International Journal of Current Pharmaceutical Research

Vol 2, Issue 2, 2010

ReviewArticle

BENZOTHIAZOLE:THEMOLECULEOFDIVERSEBIOLOGICALACTIVITIES
PRIYANKA*,NEERAJKANTSHARMA,KESHARIKISHOREJHA
CollegeofPharmacy,TeerthankerMahaveerUniversity,Moradabad,U.P.,India.Email:priya_its@rediffmail.com Received15Dec2009,RevisedandAccepted02Jan2010 ABSTRACT Alargenumber ofeffortsweremadetosynthesize differentheterocycliccompounds andtheirderivativesinthepastdecadeandwerefoundto possespromisingantitumor,anticonvulsant,antimicrobial,antitubercularandantidiabeticactivities.Althoughbenzothiazolemoietyisverysmall butisfascinatedbyscientistsbecauseofthediversebiologicalactivitiesbynotonlybenzothiazolebutitsvarioussubstitutedderivativesaswell. Thisreviewwasfocusedonthebenzothiazoleanditsderivativesthatarenowindevelopment. INTRODUCTION Thepracticeofmedicinalchemistryisdevotedtothediscoveryand development of new agents for treating disease. The process establishinganewdrugisexceedingcomplexandinvolvestalentof peoplefromvarietyofdisciplines1.Animportantaspectofmedicinal chemistryhasbeentoestablisharelationshipbetweenchemical structureandpharmacologicalactivity2. Ithasbeenestablishedthathalfofthetherapeuticagentsconsistsof heterocyclic compounds. The heterocyclic ring comprises of very coreoftheactivemoietyorthepharmacophore3. Riluzole (6trifluoromethoxy2benzothiazolamine), PK26124, RP 25279, (Rilutek) was found to interfere with glutamate neurotransmission in biochemical, electrophysiological and behaviouralexperiments.Afterthat,benzothiazolederivatives have been studied extensively and found to have diverse chemical reactivityandbroadspectrumofbiologicalactivity. Although they have been known from long ago to be biologically active, their varied biological features are still of great scientific interest. In addition, benzothiazole ring is present in various marine or terrestrial natural compounds, which have useful biological properties. In last few years it was reported that benzothiazole, its bioisostersandderivativeshadantimicrobialactivityagainst Gram negative,GrampositivebacteriaandtheyeastCandidaalbicansand antimicrobial activity especially against Enterobacter, Pseudomonas aeruginosa, E.coli, and Staphylococcus epidermidis. Other activities involves are antidiabetic15, and bradykinin B2 receptor antagonist activity16. Given below is a brief account of various alterations conducted on benzothiazole ring and their associated biological activities. 1.ANTITUMORACTIVITY The benzothiazole moiety with somesubstitutionshowspromising antitumor activity. Its aminomethylphenyl (1a), carbonitrile (1b) and bisamidinosubstituted 2styryl (1c) derivatives shows selective growth inhibitory properties against human cancer cell lines17, proliferation of cells18, cytostatisis19 respectively. Several chlorinated and fluorinated derivatives of this moiety exhibit excellentinvitroaswellasinvivoantitumoractivity. Fluorinated analogues of 2(4aminophenyl) benzothiazoles have been synthesized which successfully block Coxidation 20. Fluorinatedbenzothiazoleanalogue2(4amino3methylphenyl)5 fluorobenzothiazole(5F203,NSC703786)(1d),exhibitselectiveand potent anticancer activity. It is the favoured analogue for clinical consideration possessing enhanced efficacy in vitro and superior potencies against human breast and ovarian tumor xenografts implanted in nude mice Its lysylamide prodrug, (Phortress, NSC 710305),(1e)isunderphaseIclinicaltrialsattheUnitedKingdom. 2,6dichloroN[2(cyclopropanecarbonylamino)benzothiazole6 yl]benzamide(1f)havebeensynthesized21andisbiologicallystable derivative, containing no nitro group. This is a highly potent derivative and exhibit excellent in vivo inhibitory effect on tumor growth. The oxidation reactions of 2(4hydroxy3methoxyphenyl) benzothiazole (1g) have been studied and the synthesized compoundswerefoundto possessthe invitro growth inhibition of humanbreastcancercelllines22. Fig.2 2.ANTICONVULSIVEACTIVITY Roleofbenzothiazolesasanticonvulsiveagentswerefirstobserved in 1978 against phenyltetrazolone induced convulsions on 2(4 1

N
N H 1H-indole
N N H 1H-benzimidazole

1,3-benzothiazole
N O

Fig.1

1,3-benzoxazole

Several Benzfused heterocyclic systems as Indole, Benzothiazole, Benzimidazole, Benzoxazole(fig.1) have been studied and found to be possessing interesting pharmacological activities such as antiviral4, antibacterial5, antimicrobial6, and fungicidal activities7. Theyarealsousefulasantiallergic8,antidiabetic9,antitumor10,anti inflammatory11,anthelmintic12,andantiHIVagents13. Benzothiazole ring system consists of thiazole ring fused with benzene ring. Thiazole ring is a fivemember ring containing one nitrogenandonesulfuratomintheringsystem. Benzothiazoles are bicyclic ring system with multiple applications. In the 1950s, a number of 2aminobenzothiazoles were intensively studied as central muscle relaxants. Since then medicinal chemists have not taken active interest in this chemical family. Biologists attentionwasdrawntothisserieswhenthepharmacologicalprofile ofRiluzole14(fig.2)wasdiscovered.

F S H2N N

o
F F

arylthiosemicarbazidocarbonylthio)benzothiazoles 23(2a)andsince then several benzothiazoles containing sulphonamide derivatives 24 (2b), benzothiazolyl guinidines 25 (2c), benzothiazolamines26 (2d) were synthesized and evaluated for their activity against electroshockandphenyltetrazoloneinducedseizures.Thereviewof these literatures revealed the benzothiazole moiety as a dynamic agentagainstconvulsiveseizures. A series of 2(3H)benzoxazolone and 2(3H)benzothiazolone derivatives have been synthesized and evaluated for their anticonvulsant activity27. The compounds were assayed intraperitoneally in mice against seizures induced by maximal electroshock and pentylenetetrazole. Compound 2e and 2f was the mostactivecompoundagainstMaximalElectroshockSeizures. New sulphonamide derivatives having benzothiazole nucleus is synthesized by treating 2(4aminophenylsulphonamido)6 halo/alkyl benzothiazoles with alkyl isothiocyanate24. The synthesized compounds were evaluated for their anticonvulsant activity. 3.ANTIMICROBIALACTIVITY Microbes are causative agents for various types of disease like pneumonia, ameobiasis, typhoid, malaria, common cough and cold various infections and some severe diseases like tuberculosis, influenza,syphilis,andAIDSaswell.Variousapproachesweremade to check the role of benzothiazole moiety as antimicrobial agent from the discovery of molecule to the present scenario. Various diaminophenyl sulfonyl28 (3a). Aryl1,3,4oxadiazol5yl)mercapto methyl29 (3b), amino (substituted) acetanildes30 (3c), arylidene sulphonamide31(3d)weresynthesizedinpastdecadeandchecked for their activity against various microbial stains like E. coli, S. aureus,S.typhi,P.aeruginosa,Bacillussubtilis,Candidaalbicansand Pneumococci, and found to posses promising antiviral, antiprotozoal,antifungal,andantibacterialactivities. A series of multi substituted benzoxazoles, benzimidazoles, and benzothiazoles had been synthesized (3e3g), as nonnucleoside fused isosteric heterocyclic compounds and tested for their antibacterialactivitiesagainstStaphylococcusaureus,Streptococcus faecalis , Bacillus subtilis as gram positive and E. coli , Klebsiella pneumoniae , Pseudomonas aeruginosa as gram negative bacteria and yeast Candida albicans using twofold serial dilution technique. Thesynthesizedcompoundspossessedabroadspectrumofactivity against the tested microorganisms at MIC values between 100 and 3.12 g/ml. Benzothiazole ring system enhanced the antimicrobial activityagainstStaphylococcusaureus32. Various 8Fluoro9substitued (1,3)benzothiazolo(5,1b)1,2,4 trizoles (3h3i) were synthesisized and evaluated for antimicrobial activityagainstS.aureus,E.coliandC.Albicans 33.Allthecompounds showed good antimicrobial activity. Some 6fluoro7(substituted) (2 N panilinosulfonamido) benzothiazoles (R =onitroanilino, m nitroanilino, pnitroanilino, ochloroanilino, mchloroanilino, p chloroanilino,anilino,morpholino,piperazino,dimethylamino)were synthesized and studied for their antibacterial and antifungal activities. All compounds showed moderate activity against S. aureus,S.albusandC.ablicans34. Latrofaetal35preparedaseriesofNcycloalkylidene,Ncycloalkyl 2acylalkylidene2,3dihyro1,3benzothiazoles, and N alkyl2 acylalkylidene2,3dihydro1,3benzothiazole and testedfor invitro antibacterialandantifungalactivitiesagainstfourgrampositiveand fivegramnegativebacteria.Thefindingsobtainedshowedthatsome of the tested compounds were effective against bacterial strains, whereas, only few compounds exhibited a moderate antifungal activityagainsttheyeaststrainsevaluated The series of 2benzylsulfanyl derivatives of benzoxazole and benzothiazoles were synthesized by Koci et al36 and evaluated for their in vitro antimycobaterial activity against Mycobaterium tuberculosisandnontuberculousmycobateria,andtheactivitywas expressedastheminimuminhibitoryconcentration(MIC)inMl/l. The substances bearing two nitro groups or a thioamide group exhibited appreciable activity particularly against nontuberculous strains. Inotherwordsitcanbestatedthatbenzothiazolemoietyservesasa royalwarrioragainstalmostalltypesofmicrobes.

4.ANTIINFLAMMATORYACTIVITY Pyrazolones and pyrazolinones rank among the more venerable nonsteroidal antiinflammatory agents. Phenylbutazone and its congeners incorporating a pyrazoline3,5dione structure are more potent antiinflammatory agents. In the recent years a number of Benzothiazole derivatives have been synthesized and found to displayantiinflammatoryactivity. Oketani et al.37 studied the in vitro pharmacological profiles of 6 hydroxy5,7dimethyl2(methylamino)4(3 pyridylmethyl)benzothiazoles (4a), against the 5lipooxygenase activityofratbasophilicleukemiacells.Thisresultindicatethatthe compound potently inhibited 5lipooxygenase and thromboxane A2 synthetaseandblockedthromboxaneB2productioninratperitoneal andhumanbloodcells In the year 2003 a series of 2[(2alkoxy6 pentadecylphenyl)methylthio]1Hbenimidazole/benzothiazole has been reported (4b4c) and investigated for their ability to inhibit humancyclooxygenase2enzyme(COX2)38.Compoundswerefound topossessmoderateantiinflammatoryactivity. Dogruer et al39 synthesized sixteen (2benzothiazolone3yl and 2 benzoxazolone3yl) acetic acid derivatives and tested them for antinociceptive and antiinflammatory activity. 4[2(6Benzoyl2 benzoxazolone3yl) acetyl] morpholino, 4{2[6(2chloro benzoyl)2benzoxazolone3yl] acetyl} morpholino, 4{2[6(2 chlorobenzoyl)2benzoxazolone3yl] acetyl} morpholine, 1[2(5 chloro2benzoxazolone3yl) acetyl] pyrrolidine, methyl ((6 methyl2benzoxazolone3yl) acetate and N, N diethyl2 (2 benzothiazolone3yl) acetamide have shown more potent antinonciceptiveactivitythanothers. 2(4'butyl3'5'dimethylpyrazol1'yl)6substituted benzothiazoles (4d) and 4Butyl1(6'substituted2' benzothiazolyl)3methylpyrazol5ols (4e) have been synthesized by the condensation of 6substitued2hydrazinobenzothiazoles with 3butylpentane2,4dione and ethyl (nbutyl)acetoacetate respectively40. Selected compounds of the series were subjected to preliminary testing for their antiinflammatory activity. All the compoundsbelongingtoseriesdisplaysignificantantiinflammatory activity. 5.MISCELLANEOUSACTIVITIES Srinivasan et al41 have shown that the replacement of the urea moiety by benzothiazolesulfonamide provided inhibitors of HIV1 protease with improved potency and antiviral activities. Certain membersoftheclassshowedgoodoralbioavailabilityinrats. Original derivatives of 2piperazinyl benzothiazoles (5a) were synthesized and studied as mixed ligand for serotoninergic 5HT 1A and5HT3receptors42.Thestudiedcompoundsexhibitedsignificant affinities for these two serotoninergic receptor subtypes. Compounds with such a pharmacological profile are of clinical relevance in the treatment of psychotropic diseases e.g. anxiety, depressionandschizophrenia. Das et al.43 prepared a series of structurally novel benzothiazoles basedsmallmoleculeinhibitorsofp56lck(amemberoftheSrcfamily of non receptor protein tyrosine kinase). BMS243117 (5b) is identifiedasapotentandselectiveLckinhibitorwithgood cellular activity, whereas BMS350751 (5c) and BMS358233 (5d) are identified as potent Lck inhibitors with excellent cellular activities againstTcellproliferation. Antileishmanial activity of synthesized (1,3 Benzothiazol2yl )amino9(10H)acridinone derivatives was tested by Florence Delmasetal.44.Twoderivatives,4(6nitrobenzothiazol2ylamino) 10Hacridin9one and 1(6aminobenzothiazol2ylamino)10H acridin9one(51c)showedmoderateantileishmanialactivity. Nargund et al.45 have been synthesized a series of 8fluoro9 substituted (1,3)benzothiazole(5,1b)1,3,4triazoles, and all compounds were screened for their Anthelmintic activity against earthworm, Perituma posthuma and were found to possess markedlyhigherAnthelminticactivity. 2

Table1:Itshowsvariousbiologicalactivities Structure no. 1a Structure Activity Workers KashiyamaEetal.

CH3 N NH2 S

N CN S

Antitumor

1b

OCH 3

Antitumor

BessonTetal.

1c

OCH 3

N S

NH C
CH3

Antitumor

CaletaIetal.

NHCH(CH 3 ) 2
Antitumor HutchinsonIetal.

1d

N NH2 S

1e

CH3 F N NH S O NH2 .2HCl NH2

Underclinicaltrials forantitumor activity

HutchinsonIetal.

1f

Cl

O NH

N NH S R
H3C CH3 R2

Antitumor

YoshidaMetal.

R=

H3C O

Cl R2=cyclopropyl
1g

Antitumor WellsGetal

OMe N OH S

2a

OMe N SCONHNH S OMe

S C NHAr

Anticonvulsant

SinghS.Petal.

2b

N NHSO2 Cl S O NH C NHC2H5

Anticonvulsant

SiddiquiNetal.

2c

OMe S N N OMe

R N NHPh R1

Anticonvulsant

PandeyaS.Netal.

2d

H3C

S NH2 N

Anticonvulsant

JimonetPetal.

 2e2f

R1 (CH2)2 N O R 2eR=C2H5CO,R1=C5H10N 2fR=C3H7,R1=C5H10N O N

S S O NH2

Anticonvulsant

UcarHetal.

3a

Antimicrobial

GhoneimK.Metal.

3b

N S S CH2 N
O F N NH Cl S NH

O N

Antimicrobial

TrivediB.Hetal.

3c

Antimicrobial

PattanS.Retal.

3d

N NHO2S F R S O N S

R1

Antimicrobial

ShastryC.Setal.

3e3g

R2

Y CH2 Z R

Antimicrobial

YilidizOrenIetal.

N R1 3eY=O,Z=O;3fY=N,Z=S:3gY=S,Z=O
3h3i

N N

N S NH F

Antimicrobial

SreenivasaM.Vetal.

3hR=oNO2,3iR=mCl, 4a

HO

S NHMe N

Anti inflammatory

OketaniKetal.

N
4b4c

OR1

CH2S

X N R2

Anti inflammatory

ParamashivappaRetal.

C15H31
4bR1=H,R2=OCH3,X=NH 4cR1=CH3,R2=H,X=S

 4d4e

N R S R
1

N
CH3 CH3

Anti inflammatory

Singh,S.Petal.

5a

4dR=H/CH3/OCH3,R1=CH3 4eR=H/CH3/OCH3,R1=OH

H3C N O S (CH2)n N N

N S

Antipsychotic

Diouf,Oetal.

5b

O NH

N S O

H H3C N Cl

Lckinhibitor

Das,Jetal.

NH
5c

HO NH N NH

N H S O Cl N

Lckinhibitor

Das,Jetal.

5d
NH O

Me N N N NH S O Cl H N Me

Lckinhibitor

Das,Jetal.

SOME MARKET PREPERATIONS HAVING BENZOTHIAZOLE NUCLEUS Mirapex46 Tiaramide48

Cl

S
N

O OH CO N N

Fig.3 Riluzole47 Riluzole (6 trifluoro methoxy 2benzothiazolamine) Patent No. PK26124,RP25279(Riluteck).Riluzolewasfoundtointerferewith neurotransmission in biochemical, electrophysiological and behaviouralexperiments. CONCLUSION The reviewed aminobenzothiazoles has shown a wide spectrum of biological activities. The substituted benzothiazolylimino dithiazolidines and the 2(2'aryl1,3, 4oxadiazol5 yl)mercaptomethyl benzothiazoles are having significant antibacterial activity. Significant antiinflammatory activity is displayed by some new 2(4'butyl3'5'dimethylpyrazol1yl)6 substituted benzothiazoles and 4butyl1(6'substituted 2' benzothiazolyl)3methylpyrazol5ones. Benzothiazolylguanidines are found to have potent activity. Potent antitumor activity was demonstrated by a number of 2(4 aminophenyl) benzothiazoles. The 2(4acetamido2bromo5 methylphenylsulfonamide)benzothiazoleisfoundtobeeffectiveas antituberculor agents, whereas ethoxazolamide and oacyl 5 Fig.5

F S H2N N
Fig.4

o
F F

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