of ruthenium [74]. Several II-arene thiazine fragments derivatives with oxicams mentioned showed above that havethey are both useful anti-inflammatory in the treatment andof colon, analgesic breast activities cancers and at lowercarcinogenesis-based doses and are inflammations also safe at lower [72]. doses in gastrointestinal irritation [23]. Derivatives of 2-arylimino-5,6-dihydro-4H-1,3-thiazine act as cannabinoid3.6. Anti-Inflammatory receptor agonistsActivities for 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 (Figure5) 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. Molecules 2016, 21, 1054 13 of 19 nature (Figure 5) and they are second generation non-steroidal drugs that act as an anti-inflammatory agent [79,80]. The current medicinal use of oxicams is restricted due to their adverse effects, although a number of research efforts were done to increase their potency against inflammatory conditions with lower side effects [79,80]. Xu et al. resolved the crystal structure of cyclooxygenases in binding mode with oxicam compounds at 2–2.45 Å resolution [81,82]. The oxicam compounds bind inside the active site of cyclooxygenases through two water-mediated hydrogen bonds and this mode of interaction is different from that of other NSAIDs [81,82]. There is a hydrogen bonding interaction between the 4-OH group of thiazine and serine-530 of the cyclooxygenase while 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]. TheseMolecules fragment2016, 21, 1054 based ligands can also be used as possible covalent inhibitors and should be studied14 of 20 on different enzymes involved in various diseases.

Figure 5. Chemical structure of the oxicam 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. Antidiabetic Activities Aldose reductase reductase is considered is considered to be toone be of th onee key of enzymes the key involved enzymes in diabetic involved complications in diabetic [90–93]complications and that [90 is– 93why] and it is that a suitable is why drug it is a target suitable for drug diabetic target treatment for diabetic [94]. treatmentFor this purpose [94]. For some this 1,2-benzothiazinepurpose some 1,2-benzothiazine 1,1-dioxide acetic 1,1-dioxide acid derivati aceticves acidwere derivatives synthesized were and synthesized tested against and aldose tested reductase,against aldose among reductase, them the amongdouble halogenated them the double benzen halogenatede analogues benzeneshowed the analogues most promising showed inhibition the most capacitypromising [94,95]. inhibition The structure capacity activity [94,95]. relationsh The structureip and activity molecular relationship docking and of these molecular compounds docking with of aldosethese compounds reductase showed with aldose that saturated reductase carboxylic showed that acid saturated have a higher carboxylic binding acid affinity have a for higher the enzyme binding asafﬁnity compared for the to enzyme the unsaturated as compared carboxylic to the unsaturatedacid [94,95]. carboxylic acid [94,95].

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

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