Synthesisofglycosylated-1,2,4-thiadiazolidinesaspotentantimicrobialagents

 

SnehaU.Jadhao^*, ShirishP.Deshmukh

DepartmentofChemistry,ShriShivajiCollege,Akola-444001

*CorrespondingAuthorE-mail:jadhaosneha2@gmail.com

Aseriesof4-aryl-2-b-D-glycosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidineshavebeenpreparedbytheinteractionof1-b-D-glycosyl-3-arylcarbamideswithN-o-tolyl-S-chloroisothiocarbamoylchloride.ThenewlysynthesizedcompoundshavebeencharacterizedthroughusualchemicaltransformationsandIR,¹HNMRandMassspectralstudies.Thepolarimetricstudyofthetitlecompoundshavebeencarriedout.Thenewlysynthesizedcompoundswerescreenedfortheirinvitroantimicrobialactivitiesusingstandardcupplatemethod.Thetitlecompoundsexhibitedmildtomoderateantimicrobialactivities.

 

 

 

INTRODUCTION:

Heterocyclicstructures,inparticularazolesandazines,formthebasisofmanypharmaceuticalandagrochemicalproducts.Therearenumerousbiologicallyactivemoleculeswithfivememberedrings,containingthreeheteroatoms^1-2.Theheterocyclicderivativesofsugarpossessantibacterialandantitumoractivities³.1,2,4thiadiazolesareanimportantclassofheterocycles.The1,2,4thiadiazolesshowwiderangeofbiologicalactivities,duetothepresenceoftoxophoricN-C-Smoiety⁴.

 

1,2,4thiadiazolesareexceedinglypotentinhibitorsofhumanimmunodeficiencyvirus1HIV-1replication⁵,antibioticactivity⁶,antitumor,analgesicactivityandanti-inflammatoryactivity,antihelicopbacterpylori-activityandvariousCNSactivity⁷.

 

Keepingthisinview,weexplorethesynthesisandcharacterizationofsomenewN-glycosylthiadiazolidines(IIIa-dandVa-d).

 

MATERIALANDMETHODS:

MATERIAL:

Thereagentgradechemicalswereobtainedfromcommercialsourcesandpurifiedbyeitherdistillationorrecrystallizationbeforeuse.

 

METHODS:

Conventionalmethodemployedinthepresentexperimentsforthesynthesisof4-aryl-2-b-D-glycosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidines.

 

EXPERIMENTAL:

MeltingpointsofallsynthesizedcompoundsweredeterminedusingopencapillarytubeonMacdigitalmeltingpointapparatusandwereuncorrected.IRspectrawererecordedinsolidphaseKBrdisksonShimadzu IRaffinity-1FTIRspectrometerand1HNMRspectrainDMSO-d6onAdvance LL400NMRspectrometer400MHz.TheMassspectrawererecordedonWATERS,QTOFMicromass (LC-MS)instrument.OpticalrotationsweremeasuredonEquip-TronicsEQ801DigitalPolarimeterinDMSO.Purityofsynthesizedcompoundshasbeencheckedbythinlayerchromatography.ItwasperformedonE.Merckpre-coatedsilicagelplates.

 

GENERALPROCEDURE:

PreparationofN-o-tolyl-S-chloroIsothiocarbamoylchloride(I):

TherequiredN-o-tolyl-S-chloroIsothiocarbamoylchlorideusedwaspreparedbyalreadywell-knownprocedure⁸i.e.bypassingcalculatedquantityofgaseouschlorineintothechloroformicsolutionofo-tolylisothiocyanate.

 

Preparationof1-β-D-glycosyl-3-arylcarbamides(IIa-dandIIIa-d):

Inthetypicalpreparationof1-β-D-glycosyl-3-arylcarbamides⁹.Theinteractionofglycosylaminesandarylisocyanateshavebeencarriedoutinpyridinemediumatroomtemperaturefor24h.Afterwards,solventwasdistilledoffandstickyresiduewastrituratedseveraltimeswithpetroleumether(60-80^oC)toaffordawhitesolid.Theproductwaspurifiedfromchloroform-petroleumether.

Synthesisof4-aryl-2-b-D-glycosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidines(IVa-dandVa-d):

Achloroformicsolutionof1-β-D-glucosyl-3-phenylcarbamides(0.001M,0.298gin10ml)wasmixedwithchloroformicsolutionofN-o-tolyl-S-chloroIsothiocarbamoylchloride(0.001M,0.22gin10ml)andmixturewaskeptatroomtemperaturefor24h.Afterwards,thesolventwasdistilledofftoobtainstickyresidue.Thisresiduewaswashedseveraltimeswithpetroleumether(60-80°C)toremoveexcessofchlorine.Thenitwasdissolvedinethanolandbasifiedbyusingdil.ammonia,theproductwasisolatedasfreebase(IVa).Theproductwascrystallizedfromethanol,puritywascheckedbyTLC,m.p.174°C.

 

Similarly,thereactionsofN-o-tolyl-S-chloroIsothiocarbamoylchloride(I)wasextendedto1-β-D-glycosyl-3-arylcarbamides((IIb-dandIIIa-d)andcorresponding4-aryl-2-β-D-glycosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidines(IVb-dandVa-d)havebeenisolated.Theelementalanalysis,%yield,m.p.,opticalrotationandRfvaluesareshowninTable1.

 

 

Thereactionschemeisasfollows

Scheme

 

Table1:PhysicalCharacterizationof4-aryl-2-β-D-glycosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidines(IVa-dandVa-d)

 

InvitroAntimicrobialactivity:

Theantimicrobialactivityofnewlysynthesizedcompoundsweretestedinvitroagainstaselectedgrampositive,gramnegativeandfungiarepresentedinTable2usingcupplateagardiffusionmethod^10-11bymeasuringtheinhibitionzoneinmm.ThecompoundswerescreenforantibacterialactivityagainstEscherichiacoli,Staphylococcusaureus,KlebsiellapneumoniaeandPseudomonasaeruginosabyusingMulerHintonagarmediumandantifungalactivityagainstAspergillusnigerandTrichodermavirideweredeterminedbyusingPotatoDextroseAgarmedium.Thecompoundsweretakenataconcentrationof1mg/mLusingDimethylSulphoxide(DMSO)assolvent.Amikacin(100μg/mL)wasusedasstandardforantibacterialactivityandFluconazole(100μg/mL)asstandardforantifungalactivity.TheresultsarepresentedinTable2.

 

RESULTANDDISCUSSION:

ThesynthesisoftitlecompoundswasaccomplishedbyreactingN-o-tolyl-S-chloroIsothiocarbamoylchloridewith1-β-D-glycosyl-3-arylcarbamidesinchloroformfor24h.TheprogressofthereactionwasmonitoredbyTLC.TheresultingtitlecompoundsIVa-dandVa-dwereobtainedinhighyield.ThechemicalstructuresofthetitlecompoundsIVa-dandVa-dwerededucedbyIR,¹HNMR,massspectralanalysis^12-14andelementalanalysis,theresultsofwhicharegivenbelow:

 

SpectralCharacterization:

4-phenyl-2-b-D-glucosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidine(IIIa)

IR(KBr,cm^-1):υ3298(O-H),3041(ArC-H),2922(AliC-H),1734(C=O),1651(C=N),1294(C-N),1232(C-O),1051and904(characteristicofglucose),750(C-S).¹HNMR(DMSO-d₆,ppm):δ8.18-6.17(9H,m,Ar-H),4.97-4.26(4H,m,OH),3.66-3.09(7H,m,glucosylringproton),2.52(3H,s,CH₃).Mass(m/z):459(M⁺),444,382,368,296.Anal.CalcdforC₂₂H₂₅N₃O₆S:C,57.50;H,5.48;N,9.14;S,6.98foundC,57.46;H,5.43;N,9.01;S,6.95%.

 

 

 

4-phenyl-2-b-D-galactosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidine(IIIb):

IR(KBr,cm^-1):υ3308(O-H),3044(ArC-H),2930(AliC-H),1731(C=O),1645(C=N),1296(C-N),1230(C-O),1041and908(characteristicofgalactose),752(C-S).¹HNMR(DMSO-d₆,ppm):δ8.16-6.29(9H,m,Ar-H),4.95-4.30(4H,m,OH),3.67-3.11(7H,m,galactosylringproton),2.54(3H,s,CH₃).Mass(m/z):459(M⁺),444,382,368,296.Anal.CalcdforC₂₂H₂₅N₃O₆S:C,57.50;H,5.48;N,9.14;S,6.98foundC,57.42;H,5.45;N,9.10;S,6.93%.

 

4-phenyl-2-β-D-lactosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidine(IIIc):

IR(KBr,cm^-1):υ3431(O-H),3010(ArC-H),2918(AliC-H),1734(C=O),1647(C=N),1301(C-N),1247(C-O),1018and948(characteristicoflactose),754(C-S).¹HNMR(DMSO-d₆,ppm):δ8.29–6.92(9H,m,Ar-H),4.98–4.28(7H,m,OH),3.86-3.28(14H,m,lactosylringproton),2.066(3H,s,CH₃).Mass(m/z):607(M⁺),592,587,567,450.Anal.CalcdforC₂₇H₃₃N₃O₁₁S:C,53.37;H,5.47;N,6.92;S,5.28foundC,53.34;H,5.42;N,6.89;S,5.25%.

 

4-phenyl-2-β-D-maltosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidine(IIId):

IR(KBr,cm^-1):υ3432(O-H),3015(ArC-H),2928(AliC-H),1730(C=O),1648(C=N),1306(C-N),1250(C-O),1019and947(characteristicofmaltose),754(C-S).¹HNMR(DMSO-d₆,ppm):δ8.28–6.89(9H,m,Ar-H),4.96–4.24(7H,m,OH),3.88-3.26(14H,m,maltosylringproton),2.47(3H,s,CH₃).Mass(m/z):607(M⁺),592,587,567,450.Anal.CalcdforC₂₇H₃₃N₃O₁₁S:C,53.37;H,5.47;N,6.92;S,5.28foundC,53.31;H,5.45;N,6.91;S,5.22%.

 

4-o-tolyl-2-β-D-glucosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidine(Va):

IR(KBr,cm^-1):υ3345(O-H),3041(ArC-H),2887(AliC-H),1733(C=O),1648(C=N),1315(C-N),1149(C-O),1048and921(characteristicofgalactose),768(C-S).¹HNMR(DMSO-d₆,ppm):δ8.08-6.89(9H,m,Ar-H),5.05-4.10(4H,m,OH),3.99-3.08(7H,m,galactosylringproton),2.54and2.25(3H,s,2CH₃).Mass(m/z):512(M⁺),492,430,416,382.Anal.CalcdforC₂₂H₂₇N₃O₆S:C,53.37;H,5.47;N,6.92;S,5.28foundC,53.31;H,5.45;N,6.91;S,5.22%.

 

4-o-tolyl-2-β-D-galactosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidine(Vb):

IR(KBr,cm^-1):υ3369(O-H),3047(ArC-H),2885(AliC-H),1726(C=O),1647(C=N),1311(C-N),1147(C-O),1045and920(characteristicofgalactose),767(C-S).¹HNMR(DMSO-d₆,ppm):δ8.07-6.94(9H,m,Ar-H),5.02-4.09(4H,m,OH),3.99-3.00(7H,m,galactosylringproton),2.55-2.25(6H,m,CH₃).Mass(m/z):512(M⁺),492,430,416,382.Anal.CalcdforC₂₂H₂₇N₃O₆S:C,57.50;H,5.48;N,9.14;S,6.98foundC,57.46;H,5.43;N,9.01;S,6.95%.

 

4-o-tolyl-2-β-D-lactosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidine(Vc):

IR(KBr,cm^-1):υ3381(O-H),3057(ArC-H),2868(AliC-H),1643(C=N),1367(C-N),1247(C-O),1043and950(characteristicoflactose),754(C-S).¹HNMR(DMSO-d₆,ppm):δ8.23-6.79(8H,m,Ar-H),4.96–4.19(7H,m,OH),3.78-2.03(14H,m,lactosylringproton),2.41(3H,s,CH₃),2.07(3H,s,CH₃).Mass(m/z):921(M⁺),890,845,780.Anal.CalcdforC₂₈H₃₅N₃O₁₁S:C,54.10;H,5.67;N,6.76;S,5.16foundC,54.06;H,5.63;N,6.70;S,5.06%.

 

4-o-tolyl-2-β-D-maltosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidine(Vd):

IR(KBr,cm^-1):υ3341(O-H),3047(ArC-H),2878(AliC-H),1647(C=N),1357(C-N),1248(C-O),1045and952(characteristicoflactose),752(C-S).¹HNMR(DMSO-d₆,ppm):δ8.24-6.80(8H,m,Ar-H),4.97–4.20(7H,m,OH),3.79–3.44(14H,m,maltosylringproton),2.42(3H,s,CH₃),2.11(3H,s,CH₃).Mass(m/z):921(M⁺),890,845,780.Anal.CalcdforC₂₈H₃₅N₃O₁₁S:C,54.10;H,5.67;N,6.76;S,5.16foundC,54.07;H,5.65;N,6.74;S,5.11%.

 

ANTIMICROBIAL STUDIES:

Table2:Antimicrobialactivitiesof4-aryl-2-β-D-glycosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidines(IVa-dandVa-d)

Strongactivity(above18mm);Moderateactivity(above14to18mm);Weakactivity(above8-14mm);Inactive(below8mm)

 

FromTable2:

ThecompoundIVaexhibitedmodrateinhibitionagainstS.aureus,K.pneumoniae,whileitshowedweakinhibitoryactionagainstE.coli,P.aeruginosa,A.nigerandT.viride.

 

ThecompoundIVbshowedmoderateinhibitoryactionagainstP.aeruginosa,A.niger,T.viride,andwhileitexhibitedweakinhibitionagainstE.coli,andS.aureus.ItwasresistantagainstK.pneumoniae.

 

ThecompoundIVcshowedstronginhibitoryactionagainstA.nigerandT.viride,whileitexhibitedweakinhibitionagainstE.coli,S.aureus,andP.aeruginosa.ItshowednoactivityagainstK.pneumoniae.

 

ThecompoundIVdshowedmodrateinhibitoryactionagainstS.aureus,whileitexhibitedweakinhibitionagainstE.coli,P.aeruginosaandK.pneumoniawhileitshowednoactivityagainstA.nigerandT.viride.

 

ThecompoundVbshowedstronginhibitoryactionagainstP.aeruginosa.whileitexhibitedmoderatetoweakinhibitionagainstE.coli,S.aureus,A.nigerandT.viride.ItshowednoactivityagainstK.pneumoniae.

 

ThecompoundVa,Vc,andVdshowedmoderatetoweakinhibitoryactivityagainstE.coli,S.aureus,P.aeruginosa,K.pneumoniae,A.nigerandT.viride.

 

CONCLUSION:

Thenewlysynthesized4-aryl-2-β-D-glycosyl-3-oxo-5-o-tolylimino-1,2,4-thiadiazolidines(IVa-dandVa-d)exhibitedcomparableantibacterialandantifungalactivitiesagainsttheorganismstested.Themethodadoptedinthisinvestigationissimple,efficientandinexpensiveandisusefulinsynthesizingpharmacologicallyimportantmolecules.

ACKNOWLEDGEMENT:

AuthorsaregratefultoSAIF,ChandigarhforprovidingthespectraldataandDr.S.G.Bhadange,Principal,ShriShivajiCollege,Akolaforencouragementandprovidingnecessaryfacilities.

 

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Receivedon16.11.2017Modifiedon28.11.2017

Acceptedon14.12.2017©AJRCAllrightreserved