international journal of research in pharmaceutical ...formation. the thiazines are of great...

Razia sultana et al., (2018) Int. J. Res. Pharm. Chem & Analy., 1(1), 25-35

© Rubatosis Publications | International Journal of Research in Pharmaceutical Chemistry and Analysis 25

International Journal of Research In Pharmaceutical Chemistry and Analysis

Synthesize, characterize and evaluation of anti-bacterial and anti-fungal activity of thiazines

Razia Sultana*1, Arsalan Sarmad2, B. Syed Salman3 1Department of Pharmaceutical chemistry, 2Department of Pharmacology, 3Department of Pharmaceutics, Global college of pharmacy, Moinabad, Hyderabad, India. ABSTRACT

1,3–Thiazineshavebeenappliedasusefulstartingmaterialsinthestereoselectivesynthesisofcompoundsofpharmacologicalinterestandtheyhaveservedaschiralligantsandauxiliariesinenantioselectivetrans-formation.ThethiazinesareofgreatimportancebecausetheyactasprecursorforthesynthesisofCepha-losporins (3,6-dihydro-2H-,1,3-thiazine) and then converted to the thiazine derivatives (an heterocycliccompounds).Therefore, itwasthoughttocombinechalconesmoietytothiazinederivativetogether inamolecularframeworktoseethebiologicalactivities,additiveeffortoftheseringstowardsbiologicalactiv-itieslikeAnti-bacterialandAnti-fungalactivities.

Keywords:Thiazines; 1,3–Thiazines;Cephalosporins;anti-bacterial;anti-fungal.

INTRODUCTION

Thiazines a heterocyclic compound having fourcarbon atoms and one nitrogen atom and sulphuratom at varied positions in the sixmembered ringexist as 1,2- thiazine,1,3-thiazine and 1,4- thiazineand subsequently their derivatives having N-C-Slinkage have been used as anti-tubercular, anti-bacterial, anti-microbial, anti-tumor, insecticidal,fungicidal, herbicidal agents, transquilizers andvarious dyes etc[5-7], anti-parkinsonian[8], calciumchannel modulators, Anti- pyretic, anti-mycobacterialagents,CannabinoidreceptoragonistsandAnti-Oxidantagents.

Theheterocycliccompoundswhichcontainnitrogenandsulphurpossesanenormoussignificanceinthefieldofmedicinalchemistry.Manyresearchershavesynthesized different thiazines derivatives thatexhibit various biological activities such as anti-tubercular,anti-fungal,anti-bacterial,analgesic,anti-inflammatory etc. Some thiazine derivatives in thedevelopment phase due to their versatility of thethiazine skeleton, it’s chemical simplicity andaccessibility. Many compounds of thiazines wereknownasphenothiazines.Phenothiazinesareusedasvermifugeforlivestockandalsoasaninsecticide.[11]

The ability to treat bacterial infections whichchemotherapeuticagentsrepresentsoneofthemostimportant medical achievement of the lastmillennium.Unfortunately theemergenceofmicro-organismsresistanttoanti-bacterialagentshasbeencontinuedtothepresentday.Itwaswellknownthatbacteriaproducebeta–lactamasesandtheseenzymeshad the natural role of destroying beta–lactamantibiotics. The latest twist to this increasinglyalarming situation has been the recent isolation ofmethicillin resistant strains of Staphylococcusaureus.

The fungal diseases of humans are mainly dividedintothreegroups.Thefirsttypeisdermatophytosescaused by epidermaphyton species, microsporiumspeciesandtycophytonspeciesconsistofcontagioussuperficial skin infections that are limited to theepidermal region. The second type is CandidiasiscausedbyCandida species canaffect the skin,nailsandmucousmembranes and occasionally becomessystemic.Thethirdtypeissubcutaneous,pulmonary,lymphatic and systemic mycoses caused by

ISSN: Awaiting Research Article

Corresponding Author

Name: Razia sulthana Email: [email protected]

Article Info

Received on: 13-07-2018 Revised on: 19-07-2018 Accepted on: 20-07-2018

Copyright© 2018, Razia sulthanan, et al. Synthesize, characterize and evaluation of anti-bacterial and anti-fungal activity of thiazines, Production and hosting by Rubatosis Publica-tions. All rights reserved.


26 © Rubatosis Publications | International Journal of Research in Pharmaceutical Chemistry and Analysis

Aspergillus species and Candida species invade theskin, lungs, lymphatic tissue and various organs ofsusceptible hosts who have accidentally been incontact with the fungal environment. There areincreasingdetectionofsystemicmycosesinpatientssufferingfromdelilitatingdiseasessuchasneoplasiasinpersonsonlongteamparenteralnutrition.

Additionally, conditions that depress cell mediatedimmunity, such as the latter half of pregnancy,excessive use of corticosteroids andimmunosuppressive and defects in thymus glandtissue, results in marked enhancement ofsusceptibility to serious fungal diseases. Manyremedies have been used against fungal infectionsbut the ideal Anti-fungal agents has not yet beenfound.

The 1,3-thiazine nucleus is active core ofCephalosporinwhichareamongthewidelyusebeta-lactam anti- biotics. A large group of dyes hasphenothiazine structure, including methylene bluethiazine are used for dyes, transquilizers. Thiazinecanhelp toreducesomeof thatextrawaterweightyoumaybeholdingon to in stomach.Thiazine isafairlybasicdiureticsupplement,itreduceswaterandincreasevascularity,soitisuseasanabolicagentinmedicine.[12]

MATERIALSANDMETHODS

Chemicals:Ethanol,Cyclohexane,Benzaldehyde,Po-tassiumhydroxide, Sodiumhydroxide, Thiourea,Dimethyl formamide, Ethyl acetate, Benzene, Chloro-form,Agar-Agar,Sodiumchloride,Beefextract,Pep-tone.

Preparation of 2, 6-di Benzelidene Cyclohexa-none

Themechanisminvolvedinthepreparationofchal-conesisbyClaisenSchmidtreaction.Thereactionbe-tweenanaldehyde(R-CHO)orketone(R=O)andanaromatic carbonyl compound lacking an Alpha-hy-drogeniscalledtheClaisenSchmidtreaction.Amix-tureof30mlof10%sodiumhydroxide,50mlofeth-anoland0.01molofcyclohexanoneplacedina250mlbeaker,whichwasimmerseinicebathaswellasequippedwithamechanicalstirrer.Thestirrerwasstarted,0.02molofbenzaldehydewasaddedtothemixture and stirring continued. After 2 hours, thestirrerwas removed and the reactionmixturewaskept in an ice cold overnight. The product was fil-tered, washedwith ice cold water, followed by icecold ethanol, dried and recrystallised fromDMF orethanol.

Figure 1: Preparation of 2, 6-di Benzelidene Cyclohex-

anone

Recrystallizationforsynthesizedchalcone

Theproductorsample is taken inaconical flasktothisaddquantitysufficientofethanoluntilitgetsdis-solveonheating,filtertheproducttoremovetheim-puritiesinthepresenceofheating,andcoolthesolu-tion, yellow colour needle shape crystals are ob-tained.[38]

Preparation of 2- Imino-8-benzylidene-4-phenyl5,6-dihydro-4H,7H-(3,1)benzothiazine

Amixtureof0.01molof2,6-dibenzylidene-cyclohex-anone0.015molofthioureaand0.01molofpotas-siumhydroxidedissolvedin10mlofwaterwasre-fluxedinethanolfor16hours.Laterethanolwasre-movedunderreducedpressureandtheresiduewastreatedwithicecoldwater.Theprecipitatethusob-tainedwasfiltered,washedwithwater,driedandre-crystallizedfromethanol.

Figure 2: Preparation of 2- Imino-8-benzylidene-4-

phenyl 5,6-dihydro- 4H, 7H- (3,1) benzothiazine

Recrystallizationforsynthesizedthiazine

Theproductorsample is taken inaconical flasktothisaddquantitysufficientofethanoluntilitgetsdis-solveonheating,filtertheproducttoremovetheim-puritiesinthepresenceofheating,andcoolthesolu-tion yellow colour needle shape crystals are ob-tained.[38]

Anti–bacterialActivity

Methodfollowed-Agardiffusionmethod.

WorkingProcedure-Stocksolutionsofthesynthe-sizedcompoundsandstandarddrugsusedwerepre-pareddimethylsulfoxide taken in the concentrationofµg/0.1ml.

Cyclohexanone Benzaldehyde 2,6-dibenzelidene

cyclohexanone



Microorganisms used-Standard cultures of grampositivebacteriaStaphylococcusaureusandBacillussubtilusandgramnegativebacteriaEscherichiacoliand Pseudomonas aeruginosa species were taken.Themicroorganismswereidentifiedbyvariousstain-ing techniques and bio-chemical reactions. Themi-croorganismsweremaintainedbysub-culturingandusedatregularintervalsinnutrientagarmedium.

Preparationofinoculum-Thesuspensionofalltheorganisms were prepared as per Mac-FarlandNephlometerstandard(BailyandScott1990).A24houroldculturewasusedforthepreparationofbac-terial suspension. Suspensions of organisms weremade insterile isotonicsolutionofsodiumchloride(0.9%w/v)andtheturbiditywasadjusted.

Preparationofassaymedium

Beefextract4.0,Peptone5.0,Agar20.0,Distilledwa-ter1000ml,mentionedquantitiesofdifferentingre-dientswereaccuratelyweighedanddissolvedinap-propriate amount of distilled water. Media so pre-paredwas sterilizedbyautoclavingat120°c for15minutes.ThepHshouldbemaintainedat5.4.

Procedure: The Petri dishes were thoroughlywashed and sterilized in hot air oven at 160°c for1hour.Inoculumwasaddedto30mlofsterilenutri-entagarmediumandwaspouredintopetridishesforsolidifying. Boresweremade on themediumusingsterilebore.0.1mloftestsolutionwasaddedtotherespectivebore,0.1mloftheampicillinataconcen-trationof100µg/0.1mlwastakenasstandardrefer-ence. A control having only DMSO in the cup wasmaintainedineachplate.ThePetridisheswerekeptintherefrigeratorat4°cfor15minutesfordiffusiontotakeplace.Afterdiffusion,thepetridisheswerein-cubatedat37°c for24hoursandzoneof inhibitionwereobservedandmeasuredusingascale.Antibac-terial Activity of the compound was carried outagainstallfourmicroorganisms.Thesamemediawasusedforsub-culturingandforestimatinganti-bacte-rialactivity.

Anti-fungalActivity

Workingprocedure-Stock solutionsof the synthe-sizedthiazinesandstandarddrugwerepreparedinDMSOintheconcentrationof100µg/0.1ml.

Fungi used-Standard cultures of Candida albicansand Aspergillus niger were taken. The fungi weremaintainedbysubculturingandusedatregularinter-vals.

Sabourd’sagarmedium:40mgofSucrose,10mgofPeptone, 20mg of Agar, 1000ml ofDistilledwater,Thismediumwas found forboth sub-culturingandalsoforestimatingtheantifungalactivity.ThepHofthemediumplaysanimportantroleforthegrowthoffungi.Acidicmediumfavoursthegrowthbutexcessofacidmaynotcomeagartosolidify.HencethepHof

amediumwasadjustedusing0.1%lacticacid.ThepHshouldbemaintainedat5.6.

Preparation of assay medium: The mentionedquantitiesofadifferentingredientswereaccuratelyweighed anddissolved inwater. Thepreparedme-dium was sterilized in autoclave at 1210c for 15minutes.

Workingprocedure:Aninoculumwaspreparedbysuspendingasingleisolatedcolonyinabout5mlofnormal saline This is mixed slowly to achieve asmoothsuspension.Lateronedropoftween20wasaddedforfilamentousfungiandthemouldwasbro-kenbyshaking.Asterilecottonswabwasmoistenedintheinoculumssuspensionandexcessofmoisturewasremovedbyrollingthecottonswabontheinsideof the tube, above fluid level 30 ml of sterile hotSabouraud’sagarmediumwaspouredineachplateandallowtohardenonalevelsurface.ThesurfaceofSabouraud’s agarmedium plate was streakedwiththehelpofmoistenedcottonswabinallthedirectionions.ThesurfaceofSabouraud’sagarplatewasdriedout 350C. Later 5 bores per plateweremadeusingsterilecorkborer.Theaboveoperationwascarriedoutinasepticconditionand0.1mltestsolutionwasaddedtotherespectiveboreand0.1mlAmphotercinwas taken as standard reference. A control havingonlyDMSOwasmaintainedineachplate.Theplatesareincubatedat350cfor48hours.Laterthevaluesofzonesofinhibitionwererecorded.[41-50][13]

RESULTSANDDISCUSSION

Thinlayerchromatography

Solventfront=4.7cm

Spot1:Chalcone=4.2cmRf=0.93

Spot2:Thiazine=4.3cm,Rf=0.91

Antibacterialactivity:structuralactivityrelation-ship

TheantibacterialactivityofnewlysynthesizedChal-cone or 2,6-dibenzylidene cyclohexanone and thia-zine derivativeswere evaluated against gram posi-tivebacteriathatisStaphylococcusaureusandBacil-lussubtilisandgram-negativebacteriathatisEscher-chiacoliandPseudomonasaeruginosa.ThestandarddrugusedasAmpicillin.

Thezoneofinhibitionshownbythecompound2,6-dibenzylidenecyclohexanoneorChalconeagainstBa-cilliussubtilisis17mm.Amongallthecompounds2-imino-8-benzylidine-4–phenyl-5,6-dihydro4H,7H(3,1)benzothiazineis21mm,hadshownhigh-estzoneofinhibitionindicatingthatintroductionofgroupssuchasN&SenhancestheactivityagainsttheBacillussubtilius.



Table 1: Characteristic of Cyclohexanone and 2,6-dibenzylidene cy-clohexanone

S.no Name of the com-pounds Characteristic

UV Cyclohexanone 287 nm

UV 2,6-dibenzylidene cy-clohexanone 328.5 nm

IR (δmax)

2,6-dibenzylidene cy-clohexanone 1660 cm-1 (C=O)

IR (δmax)

2,6-dibenzylidene cy-clohexanone 1656 cm-1 (C=O)

NMR 2,6-dibenzylidene cy-clohexanone

δ7.2-7.5(10H, ArH), δ7.6 (1H, proton of benzylidene group), δ7.8(1H, proton of benzylidene group), δ3.5 (1H, proton of C-3), δ2.9-3.1(2H, pro-

ton of C-5), δ1.6-1.9(2H, proton of C-4)

UV 2-imino-8-benzyli-

dene-4-phenyl-5,6-di-hydro-4H,7H-(3,1)

benzothiazine

284 nm

IR

2-imino-8-benzyli-dene-4-phenyl-5,6-di-

hydro-4H,7H-(3,1) benzothiazine

3300-3450 (=NH), 3100-3250 (NH), 1678-1681 (C=N), 1370-1380 (C-N), 1570-1580 (Aromatic)

NMR 2-imino-8-benzyli-


benzothiazine

δ7.3-7.5 (10H, ArH), δ7.6 (1H, proton of benzylidene group), δ6.6 (1H, proton of imino group), δ6.8 (1H, proton of =NH group), δ5.0 (1H, proton of S-CH group), δ3.3 (1H, proton of C-7) δ1.8-2.8 (2H, protons of C-5),

δ1.3-1.4(3H, protons of C-6)

Mass 2-imino-8-benzyli-


benzothiazine

M+331 m/e 303,269,242,91,77

Figure 3: UV spectrum of Cyclohexanone and 2,6-dibenzylidene cyclohexanone



Figure 4: Mass spectrum of Cyclohexanone

Figure 5: Mass of 2,6-dibenzylidene cyclohexanone



Figure 6: NMR spectrum of 2,6-dibenzylidene cyclohexanone

Figure 7: NMR spectrum of Cyclohexanone



Figure 8: IR spectrum of Cyclohexanone

Figure 9: IR spectrum of 2,6-dibenzylidene cyclohexanone

Table 2: Antibacterial activity of Compounds

Sl.no Name of the Compound

Zone of inhi-bition of ba-cillus subtilis

Zone of inhibi-tion of staphylo-

coccus aureus

Zone of inhi-bition of esch-

erichia coli

Zone of inhibi-tion of pseudo-

monas aeru-ginosa

1 2,6-dibenzylidene cy-clohexanone 17 15 12 13

2 2-imino-8-benzylidene-4-phenyl-5,6-dihydro-4h,7h-(3,1) benzothia-

zine

21 18 15 17

Con-trol Dmso - - - -

Std Ampicillin 37 30 32 31

Table 3: Antifungal activity of Compounds

S.no Name of the compound Zone of inhibition of candida albicans

Zone of inhibition of aspergillus niger

1 2,6-dubenzylidene cyclohexanone 13 14

2 2-imino-8-benzylidene-4-phenyl-5,6-dihy-dro-4h,7h-(3,1) benzothiazine 15 18

Control Dmso - - Stand-

ard Amphotericin b 19 17



The zone of inhibition exhibited by the compoundagainststaphylococcusaureus is15mm.AmongallthecompoundsonederivativethatishadshowntheactivityagainstStaphylococcusaureusindicatingtheintroductionofnitrogenandsulphurinenhancestheactivity.

The zones of inhibition shown by the compoundagainstEscherchiacoliandPseudomonasaeruginosa

are12and13mmrespectively.Amongallthecom-pounds exhibited maximum zones of inhibitionagainstEscherchiacoliandPseudomonasaeruginosaby15and17mmrespectively, indicatingthe intro-ductionofnitrogenandsulphurinenhancestheac-tivityagainstgramnegativebacteria.

The synthesized compound 2-imino-8-benzylidene-4-phenyl-5,6-dihydro-4H,7H-(3,1)benzothiazine

Figure 10: fragmentation pattern of 2-imino-8-benzylidene-4-phenyl-5,6-dihydro-4H,7H-(3,1) benzothiazine

Figure 11: Preparation of 2-imino-4-benzylidene-4-phenyl-5,6-dihydro-4H,7H-(3,1) benzothiazinefrom cyclo-

hexanone



shown anti-bacterial activity but none of themhadgreateractivitythanstandardreference,Ampicillin.

Anti-fungal activity: structure activity relation-ship

TheantifungalactivityofnewlysynthesizedchalconeandthiazinederivativeswereevaluatedagainsttwofungithatisCandidaalbicansandAspergillusniger.ThestandardreferencedrugwasAmphotericinB.

Thezoneofinhibitionshownbythecompound2,6-dibenzylidene cyclohexanone against Candida albi-cans is 13mm. The compound 2-imino-8-benzyli-dene-4-phenyl-5,6-dihydro-4H,7H-(3,1) benzothia-zineis15mmandhadshownthehighestzoneofin-hibition indicating that the introductionofnitrogenandsulphurenhancestheactivity.

Thezoneof inhibitionshownby thecompoundAs-pergillusniger is 15mm.The compound2-imino-8-benzylidene-4-phenyl-5,6-dihydro-4H,7H(3,1) ben-zothiazineis18mmandshownthemaximumactivityagainstAspergillusnigerindicatingtheintroductionofnitrogenandsulphurindicatingthatintroductionofnitrogenandsulphurenhancestheactivity.

The thiazine had shown the antifungal activityagainst Candida albicans and Aspergillus niger butnoneofthecompoundshadgreaterpotencythanthestandardreference,AmphotericinB

DISCUSSION

Thecompound2,6-dibenzylidenecyclohexanonehasbeenpreparedbycondensingonemoleofcyclohexa-nonewithtwomolesofbenzaldehyde.Theformationof 2,6-dibenzylidene cyclohexanone has been indi-catedbyitsUVspectrum.Thestartingmaterialcyclo-hexanone exhibited λmax at 287 nm. The compound2,6-dibenzylidene cyclohexanone exhibited λmax at328.5nm.Thisclearlyindicatethatthebathochromicshiftmaybeattributedbecauseof=CH-ARchromo-phore.

Thecompound2,6-dibenzylidenecyclohexanonehasbeenindicatedbyitsinfraredspectraspectrum.Thestartingmaterial exhibit γmaxat1680 cm-1due toC=Ogroup.Theappearanceof2,6-dibenzylidenecy-clohexanoneexhibitedγmaxat1660cm-1duetoC=Ogroup. The appearance of a characteristic bond atC=Oismainlyduetoα,β,andα’,β’unsaturation.Thisclearly indicate the formation of 2,6-dibenzylidenecyclohexanone.

The formation of 2,6-dibenzylidene cyclohexanonehasalsobeenindicatedbyitsnuclearmagneticreso-nancespectrum.Thepresenceofsignalsatδ7.2-7.5(10H,aromaticprotons,δ7.6(1H,protonofbenzyli-denegroup),δ7.8(1H,protonofbenzylidenegroup),δ3.5(1H,protonofC-3),δ2.9-3.1(2H,protonsofC-5)andδ1.6-1.9(2H,protonsofC-4)clearlyindicatetheformationof2,6-dibenzylidenecyclohexanone.

The compound 2- imino-8-benzylidene-4-phenyl-5,6-dihydro-4H,7H-(3,1)benzothiazinehasbeenpre-paredbycyclocondensationof2,6-dibenzylidenecy-clohexanonewiththioureainthepresenceofpotas-siumhydroxide.Theformationof2-imino-8-benzyl-idene-4-phenyl-5,6-dihydro-4H,7H-(3,1) benzothia-zinehasbeenindicatedbyitsUVspectrum.Thecom-pound 2,6-dibenzylidene cyclohexanone exhibitedλmaxat328.5nm.Thecompound2-imino-8-benzyli-dene-4-phenyl-5,6-dihydro-4H,7H-(3,1) benzothia-zineexhibitedλmax284nm.Thisclearlyindicatethatthehypsochromicshiftmaybeattributedbecauseofcyclocondensation.

The formation of 2-imino-8-benzylidene-4-phenyl-5,6-dihydro-4H,7H-(3,1)benzothiazinehasbeen in-dicatedbyitsinfraredspectrum.Thecompound2,6-dibenzylidenecyclohexanoneexhibitedacharacter-isticbondat1660cm-1(C=O).Theabsenceof1660cm-1 and presence of 3411 (=NH) and 3203 (=NH)clearly indicate the formationof 2-imino-8-benzyli-dene-4-phenyl-5,6-dihydro-4H,7H-(3,1) benzothia-zine.Theformationof2-imino-8-benzylidene-4-phe-nyl-5,6-dihydro-4H,7H-(3,1)benzothiazine has alsobeen indicated by its nuclear magnetic resonancespectrum.Thepresenceof signalsatδ7.3-7.5 (10H,aromaticprotonofbenzylidenegroup),δ6.6(1H,pro-tonofiminogroup),δ6.8(1H,protonof=NHgroup),δ5.0(1H,protonofS-CHgroup),δ3.3(1H,protonofC-7),δ1.8-2.8(2H,protonsofC-5),δ1.4-1.5(2H,pro-tonsofC-6)clerlyshowtheformationof2-imino-8-benzylidene-4-phenyl-5,6-dihydro-4H,7H-(3,1) ben-zothiazine.

The formation of 2-imino-8-benzylidene-4phenyl-5,6-dihydro-4H,7H-(3,1)benzothiazinehasalsobeenconfirmedby itsmassspectrum.Themolecular ionpeak of 2-imino-8-benzylidene-4-phenyl-5,6-dihy-dro-4H,7H-(3,1) benzothiazine has been at 331,whichisingoodagreementwiththecalculatedmo-lecularweightof thecompound.Theprobable frag-mentation pattern of 2-imino-8-benzylidene-4-phe-nyl-5,6-dihydro-4H,7H-(3,1)benzothiazinehasbeendepictedasshownbelow.

CONCLUSION

ThemethodfollowedforthesynthesisofChalcone/2,6-dibezylidene cyclohexanone is by ClaisenSchmidtreactionandtheyieldwasfoundtobe2.67grams.ThemethodfollowedforthesynthesisofThi-azine/2-Imino8-benzylidene-4-phenyl-5,6-dihydro-4H,7H-(3,1) benzothiazine is by Michael additionmechanismandtheyieldwasfoundtobe3.43grams.TheAnti-microbialactivitysuchasAnti-bacterialac-tivity and Anti- fungal activity of Chalcone/ 2,6-dibenzylidene cyclohexanone was evaluated. TheAnti-microbialactivitysuchasAnti-bacterialactivityandAnti- fungal activity of Thiazine or 2- Imino-8-benzylidene-4-phenyl-5,6-dihydro-4H,7H-(3,1) ben-zothiazinewasevaluated.



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international journal of research in pharmaceutical ...formation. the thiazines are of great...

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