recent advances in the chemistry and biology of...

Review Article

Recent Advances in the Chemistry and Biology of BenzothiazolesRupinder K. Gill1,2, Ravindra K. Rawal1, and Jitender Bariwal1

1 Department of Pharmaceutical Sciences, ISF College of Pharmacy, Moga, Punjab, India2 Research Scholar, Punjab Technical University, Jalandhar, Punjab, India

Benzothiazole is a privileged heterocyclic scaffold having a benzene ring fused with a five-memberedthiazole ring. This moiety has attracted considerable attention because of its wide range ofpharmacological activities such as antitubercular, antimicrobial, antimalarial, anticonvulsant, anthel-mintic, analgesic, anti-inflammatory, antidiabetic, antitumor activity, etc. In the last few years, somenovel benzothiazoles have been developedwith varied biological activities. To access this scaffold in highyield and to introduce diversity, a variety of new syntheticmethods have been invented. In this review,wehighlight the development of novel benzothiazoles for various biological activities along with the bestsynthetic protocols for their synthesis.

Keywords: Anthelmintic / Anticancer / Antitubercular / Benzothiazoles / Mycobacterium tuberculosis /Thioformanilides

Received: September 12, 2014; Revised: November 28, 2014; Accepted: December 1, 2014

DOI 10.1002/ardp.201400340

Introduction

Benzothiazole belongs to the family of bicyclic heterocycliccompoundshavingbenzenenucleusfusedwithfive-memberedring comprising nitrogen and sulfur atoms. Benzothiazole is animportant scaffold with a wide array of interesting biologicalactivitiesandtherapeutic functions includingantitubercular [1–2], antimicrobial [3–4], antimalarial [5], anticonvulsant [6–7],anthelmintic [8], analgesic [9], anti-inflammatory [10], antidia-betic [11] and antitumor [12] activities. Moreover, benzothia-zoles are present in a range of marine or terrestrial naturalcompounds that have useful biological activities. Benzothia-zoles have been therapeutically useful in the treatment ofvarious diseases such as neurodegenerative disorders, localbrain ischemia, central muscle relaxants and cancer [13].Benzothiazoles have promising biological profile and are easyto access which makes this pharmacophore an interestingmoiety for designing new benzothiazoles. Benzothiazolemoiety has wide applications in dyes such as thioflavin [14].Some of the marketed drugs comprising benzothiazole areshown in Fig. 1 [15–17].

Some reviews have been recently reported in literature,briefly describing the synthetic strategies and biological

activities of benzothiazole nucleus [18–21]. The main featurethat was missing in the recently reported review [18] is theunexplained synthetic methodologies with reference tothe scope of the functional group compatibility and SAR ofthe molecules under consideration. In the present review wediscuss the effect of functional groups on yields of the productand robustness of the methodology along with the SARstudies. This makes this review distinguished and out of theleague which will appeal the researches around the globeand serve as an ideal platform to synthesize new potentbenzothiazoles. We have included detailed synthetic meth-odologies used to access benzothiazoles and special care hasbeen taken to cover the most relevant and importantliterature reports.

Pharmacological profile

The benzothiazoles have shown wide range of pharmacolog-ical profile and accordingly they may be classified into thefollowing categories.1. Benzothiazole as antitubercular agent2. Benzothiazole as antimicrobial agent3. Benzothiazole as antimalarial agent4. Benzothiazole as anticonvulsant agent5. Benzothiazole as anthelmintic agent6. Benzothiazole as analgesic, anti-inflammatory agent7. Benzothiazole as antidiabetic agent8. Benzothiazole as anticancer agent

Correspondence: Dr. Jitender Bariwal, Department of Pharma-ceutical Sciences, ISF College of Pharmacy, Moga-142001, Punjab,India.E-mail: [email protected]: þ91 1636 239515

Arch. Pharm. Chem. Life Sci. 2015, 348, 155–178 Archiv der PharmazieARCHRCH PHARMHARM

� 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com 155

Benzothiazole as antitubercular agentTuberculosis (TB) is a fatal contagious disease caused byinfection with Mycobacterium tuberculosis but also with M.bovis andM. africanum, which can affect almost any tissue ororgan of the body, the most common site of infection of thedisease being the lungs [22]. The lack of efficacy ofantimycobacterial agents is due to the ability of M.tuberculosis to develop alternative metabolic routes andinsufficient drug permeability through mycobacterial cellwall.

The mycobacterial cell wall consists of three main compo-nents that form the mycolyl-arabinogalactan-peptidoglycan(mAGP) complex. Mycolic acid, which is the outermost layer ofcell wall, consists of high-molecular-weight R-alkyl-b-hydroxyfatty acids and is mainly present as trehalose monomycolate(TMM), trehalose dimycolate (TDM or cord factor) and estersof arabinogalactan [23]. The first line chemotherapeutics forthe treatment of TB include isoniazid and ethambutol whichinhibit mycobacteria by distressing the synthesis of mycolicacids and arabinan, respectively. A range of multi-drugresistant strains of TB (MDRTB) and drug resistant tuberculosis(XDR-TB) have also emerged [24, 25]. Thus, there is a need todevelop novel, nontoxic, cell permeable, multidrug resistantantitubercular agent. In spite of numerous attempts forsynthesis of novel anti-TB agents, benzothiazole alwaysdisplayed a most versatile class of compounds againstmicrobes [26–30]. Some prominent reports from recentliterature have been discussed in this section.

A series of novel, 2-(2-(4-aryloxybenzylidene)hydrazinyl)-benzothiazoles have been designed on the basis of molecularhybridization approach by combining the 2-hydrazinylben-zothiazole and 4-(aryloxy)benzaldehyde. Almost all thesynthesized compounds displayed significant activity (MIC¼1.5–29.00mg/mL against M. tuberculosis H37Rv). Amongthem, five of the tested compounds exhibit MIC value of<3.0mg/mL, whereas, chloro substituted (E)-6-chloro-2-(2-(4-(2,4-dichlorophenoxy)benzylidene)hydrazinyl)benzothiazole1 displayed most potent activity (MIC of 1.5mg/mL) [1].

Several derivatives of benzimidazolyl-1,3,4-oxadiazol-2-yl-thio-N-phenyl-(benzothiazolyl)acetamides havebeen screened

byPatelandco-workers for theiractivityagainstM.tuberculosisH37Rv. In this series, 2-(5-((1H-benzo[d]imidazole1-yl)methyl)-1,3,4-oxadiazole-2-ylthio)-N-(6-fluorobenzo[d]thiazole-2-yl)-acetamide 2a and 2-(5-((1H-benzo[d]imidazole1-yl)methyl)-1,3,4-oxadiazole-2-ylthio)-N-(6-methoxybenzo[d]thiazole-2-yl)acetamide 2b were found to be most potent [2].

Silver(I) and gold(I) complexes of 2-(2-thienyl)benzothia-zole (BTT) 3 with metal/ligand composition of 1:2 and 1:1,respectively have been evaluated by Cuin and co-workerswhich shows good activity againstM. tuberculosis. The ligandhas been treated with silver(I) nitrate or gold(I) chloride inmethanol to afford silver ([Ag(BTT)2NO3]–AgBTT2) and gold([Au(BTT)Cl].1/2H2O–AuBTT) complex, respectively. Interesting-ly, silver(I) complex has been found to be more effective ascompared to commercial drug silver sulfadiazine. However,BTT has been found to be less active against M. tuberculosis[31].

Mannich bases of sulfadiazine, sulfamethoxazole, sulfacet-amide with 2-amino-3-methyl-benzothiazole, 2-amino-5-chloro-benzothiazole and 2-amino-5-chloro-6-fluoro-benzo-thiazolehavebeen reported todetermine their efficacyagainstMycobacterium. From this series, compound 4a (N0-(benzo[d]-thiazol-2-ylaminomethyl)sulfanilamide),4b (N0-(5-chlorobenzo-[d]thiazol-2-ylaminomethyl)sulfanilamide), 4c (N0-(5-chloro-6-fluorobenzo[d]thiazol-2-ylaminomethyl)sulfanilamide), 4d (N0-(5-chlorobenzo[d]thiazol-2-ylaminomethyl)-N0-(pyramidin-4-yl)-sulfanilamide) were found potent inhibitors of M. tuberculosisH37 RV strains [32] (Fig. 2).

Benzothiazoles as antimicrobial agentsAn antimicrobial agent reduces/blocks the growth andmultiplication of bacteria [33]. These agents are among themost common and often injudiciously used therapeutic drugsworldwide [34], and consequently resulted in emergence ofantibiotic-resistant pathogens. Regardless of considerableadvancement in the field of antimicrobial therapy, infectiousdiseases caused by bacteria or fungi remain amajor challenge.Thus, there is an ever-increasing need to develop newmolecules with better antimicrobial profile. For this, differentapproaches have been employed by modifying the benzo-thiazole or by synthesizing hybrid molecules having synergis-tic effect through the combination of differentpharmacophores to enhance the antibacterial and antifungalpotential. Few of such examples have been summarized here.

Thiourea derivatives of benzothiazoles 5 have been foundto possess significant antimicrobial activity. In vitro studyrevealed that higher activity is exhibited against fungi thanbacteria, while compounds bearing NO2 at position-5 ofbenzothiazole nucleus displayed significant activity againstboth the bacteria and fungi [35].

A series of Schiff bases of benzothiazole, 5-[2-(1,3-benzothia-zol-2-yl-amino)ethyl]-4-(arylideneamino)-3-mercapto-(4H)-1,2,4-triazoles 6 have been investigated for antibacterial and antifun-gal activity by Soni and co-workers. Compound 6a, 5-[2-(1,3-benzothiazol-2-yl-amino)ethyl]-4-(4-dimethylaminobenzyli-deneamino)-3-mercapto-(4H)-1,2,4-triazole possesses highest

N

SH2N

O F

FF

Riluzole

NH

SO

OH

NHSO

OO Ph

Sibenadet Hydrochloride(Viozan)

N

SNH2

HN

Pramipexole

Figure 1. Marketed drugs of benzothiazole.

Arch. Pharm. Chem. Life Sci. 2015, 348, 155–178R. K. Gill et al. Archiv der Pharmazie

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antibacterial activity, while compound 6b, 5-[2-(1,3-benzo-thiazol-2-yl-amino)ethyl]-4-(3,4-dimethoxybenzylideneamino)-3-mercapto-(4H)-1,2,4-triazole exhibits excellent activityagainst both the C. albicans and A. niger [36].

Amide linkage of 2-amino thiophene with 2-aminobenzo-thiazole as in compound 7 displayed comparable activity withchloroamphenicol against S. aureus (MIC¼3.125mg/mL),whereas about 50% decrease in activity has been observedagainst S. pyogenes than chloroamphenicol [3]. In anotherseries, thiazoles 8 and pyrazolo[1,5-a]pyrimidines 9 werefound to be most active against A. fumigatus and F.oxysporum (MIC¼ 6.25mg/mL) [3] (Fig. 3).

Further, imidazo[2,1-b][1,3]benzothiazoles 10 and 11 havebeen reported for their strong inhibitory activity againstbacterial and fungal strains compared to standard antibacte-rial (amoxicillin and cefixime) and antifungal (fluconazole)[37]. Substitution on side chainwith guanidine propanoic acidas in compound 3-(3-(6-bromobenzo[d]thiazol-2-yl)guani-dino)propanoic acid 12 displayed better activity profile thanthe standard ciprofloxacin against Pseudomonas aeruginosa

(MIC 3.125 and CpMIC 19.5mg/mL). In addition, Schiff bases ofbenzothiazole and quinazolinone linked through iminelinkage, 6-bromo-2-(2-methyl-2-phenyl-1,2,3,4-tetrahydro-quinazolin-4-imino)benzo[d]thiazol-2-amine, 13, exhibitedhighest activity against Salmonella paratyphyi (MIC¼ 3.125and ciprofloxacin MIC¼43.4mg/mL) [38]. Another compound14, exhibited moderate inhibitory activity against fewbacterial strains (Escherichia coli, Staphylococcus aureus)and fungal strains (Candida albicans, Aspergillus niger) [4](Fig. 4).

Further, thiazolidines 15 and azetidin-2-ones 16 have beeninvestigated for their antimicrobial activity. Among them,compounds 15c, 15d, 15g, 16c and 16f were found as mostactive antibacterial agents whereas compounds 15c, 15d, 15f,16e and 16g were found to be potent antifungal agents [39].Afterward, more thiazolidinone incorporated benzothiazoleshave been synthesized and evaluated for antimicrobialactivity. The most active compounds identified from theabove series was 3-(4-(benzo[d]thiazol-2-yl)phenyl)-2-(4-methoxyphenyl)thiazolidin-4-one 17a and 3-(4-(benzo[d]-

S

NNH

Cl

N

O

Cl

Cl

1

N

N

O

NN

S

2a: R = F2b: R = OCH 3

S

N S

BTT 3H2N

SN

O

OR3

NH S

N R1

R2

44a4b4c4d

: R: R: R: R

11

1

1

= H, R2 = H, R3 = H= Cl, R2 = H, R3 = H= Cl, R2 = F, R3 = H= Cl, R2 = H, R3 = C4H3N2

S

N

R

HN

O

2

Figure 2. Benzothiazoles as antitubercular agents

S

N

NH

NH

O2N

S

R

O

5R = 4-NO2-Ph, thiophen-2-yl, Ph,

n-butyl, morpholin-2-yl

S

NNH

N

NNSH

N

66a: R = 4-N(CH3)26b: R = 3,4-OCH3

S

N

NH

OCN

S N

8

SN

HNO

S

NH2

HN

7

S

NNH

O

NN

N

HN

9

O

O

R

Figure 3. Benzothiazoles as antimicrobial agents.

Arch. Pharm. Chem. Life Sci. 2015, 348, 155–178Recent Advances in the Chemistry and Biology of Benzothiazoles Archiv der Pharmazie

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thiazole-2-yl)phenyl-2-(4-hydroxy-phenyl)thiazolidin-4-one17b, which exhibited significant activity against E. coli andC. albicans (MIC¼ 15.6–125mg/mL) [40]. Another compound,4-(4-hydroxyphenyl)-4H-pyrimido-[2,1-b]-[1,3]benzothiazolecurcumin 18, has been identified as a potent antibacterialagent againstmany species (Pseudomonas aeruginosa, Salmo-nella typhi, Escherichia coli, Bacillus cereus and Providenciarettgeri), particularly it has equipotent activity with ciproflox-acin against S. aureus [41].

In another comparative study of some heterocyclic com-pounds containing oxazole 19a and benzothiazole 19bnucleus, it has been observed that benzothiazoles are moreactive than the oxazole bearing derivatives in antimicrobialassay [42]. Several benzothiazoles bearing 1,2,3-triazolenucleus have been screened for antimicrobial activity andcompound 20a was found as most potent compound againstS. aureus, E. faecalis, S. typhi, E. coli, K. pneumonia, P.aeruginosa, with MIC value 3.12mg/mL. Whereas, compound20b displayed maximal potency against all the fungal strainssuch as C. tropicalis, C. albicans, C. krusei, Cryptococcusneoformans, A. niger, A. fumigatus [43] (Fig. 5).

Recently, a series of 6-(benzothiazol-2-yl)pyrido[2,3-d]-pyrimidine 21 has been evaluated for their antibacterialand antifungal activity by Lavanya and co-workers. Amongthe newly synthesized compounds, most of the compoundsexhibited significant antibacterial and antifungal activityagainst Staphylococcus aureus, Escherichia coli, Klebsiellapneumoniae, Pseudomonas aeruginosa, Streptococcus pyo-genes, Aspergillus flavus, Aspergillus fumigatus, Candidaalbicans, Penicillium marneffei and Mucor than the standarddrugs ciprofloxacin and clotrimazole [44] (Fig. 6).

Benzothiazoles as antimalarial agentMalaria is a parasitic disease caused by the bite of an infectedanopheles mosquito in tropical and subtropical zones of theworld. The easiest way to prevent malaria is to takeantimalarial drugs prophylactically before entering in anendemic area. Antimalarial agents are classified according to

their target at different stages of the life cycle of the parasite.However, some of themosquitoes are reported to be resistantto the commercial antimalarial drugs that are used in thetreatment of malaria [45] and also to insecticides used invector control [46]. Thus, there is a need to develop new drugsthat should aid in resistance management. New benzothia-zoles having broad antimalarial potential are discussed in thissection.

A series of amodiaquine analogues 22–24 of benzothiazoleshave been screened for antiplasmodial activity against W2and K1 chloroquine resistant strains of Plasmodium falcipa-rum. These compounds also block the formation of toxicquinone imine and aldehyde metabolites as benzo-heterocy-clic ring system is attached to the 4-amino-7-chloroquinolinering, without affecting antiplasmodial activity. From thisseries, compounds 22, 23, and 24 possess excellent ability toinhibitW2 andK1 chloroquine resistant strains of Plasmodiumfalciparum [47].

Further, several derivatives of 2,6-substituted and 2,4-substituted-benzo[d]thiazoles 25 have been screened formosquito repellent activity against Anopheles arabiensis.Among them, compounds 25b, 25c and 25d displayed highestrepellent activity equivalent to the positive control N,N-diethyl-m-toluamide (DEET) [5] (Fig. 7).

Benzothiazoles as anticonvulsant agentEpilepsy is a central nervous system disorder in which thenormal neuronal activity is disturbed, causing strangesensations, emotions, abnormal behaviour or sometimesconvulsions, muscle spasms and loss of consciousness. Epilepsymay happen due to an imbalance of neurotransmitters,abnormality in brain wiring, change in ion channels orsometime combination of these and other factors [48].Currently, various novel anticonvulsants have been usedclinically such as pregabalin, stiripentol, zonisamide, tiaga-bine, lamotrigine, levetiracetam, topiramate and manyothers. However, these drugs have limited use because oftheir serious side effects such as headache, nausea,

N

S

N

NHN

F

R

F 10R = Br, F

N

S

N

NH

FR

F11

R = Br, F

NH

N

NN

O

O

NN

S

N

S

14

S

N

Br12

S

NN

BrNH

HN

13

NHNH

HNOH

O



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hepatotoxicity, anorexia, ataxia, drowsiness, gastrointestinaldisturbances and hirsutism [49–53]. To overcome these sideeffects, various efforts have been made by researchers todevelop new promising anticonvulsant agents. Here, we havespotted some recent literature reports where new benzo-thiazoles have been investigated for their potential anticon-vulsant property.

A series of 6-substituted-[3-substituted-prop-2-eneamido]-benzothiazoles and 6-substituted-2-[(1-acetyl-5-substituted)-2-pyrazolin-3-yl]aminobenzothiazoles have been evaluatedfor neurotoxicity, hepatotoxicity and behavioural study byBhusari and co-workers. From this study, compound 6-methyl-2-[(1-acetyl-5-(4-chlorophenyl))-2-pyrazolin-3-yl]aminobenzo-thiazole 26 was found to be the most promising compound,equivalent to standard phenytoin [54].

A series of N-(substituted benzothiazol-2-yl)amides havebeen synthesized and evaluated for their anticonvulsant andneuroprotective effects. TheN-(6-methoxybenzothiazol-2-yl)-4-oxo-4-phenylbutanamide 27 displayed greatest neuropro-tective effect by lowering the levels of MDA and LDH [55].Replacement of heterocyclic ring with quinazolin-4-one andsubsequently derivatization on benzene ring of benzothia-zole gave some potent anticonvulsant compounds. Variety of

substitution have been tried at benzene ring, among thesenew derivatives, compounds 3-(benzo[d]thiazol-2-yl)-6-bro-mo-2-ethylquinazolin-4(3H)-one 28a and 6-bromo-2-ethyl-3-(6-methoxybenzo[d]thiazol-2-yl)quinazolin-4(3H)-one 28bhave shown excellent activity against tonic seizure in themaximal electroshock (MES) model and clonic seizure by PTZ-induced seizure model, respectively [6].

S

NNH

Cl

NHO N

SO

S

NNH

ClNH

O

Cl

O

15 16

S

NN

O

HO

OH

O

OH

O18

S

NN N O

O

OR

19a

R = CN, NO2, OCH3

SN

N

NNN

NN

N

20

R1

R

R1

R

20a: RF,=R 1 = F20b: RH,=R 1 = Br

15a: R = H15b: R = 2-Cl15c: R = 2,4-Cl15d: R = 2-CH3

15e: R = 2-OCOCH315f : R = 2-OCH315g: R = 4-NO 2

16a: R = H16b: R = 2-Cl16c : R = 2,4-Cl16d: R = 2-CH3

16e: R = 2-OCOCH316f : R = 2-OCH316g: R = 4-NO 2

R

R

N

SN

S

O

R

17a: R = CH317b: R = OH

17

O

N

OCnH2n+1

19b


S

N

NN

NHNH

N

Cl

H2NO

R

21

21a: R = 4-Cl21c : R = 4-OCH321e : R = 4-F

21b: R = 4-NO221d: R = 2,4-(CH3)221f : R = 4-C2H5



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In an another series of N-(benzo[d]thiazol-2-ylcarbamoyl)-2-methyl-4-oxoquinazoline-3(4H)-carbothioamides, compound29a, [2-methyl-4-oxoquinazoline-3(4H)-carbothio-N-(6-chlor-obenzo[d]thiazol-2-ylcarbamoyl)amide, and 29b, [2-methyl-4-oxoquinazoline-3(4H)-carbothio-N-(6-trifluoromethoxybenzo-[d]thiazol-2-ylcarbamoyl)amide were found very potent com-pared with standard phenytoin and ethosuximide, in anticon-vulsant assay. These compounds also exhibit anticonvulsantactivity against (S)-2-amino-3-(3-hydroxyl-5-methyl-4-isoxa-zolyl)propionic acid (AMPA) and g-amino butyric acid (GABA)induced seizures [56].

A novel series of N-[(benzo)thiazol-2-yl]-2/3-[1,2,3,4-tetra-hydroisoquinolin-2-yl]ethan/propanamides 30 have beensynthesized by Zablotskaya and co-workers. Most of the

compounds from this series were found to be potentanticonvulsants. Interestingly, antiphenamine action washighly expressed for thiazolyl propanamide derivatives 30c[7] (Fig. 8).

Benzothiazoles as anthelmintic agentsAnthelmintics are used to treat infections with parasiticworms by either stunning or killing them. Recent reports ondevelopment of resistance by parasites insist researchers tosearch for newer drugs with more selectivity and lowertoxicity profile. Number of benzothiazoles has been synthe-sized for better anthelmintic property. Benzothiazoles areconsidered as sulfur isosteres of benzimidazole and are wellreported for anthelmintic activity.

NH

X

OH

NSR1

R2

25

25a: X = CH, R1

1

1

= 4-OH, R2 = 6-Cl25b: X = CH, R = H, R2 = 6-Cl25c : X = CH, R = 4-NO2, R2 = 6-Cl25d: X = N, R1 = 4-OCH3, R2 = 6-Br25e : X = CH, R1 = 4-OCH3, R2 = 4-CH3

NCl

HN S

N HN

N

NCl

HN S

N HN

N

NCl

HN S

N HN

N

22 23

24

Figure 7. Benzothiazoles as antimalarial agents.

S

NNH

NN

O

Cl

26

N

N

O

N

SBr

R

28a: R = H28b: R = OCH3

S

NNH O

OO

27

N

N

OC

NH

HN

O

S S

N

R

29a: R = Cl29b: R = OCF3

N S

N

30

n NH

O

30a: n = 130b: n = 230c: n = 3

29

28

Figure 8. Benzothiazoles as anticonvulsant agents.


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New series of substituted 2-amino-benzothiazoles 30 havebeen reported for anthelmintic activity against Eudriluseugeinae and Megascoplex konkanensis. Most of the newcompounds have shown appreciable anthelmintic activityequivalent to standard mebendazole. Compound 31 has thebetter anthelmintic activity among 2-amino-substitutedbenzothiazoles substituted with chloro, fluoro, bromo,methyl, ethyl, methoxy or dimethyl group at sixth positionof benzothiazole [57]. Substitution with heterocyclic systemsat position-2 of benzothiazole provides some potent anthel-mintic compounds. Among other derivatives of 3-(2-hydrazi-nobenzothiazole)-substituted indole-2-one, compound 32a,band 33 have shown the most potent activity comparable tostandard drug albendazole in in vitro assay [58] (Fig. 9).

Similarly, a series of 1-[2-(substituted phenyl)-4-oxothiazo-lidin-3-yl]-3-(6-fluoro-7-chloro-1,3-benzothiazol-2-yl)ureas 34have been reported for anthelmintic activity against Peritumaposthuma. Compounds 34a and 34b containing methyl andmethoxy group at C-3 and C-2 position of phenyl ring havebeen found to be the most potent compounds [8] (Fig. 10).

Benzothiazoles as analgesic andanti-inflammatory agentsNon-steroidal anti-inflammatory drugs (NSAIDs) exert theiranalgesic effect by peripheral inhibition of prostaglandin (PG)through inhibition of the cyclooxygenase (COX) enzyme,which catalyzes the conversion of arachidonic acid into PG[59]. However, PG has a dual function, mediation ofinflammation [60] and cytoprotection against HCl [61] inthe stomach and intestine. Long term use of NSAIDs for thetreatment of pain and inflammation may lead to gastrointes-tinal (GI) disorders and renal toxicity [62]. Hence, there isalways a need to overcome ulcerogenic effect and improve-ment in analgesic and anti-inflammatory activity by develop-ment of NCE’s.

Several derivatives of 2-amino-6-substituted benzothiazole35 and 2-chloro-acetyl-amino-6-substituted benzothiazole 36have been screened for anti-inflammatory activity. Most ofthe compounds have shown significant anti-inflammatoryactivity in in vitro models [63]. It has been found thatbenzothiazoles bearing pyrazolyl system as in compound 37

are more potent as they are comparable with the standarddrug pentazocine [64].

Further, 1,2,3-triazole has been attached to 2-mercapto-benzothiazole ring and investigated for their anti-inflamma-tory activity. Compound 38b exhibited potent selective COX-2inhibition whereas compounds 38a–d possess excellent anti-inflammatory activity as compared to the standard drugibuprofen. Moreover, these compounds have no ulcerogenicpotency [10].

In an another study, some novel derivatives of 4H-pyrimido[2,1-b][1,3]benzothiazole-3-carboxylates 39 have been evalu-ated for their anti-inflammatory potential. Number ofcompounds from this series showed significant activity.However, compound ethyl-(4R)-2-amino-6-chloro-4-(3,4,5-tri-methoxyphenyl)-4H-pyrimido[2,1-b][1,3]-benzothiazole-3-carboxylate 39 has been found to possess the most promisinganti-inflammatory activity for further studies [65] (Fig. 11).

Recently, pyrazolo[3,4-d]pyrimidines 40 have been attachedwith benzothiazole and investigated for their in vivoacute toxicity, analgesic, anti-inflammatory, and ulcerogenicpotential. Compound 1-(1,3-benzothiazol-2-yl)-4-(4-dimethyl-aminophenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine 40bshowed the most potent analgesic and anti-inflammatoryactivity. In addition, these compounds were found to havesignificant gastrointestinal protection activity [9] (Fig. 12).

Benzothiazoles as antidiabetic agentsDiabetes is a group of metabolic diseases that leads to highblood glucose level. In type-1 diabetes, insulin production isinadequate, while in case of type-2 diabetes, body cells do not

S

NNH2

O2N31 N

HO

N NHO

NS

Cl

33

NH

O

N NHR N

S

32a: R = Cl32b: R = NO2

32

Figure 9. Benzothiazoles as anthelminticagents.

S

N

FCl

NHNH

NOSO

R

34a: R = 3-CH334b: R = 2-OCH3

34

Figure 10. Benzothiazoles as anthelmintic agents.


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respond properly to insulin (insulin resistance). This results indisorders such as polyuria (frequent urination), polydipsia(increasingly thirsty) and polyphagia (hungry) [66]. Excess ofglucose level in blood may also lead to serious healthproblems such as damage to the eyes, kidneys, nerves, heartdisease, stroke and even sometimes the need to remove alimb. Pregnant women may also get diabetes, calledgestational diabetes [67]. There are some reports in literaturewhere benzothiazoles have been screened for their antidia-betic property.

Substitution on side chain of 2-amino-benzothiazole with2-(substituted amino)acetamide as in compound N-(6-chlor-obenzo[d]thiazol-2-yl)-2-morpholinoacetamide 41, haveshown maximum glucose lowering effects comparable tothe standard drug glibenclamide, when tested for itshypoglycaemic activity by streptozotocin-induced diabeticmodel in rat [11]. It is believed to act by activating thesulfonylurea receptor 1 (SUR1), the regulatory subunit of theATP-sensitive potassium channels (KATP) in pancreatic betacells. This causes the depolarization of cell membrane andleads to opening of voltage-dependent calcium channel and,

hence, increase in release of intracellular calcium in the betacell and subsequent stimulation of insulin release.

Several derivatives of novel (E)-3-(benzo[d]thiazol-2-yl-amino)phenylprop-2-en-1-ones 42 have been evaluated fortheir antidiabetic activity, and majority of the compoundshave shown appreciable antidiabetic activity [68].

In another study, various benzothiazoles have beensynthesized which enhance the rate of glucose uptake in L6myotubes in AMPK-dependent manner. Among them, 6-ethoxy substituted benzothiazole as in compound 43 enhan-ces the rate of glucose uptake by up to 2.5-folds in comparisonwith vehicle-treated cells and up to 1.1-fold, compared to 2-chloro-5-((Z)-((E)-5-((5-(4,5-dimethyl-2-nitrophenyl)furan-2-yl)-methylene)-4-oxothiazolidin-2-ylidene)amino)benzoic ac-id (PT-1, 44). It has been observed that compound 43fits in thethree pharmacophoric features that are considered to beessential for the activity such as hydrophobic, aromatic and H-bond acceptor [69] (Fig. 13).

Benzothiazole as anticancer agentsA large number of benzothiazole derivatives have shownpotent anticancer activity. Some of the recent literaturereports are summarized in this section.

Novel derivatives of N-alkylbromo-benzothiazoles 45 havebeen evaluated for their anticancer potency. Most of thecompoundsinthisserieshaveshownsignificantcytotoxicactivity.However, compound 45, (3-bromo-propyl)-(6-methoxy-benzo-thiazol-2-yl)amine has been found to be the most promisinganticancer agent against the PC-3 (IC50¼ 0.6mM), THP-1 (IC50¼3mM) and Caco-2 cell lines (IC50¼9.9mM), respectively [70].

Further, cadmium and indium complexes of benzothiazoleshave been synthesized and tested for their anticancer activityby cell-based cytotoxicity assays. It has been found thatligands (2-(pyridin-2-yl)benzo[d]thiazole and 2-(pyridin-4-yl)-

S

NNH2

S

NNH

O

Cl

35 36

R = H, CH3, OCH3, F, Cl

S

N

NN

R37

R = Br, OC2H5, Cl, OCH3

S

NS N

NN

3838a: =R o-Cl 38b: p-F 38c: p-Br 38d: p-NO2

N

SN

NH2

OO

OO

O

Cl

39

R = H, CH3, OCH3, F, Cl

R R

R

Figure 11. Benzothiazoles as analgesic and anti-inflammatory agents.

S

NN

N

N N

R

40a: R = 3-NO240b: R = 4-N(CH3)2

40

Figure 12. Benzothiazoles as analgesic and anti-inflammatoryagents.


ARCHRCH PHARMHARM


benzo[d]thiazole) are biologically inactive, while the cadmi-um complex 46 and 47 exhibits significant cytotoxic activity inpancreatic cancer cell lines with IC50 values <16.0mM [71].

Further, new amidino derivatives of phenylene-bisbenzo-thiazoles 48 have been screened for their antiproliferativeactivity against several human cancer cell lines, aswell as DNA-binding properties and all of new compounds exhibitedsignificant antiproliferative effects on tumor cells in concen-tration dependant manner. The most cytotoxic compoundwas diimidazolinyl substituted phenylene-bisbenzothiazole48a with IC50¼ 5.3, 0.87, 6.19, 1.49, 6.63, 7.38 against MCF-7,SK-BR-3, SW620, MiaPaCa-2, WI38 and HeLa cancer cell lines.In addition, imidazolyl substituted phenylene-benzothiazole48b has displayed highest selectivity towards tumor cells as itis devoid of cytotoxic effects on normal fibroblasts [72].

Substitutionwith heterocyclic ring systems at position-2 of 2-amino-benzothiazole provides new derivatives of dasatinib.The 4-benzothiazole-amino-quinazolines 49were investigatedfor their in vitro cytotoxic activity. Among these derivatives,compounds bearing 2,4,6-trimethylaniline as in compound 49have shown the most potent anticancer activity. Further,compounds in the series 49a and 49b have been found topossess significant dual Src/Abl kinase inhibitory activity [12](Fig. 14).

A novel series of N-(pyridine-2-yl-methylene)benzo[d]thia-zol-2-amine and its Cu(II), Fe(III), Co(II), Ni(II) and Zn(II)complexes have been synthesized and evaluated for theiranticancer potential. Zn complex 50 has been found mostactive in human breast carcinoma (MCF-7), liver carcinoma(HEPG2), colon carcinoma (HCT116) and larynx carcinoma(HEP2) cell lines [73].

Another series of new benzothiazole-pyrrole based con-jugates 51 have been reported for cytotoxic activity againstMCF-7 cell line. Compounds 51a and 51bwere found effectivein inducing apoptosis in MCF-7 cells. Compound 51a has alsoshown down-regulation of oncogenic expression of Ras andits downstream effector molecules such as MEK1, ERK1/2,p38MAPK and VEGF [74].

Substitution of pyrazolo[1,5-a]pyrimidine carboxylic acid atposition-2 of amino benzothiazole scaffold through an amidefunctionality has been reported and the resulted compounds52 have been screened for their anticancer activity againstfive human cancer cell lines; among these compounds, twocompounds 52a and 52b were found to possess appreciableanticancer activity. Both of these compounds also havepotential to arrest G2/M cell cycle in A549 cancer cell lineand cause reduction in Cdk1 expression level [75] (Fig. 15).

These reports explain the importance of benzothiazoles fortheir leadingpharmacologicalactivities.However, constructionof benzothiazole ring in high yield is still a challenging task.

Synthetic methodology

There are a number of methods that have been used tosynthesize benzothiazoles. Here, in this section we haveelaborated themost efficient and practically easymethods forthe synthesis of benzothiazoles. For better understanding anddepending on the starting material used, we have divided itinto six different sections.

Synthesis of benzothiazoles by utilizing2-aminothiophenolSynthesis of benzothiazoles from different aldehydes,using aminothiophenolAn efficient synthesis of 2-substituted benzothiazoles 55 hasbeen reported in high yield by condensation of 2-amino-thiophenol 53 and substituted aromatic aldehydes 54 in N,N-dimethylformamide (DMF) and sodium metabisulfite(Na2S2O5) under reflux conditions of 2h [76] (Scheme 1).

Further, somewhat similar method has been utilized forsynthesis of benzothiazoles 57 by initially treating aromaticaldehyde 56, (diethylamino)phenyl)-1,3,5-triazine-2,4-diyl)bis-(oxy))dibenzaldehyde (DIPOD) with solution of NaHSO3 inethanol at room temperature and then subsequently addedo-aminothiophenol 53 in DMF under reflux conditions for 3h

S

HN S

N

O

R2

R1

42R1 = H, CH3, OC2H5R2 = H, CH3R3 = Br, Cl, F, CH3, OCH3

R3S

NNH

Cl

CH2

O N

O

41

S

N SS

NO

43

NO2

O

NH

S

O N

Cl

OHO

PT-1 , 44Figure 13. Benzothiazoles as antidiabeticagents.


ARCHRCH PHARMHARM


to afford targeted compound 57 in 74% yield [26]. Synthesisof benzothiazole from o-aminothiophenol and substitutedbenzaldehydewith somemodifications is common, as found inmany literature reports [77, 78] (Scheme 2).

In a quite similar approach, synthesis of benzothiazoles 59from aryl aldehyde and o-aminothiophenol 53 involves the

reaction of o-aminothiophenol 53 with aryl aldehyde 58 inthe presence of 30% H2O2 and cerium ammonium nitrate(NH4CeNO2) in acetonitrile at 50°C [79, 80] (Scheme 3). Besidethis, 2-substituted benzothiazoles 59 have also been synthe-sized from substituted aldehyde and o-aminothiophenol inpresence of various catalysts and reaction conditions such as

S N

N

NZn

N

N

SN

50

S

NN

R6

R5 R4

R3

R1

R2

51

51a: R1 = R3 = H, R2 = OCH3, R4 = R5 = R6 = 3,4,5-OCH351b: R1 = R2 = R3 = 3,4,5-OCH3, R4 = H, R5 = OCH3

NN N

HN

OS

N R4

R5R1

R2

R352

52a: R1 = R3 = R4 = R5 = H, R2 = F52b: R1 = R2 = R3 = OCH3, R4 = R5 = H Figure 15. Benzothiazoles as anticancer agents.

S

N

O

HN Br

45

N

S

N

CdO

O O

O

H2O

S

NN

S

NNCd

O O

OO

OH2

46 47

S

N N

S

HN

NN

NH

Cl-Cl-

48a =

48b =

N

N

R

OHN S

NHN

O

R1

49a: R = 2-Cl, 6-CH349b: R = 2,4,6-OCH3

N O N O

N O N O

N OO

4849

,

,

etc.

R1

Figure 14. Benzothiazoles as anticancer agents.


ARCHRCH PHARMHARM


montmorillonite, SiO2/graphite; under MW and p-TsOH [81],diethyl bromophosphonate/t-butyl hypochlorite; acetonitrile[82], H2O2/HCl in ethanol [83], AcOH/air; MW or thermalheating [84] and Baker’s yeast, dichloromethane [85], etc.

Solid-phase synthesis of benzothiazoles from 2-amino-thiophenol has been reported using hydroxymethyl groupof Wang resin or the R-amino group of an amino acid 60bound to Wang resin as starting point [86]. 4-Fluoro-3-nitrobenzoic acid 61was attached to supporting resin byN,N0-diisopropylcarbodiimide (DIPCDI) and 4-(dimethylamino)pyri-dine (DMAP) (1.0 equiv) in DMF (Scheme 4). Thereafter, sulfurgroup has been introduced by nucleophilic aromatic substi-tution of aryl fluoride by triphenylmethyl mercaptan (Trt-SH)in DMF, in the presence of N,N-diisopropylethylamine (DIEA)to afford intermediate 62, followed by reduction of nitrogroup of 62 with SnCl2 in DMF to get access to the anilineintermediate. Then, thiol group was unmasked to obtainresin-bound 2-amino-4-carboxythiophenol 63 by treatingwith TFA-triethylsilane (TES)-CH2Cl2 (2:5:93). Finally, a seriesof benzothiazoles have been synthesized by treating com-pound 63 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ)-mediated oxidative cyclo-condensation with variousaldehydes. Thereafter, resin-bound benzothiazoles werecleaved from resin by utilizing TFA-H2O (19:1) to give accessto substituted benzthiazoles 64 in good yield. It has beenobserved that substitution of aliphatic, cyclohexyl, thiopheneand unsubstituted phenyl ring at 2-position of benzothiazoleenhances the yield. However, phenyl ring substituted withelectron withdrawing or electron donating groups providescomparatively less yield. Bulky substitutions such as naphtha-lene ring also provides very low yield (Scheme 4).

Recently, a facile method for the synthesis of benzothiazolehas been described by Gulcan and co-workers using o-aminothiophenol 53 and 4-tert-butyl-2,6-diformylphenol 65(2:1 ratio) under refluxing condition in ethanol for 24h toafford desired benzothiazole 66 in high yield [87] (Scheme 5).

Synthesis of benzothiazoles from carboxylic acids, usingaminothiophenolA peculiar method for synthesis of naphthyridine derivativesof benzothiazole 71 has been described by You and co-workers [88]. In this method, o-aminothiophenol 67 under-goes cyclization on treatment with naphthyridine-3-carbox-ylic acid 68 in presence of polyphosphoric acid (PPA) at 170–250°C and affords compound 69 in moderate yield. Conse-quently, intermediate 69 was nitrated to give intermediate70, which is followed by reduction of compound 70with Pd/Caffording the final product 71 in 40–73% yield (Scheme 6).

Recently, a robust method for the coupling of 2-amino-thiophenol 53 with amino acid (or ester) 72 has beendeveloped by Santos and co-workers to give access to 2-substituted benzothiazoles 73 [89]. In this reaction, 2-amino-thiophenol 53 was reacted with amino acid (or ester) such asglycine ethyl ester and D-valine to give correspondingbenzothiazole 73, in the presence of dehydrating agent suchas PPA at 220°C within 4h. It has been observed thatbenzothiazoles are produced in high yield when ethyl ester ofamino acid has been used as starting material instead ofamino acid (Scheme 7).

A convenient single step method for the synthesis of 2-aryl benzothiazoles 75 has been reported by utilizingsubstituted aminobenzoic acid 74 and 2-aminothiophenol53 in the presence of PPA at higher temperatures [90, 91].Simultaneously, 4-nitrobenzoic acid 76 was employed forsynthesis of benzothiazole 77, subsequent reduction of 77using Fe/NH4Cl gave access to compound 75 in 90% yield. Ithas been observed that electron withdrawing groups on thebenzoic acid counterpart gave high yields of the product(Scheme 8).

Synthesis of benzothiazoles from alcohols, usingaminothiophenolThere are few reports in literature where alcohols have beenused as starting material. One-pot tandem approach wasreported by Rangappa and co-workers for synthesis ofbenzothiazoles 79 in excellent yields, using variety of alcohols78 and o-aminothiophenol 53 without any oxidant [92]. Thisprocess includes oxidation of alcohols to aldehydes followedby cyclization with o-aminothiophenol 53 and finally propyl-phosphonic anhydride (T3P) mediated dehydrogenationunder mild reaction conditions (0–25°C). Closer look to thescope of reaction depicts that the reaction of o-amino-thiophenol 53 with variety of aromatic, aliphatic andheterocyclic substituents reacts well under these optimizedreaction conditions and provides access to high yield of theproduct (Scheme 9).

Synthesis of benzothiazoles from diones, usingaminothiophenolGuzel and co-workers have reported the synthesis of 3H-spiro-[1,3-benzothiazole-2,30-indol]-20(10H)-ones 83 and 10-methyl-3H-spiro[1,3-benzothiazole-2,30-indol]-20(10H)-ones 84 utiliz-ing 5-substituted 1H-indole-2,3-diones 80 or 5-substituted 1-

NH2

SH+

R

O Na2S2O5

DMF, ref lux 2 h S

NR

26 examples53 54 55

HO O HO O

OH

OH

, ,

, etc.

R =

Scheme 1. Synthesis of benzothiazoles from substitutedaldehydes, using aminothiophenol.


ARCHRCH PHARMHARM


methyl-1H-indole-2,3-diones 82 as starting material [93]. Thereactionsequence startsbygeneratingcarbanionontreating5-substituted1H-indole-2,3-diones80withNaH inDMF, followedby addition of iodomethane 81 to get access to 5-substituted 1-methyl-1H-indole-2,3-diones 82. Finally, 3H-spiro[1,3-benzo-thiazole-2,30-indol]-20(10H)-ones 83 and 10-methyl-3H-spiro-[1,3-benzothiazole-2,30-indol]-20(10H)-ones 84 were obtainedby reacting 2-aminothiophenol 53 with 5-substituted-1H-indole-2,3-diones 80 or 5-substituted 1-methyl-1H-indole-2,3-

diones82, respectivelyunderoptimizedconditionsingoodyield(Scheme 10).

Synthesis of benzothiazoles from amines, usingaminothiophenolVery recently, a very simple method has been adopted byNarender and co-workers for the synthesis of 2-substitutedbenzothiazoles using molecular iodine [94]. The reaction ofamine 85 with 2-mercaptoaniline 53 in the presence of

N N

NO O

OHHO

N

56

SH

NH2

a) NaHSO3, C2H5OH, r.t.

53

N

NN

O

O

NN

S

N

S

57

b) , DMF, reflux, 3 h

Yield: 74%1 example

Scheme 2. Synthesis of benzothiazoles from aldehyde, using a minothiophenol.

NH2

SH+

HO

H2O2/CAN

neat, 50°C S

NHO

53 58 59O

Scheme 3. Synthesis of benzothiazoles from dif-ferent aldehydes, using aminothiophenol.

YH

FNO2

O OHi) DIPCDI, DMAP,

DMF, r.t., 4 hii) Trt-SH, DIEA,

DMF, r.t., 24 h

Y

ONO2

S-Trt

i) SnCl2 in DMF, r.t., 24 h

Y

ONH3

S-H

ii) TFA-TES-CH2Cl2

= polystyrene

Y = Wang or Wang-CO-CH(R)-NH-

i) R1-CHO, DDQ, CH2Cl2,24 h, 25°C

ii) TFA-H2O (19:1), r.t., 1 h S

NR1R2

O

6364

62

R1 = Ph, 4-OCH3-C6H4, 4-Cl-C6H4, naphthyl,4-NO2-C6H4, cycloalkyl, thiophen-3-yl, C7H15

R2 = OH,NH

OH

+

6061

O

Scheme 4. Solid-phase syntheses of benzothiazoles from 2-aminothiophenol.


ARCHRCH PHARMHARM


molecular iodine afforded the desired benzothiazole 86 atroom temperature. It has been observed that electronwithdrawing substitutent on the aromatic amines (at position4 of phenyl ring) gave increased yields of the product than theelectron donating substitutents. However, heterocyclicamines such as pyridin-2-yl-methanamine gave moderateyield (Scheme 11).

By utilizing three-carbon synthonA three carbon synthon 1-(1H-1,2,3-benzotriazol-1-yl)-3-chloroacetone 91 has been utilized for the synthesis of 2-aminobenzothiazoles 95. Compound 91 has been synthesizedby reacting chloroacetyl chloride 90 with trimethylsilylme-thylbenzotriazole 89. Compound 91 behaves as 1,2-dielec-trophile and hence, undergoes [2þ3]-type heterocyclizationwith thiourea 92 to give intermediate N-[4-(1H-1,2,3-benzo-triazol-1-ylmethyl)-2-dimethylamino-1,3-thiazol 93 in 54%yield. Subsequently, intermediate 93 undergoes benzannela-tion step by reacting with substituted chalcones 94 in ethanolin presence of sodium ethoxide to afford 2-aminobenzothia-zole 95 in 25–74% yield. Highest yield was observed for the

compound comprising disubstituted phenyl ring at 5, 7position of benzothiazole nucleus whereas compound com-prising monosubstituted phenyl ring at position 5 or 7provides low yield [95] (Scheme 12).

Synthesis through metal catalyzed reactionSeveral methods have been reported for the synthesis ofbenzothiazoles using various metal catalyzed reactions. Anunprecedented palladium and copper-catalyzed procedure

OH O

O+

NH2

SH

Ethanol

ref lux, 24 h

N

S

OH N

S

53 65 66Yield: 77%1 example

Scheme 5. Synthesis of benzothiazole from 4-tert-butyl-2,6-diformylphenol using o-amino-thiophenol.

R1

NH2

SH+

N Y

HOOCO

ZR3

F PPA, N2170−250°C, 4 h

N Y

O

ZR3

FS

NR1

HNO3, H2SO435− 40°C, 2 h

N Y

O

ZR3

FS

NO2N

N Y

O

ZR3

FS

NH2N

10% Pd/C

69

70 71

Y = C, NZ = H, F, (S)-CH(CH3)CH2O-R1 = H, Cl, NO2, NH2

r.t., 4 h

Yield: 40−73%

Yield: 15−51%

67 68

Scheme 6. Synthesis of benzothiazoles from carboxylic acids, using aminothiophenol.

NH2

SH

53

+ HO X

ONH2

R1

PPA

220°C, 4 h S

NX

NH2

R1

Yield: 40-- 55%

X-R1 = CH2, CH-(R)-iPr

2 examples

7273

Scheme 7. Synthesis of benzothiazoles from amino acids, usingaminothiophenol.


ARCHRCH PHARMHARM


NH2

COOH

R1 +NH2

SH

R = H, 2-Cl, 3-CH3

S

NNH2

R1

PPA

75

NO2

COOH

+NH2

SH S

NNO2

PPA

Fe powder, NH4Cl75% C2H5OH, ref lux 2 h

73 53

76 5377

Yield: 50-- 60%

Yield: 90%

R220°C, 3 h

180°C, 5 h

R

R1 R R

R1

Scheme 8. Synthesis of benzothiazoles fromaminobenzoic acid and aminothiophenol.

OH+

NH2

SH

T3P/ DMSOEthyl acetate

0°C to r.t. 2-4 h S

N

78 53

Yield: 85-90%7 examples

R

R = H, 3-CN, 3-Cl, 2,4-F,2-OCH3-4-F, 2-CH3-5-F

79

R

Scheme 9. Synthesis of benzothiazoles from alco-hols, using aminothiophenol.

NH

RO

O

NaH, CH3I

DMF, 0.5 h ref lux, 4 h N

RO

O

80 82

NH2

SH

EtOH,ref lux, 5 h

EtOH,ref lux, 5 h

NH2

SH

NH

RO

HNS

N

RO

HNS

83 84

R = CH3, Cl, NO2R = CH3, CF3O, Cl, Br, NO2

3 examples 5 examples

81

53 53

Yield: 39-75%Yield: 60-74% Scheme 10. Synthesis of benzothiazolesfrom diones, using aminothiophenol.


ARCHRCH PHARMHARM


has been developed by Kundu and Nandi for the synthesis of(E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles 99[96]. The 3-(2-aminophenylthio)prop-1-yne 96 has beenreacted with substituted aryl iodides 97 under palladium–

copper catalyzed reaction condition at room temperature toafford disubstituted alkynes 98, within 24h. Compound 98after tosylation followed by cyclization with CuI in thepresence of triethylamine in THF gave access to (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles 99 in 63–80% yield. Presence of 4-methyl and 2,4-dimethoxy groupon aryl iodide gave targeted compounds in higher yield ascompared to 3-iodo and 1-naphthyl ring (Scheme 13).

Another strategy has been reported by Batey and co-workers for the synthesis of 2-aminobenzothiazoles 101 viapalladium-catalyzed oxidative intramolecular C–S bond for-mation/C–H functionalization, utilizing an unusual co-cata-lytic Pd(PPh3)4/MnO2 system under mild reaction conditions[97]. It has been observed thatMnO2 alone was not efficientlyable to catalyze this reaction, hence a combination of Pd(PPh3)4 and activated MnO2 has been used for oxidativecyclizations. Variety of N-arylthioureas 100 was used in thisreaction and all of them provided high yield under thesereaction conditions (Scheme 14).

A simple approach has been utilized by Li and co-workersthrough cyclization of o-iodothiobenzanilides 102 using Pd/Cas a catalyst at room temperature for the construction of C–Sbond without using any ligand or additive [98]. This approachprovides excellent yields under mild reaction conditions forvaried substituents. Functional group and substrate compati-bility studies indicates that the electron withdrawing ordonating groups at phenyl ring have very little effect on theyields whereas substituents at o-position of phenyl ring gavethe low product yield (Scheme 15).

In an another approach, synthesis of 2-arylthiobenzothia-zoles 110 has been reported by ligand-assisted Cu(I)-catalyzedsequential intra- and intermolecular S-arylation in a one potprotocol [99]. Despite of the Cu-catalyzed C–C, C–N and C–Obond formation reactions [100–103], the chemistry of C–Sbond formation [104–107] is less explored because of reducedcatalytic efficiency due to higher affinity of thiol for metalsand also possibility of thiol towards oxidative dimerization. Inthis approach, synthesis of 2-arylthiobenzothiazoles 110involves the intramolecular S-arylation of dithiocarbamatesalt 107 prepared from carbon disulfide 105 and aniline 104 to

provide benzothiazol-2-thiol 107. Further, the intermolecularC–S coupling reaction produces 2-arylthiobenzothiazoles 110in a single step. The optimized reaction condition thatprovides high yield of 2-arylthiobenzothiazoles 110 utilizesCuI as precatalyst, K2CO3 as base, phenanthroline as ligand.However, use of less expensive cyclohexyl-1,2-diamine ligand109 provides even higher yield in shorter reaction time (4h).Superiority of this method is due to the use of inexpensivemetal catalyst, ligand and requires low catalyst loading withmild reaction conditions and shorter reaction times. Substitu-tion of 4-nitrophenyl ring at 2-position of benzothiazole gavebetter yield while unsubstituted phenyl ring and 6-methoxygroup provide lower yield (Scheme 16).

Synthesis of benzothiazoles by utilizinganilinesVarious amines have also been used for the construction ofbenzothiazoles, we present a few of such examples in thissection. A simple and convenient base-promoted strategy hasbeen reported for the synthesis of a variety of 2-mercapto-benzothiazoles 112. This tandem reaction utilizes commer-cially available o-haloanilines 111 and carbon disulfide 105which were allowed to react in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give corresponding2-mercaptobenzothiazoles 112 in good to excellent yields[108]. Surprisingly, this intramolecular tandem condensationor S-arylation reaction has been achieved in absence oftransition metal catalyst. The optimal parameters for thissynthetic protocol to react aniline and carbon disulfideutilizes DBU as a base, toluene as a solvent at 80°C for 16–24h. The plausible mechanism of this reaction involves thenucleophilic attack of nitrogen from o-haloaniline 111 onactivated carbon disulfide 105 to afford the intermediate 113(step a). Thereafter, via an intramolecular SNAr reactionintermediate 113 may possibly be converted into the product112 (Step b).When o-iodoanilinewas used as startingmaterialboth methyl and fluorine group on phenyl ring providesexcellent yield at 80°C. While, substitution of weak electron-withdrawing group, such as Br, strong electron-withdrawinggroup, such as CO2Me, CF3O and CN, along with an electron-donating Me group at para position afforded corresponding2-mercaptobenzothiazoles in satisfactory yields at 100°C.Interestingly, disubstituted compounds at para and ortho toamino group also afforded high yield of 2-mercaptobenzo-thiazoles. However, o-chloroanilines are not favorable for thisreaction even at higher temperature and longer reactiontimes (Scheme 17).

In another approach, synthesis of benzothiazole 118 hasbeen reported from substituted anilines 114. Reaction ofanilines 114 with 4-nitrobenzoylchloride 115 gave access tosuitable benzanilides which upon treatment with Lawesson’sreagent provided corresponding thiobenzanilides 116. Sub-sequently through Jacobson’s cyclization, thiobenzanilideswere converted to their respective 2-(4-nitrophenyl)-6-ben-zothiazoles 117, by utilizing K3[Fe(CN)6] as reagent underreflux condition for 30min. Finally, the targeted

R NH2 +

NH2

SH

I2, air

CH3CN, r.t. 30 min S

NR

85 53 86Yield: 60-82%11 examplesR = Ph, 4-OCH3C6H4, C7H5O2, 4-ClC6H4,

3,4-ClC6H3, 4-FC6H4, 4-CH3C6H4, 4-CF3C6H4, 4-OCF3C6H4, C6H4N, etc.

Scheme 11. Iodine mediated synthesis of benzothiazole using2-aminothiophenol.


ARCHRCH PHARMHARM


benzothiazoles 118 were obtained by reduction of nitrogroup using SnCl2 [74, 90, 109, 110] (Scheme 15). Using similarstrategy, Stevens and co-workers [111] have reported thesynthesis of benzothiazoles employing fluorinated nitro-benzanilides as starting material. All the fluoro substitutednitro-benzanilides provide access to corresponding benzo-thiazoles in excellent yield except 4,6-difluoro and 5,7-difluoro nitro-benzanilides (Scheme 18).

In another approach, synthesis of benzothiazoles 123 fromvariety of isothiocyanates 120 has been reported fromsubstituted anilines 119 [112, 113]. The isothiocyanates 120were allowed to react with 2,6-dimethyl and 2,6-dichloroaniline 121 inmethanol to affordN,N0-disubstituted thioureas122, followed by oxidative cyclization of 122with bromine togive access to the targeted compounds 123 in moderate yield.

It was observed that benzothiazoles were obtained in highyield when reacted with 2,6-dichloro aniline instead of 2,6-dimethyl aniline. In addition, para substituted anilinesgave benzothiazoles in better yield as compared to metasubstituted aniline. Noticeably, anilines comprising electronwithdrawing group at para or meta position providebenzothiazole in high yield as compared to electron donatinggroups (Scheme 19).

In some other protocols, synthesis of benzothiazoles hasbeen achieved using nearly the same procedure as describedin Scheme 16, however, a slight variation from the abovementioned method lies in synthesizing the substitutedphenylthiourea which was achieved by treating substitutedanilines 124 with saturated solution of ammonium thiocya-nate in water. Subsequently, substituted phenylthioureas 126

NH

NN

+ Cl Si NaHDMF, 0°C to r.t. N

NN

Si87 88 89

Cl

OCl

NN

N

91

Cl

O

R1

R2NH2

S

92N

NN

S

N NR1

R2

93

R3

O

C2H5ONa / C2H5OHref lux, 12 h

S

NN

R4

R3

R1

R2

95

R1 = H, Ph, 4-Cl-C6H4, 4-NO2-C6H4R2 = H, PhR3 = H, Ph, 4-CH3-C6H4R4 = Ph, 4-CH3O-C6H4, 4-NO2-C6H4,

4-Cl-C6H4

r.t., 10-20 s

C2H5OH, ref lux, 12 h

5 examples

90

94

Yield: 25-74%

R4

Scheme 12. Synthesis of 2-aminobenzothiazoles by utilizing three-carbon synthon.

NH2

S+

96 97

(PPh3)2PdCl2, CuI, Et3N

CH3CN, r.t.24 h

NH2

S

i) p -TsCl, py, CH2Cl2, r.t., 10 h

ii) CuI, Et3N, THF, ref lux, 36 h

S

N H H

ArH

Ts

99

Ar

Ar = Ph, 1-naphthyl, 2-naphthyl, 3-Cl-C6H4, 2-CH3-C6H4,4-CH3-C6H4, 4-OCH3-C6H4, 2-OCH3-CO-C6H4, 2-thienyl,2,4-OCH3-pyrimidin-5-yl, 5-iodo-2-thienyl, 3-iodophenyl,4-iodophenyl

Ar I

98

13 examplesYield: 63-80%

Scheme 13. Synthesis through metal-catalyzed reaction.


ARCHRCH PHARMHARM


were cyclized in the presence of bromine in chloroform to give2-aminobenzothiazoles 127 [25, 70, 114] (Scheme 20).

Further, ethyl 4-aminobenzoate 129 has also been used asstarting material for the synthesis of substituted benzothia-zole 130 by reacting with potassium thiocyanate, usingcopper sulfate as catalyst in methanol under reflux conditionsfor 6 h [72] (Scheme 21).

Synthesis of benzothiazole by using thioureasSubstituted thioureas have proven to be important syntheticstarting materials for the synthesis of substituted benzothia-zoles. Cyclohexanone 131 when reacted with thiourea 132 inpresence of molecular iodine, followed by neutralization ofhydroiodic salt 133 with NaHCO3 gave access to 2-amino-

4,5,6,7-tetrahydrobenzothiazole 134 in moderate to goodyield [115] (Scheme 22).

Syntheses of optically active 2-aminobenzothiazoles havebeen reported through optically active isothiocyanates 136[112]. The thiourea 138 has been prepared from opticallyactive isothiocynates 136 by coupling with 4-fluoro-3-chloro-aniline 137. The final 2-amino substituted benzothiazole 139was obtained by oxidative cyclization with bromine inchloroform in high yield. It has been observed thatunsubstituted phenyl and carbocyclic substituted 2-amino-benzothiazole were obtained in better yield whereasaliphatic and substituted phenyl ring on 2-aminobenzothia-zole were obtained in poor to moderate yield irrespective ofelectron donating and electron withdrawing group at para-position of phenyl ring (Scheme 23).

Chemoselective synthesis of benzothiazoles 143 has beenreported by Kumbhare and co-workers through oxidativecyclization of thiourea 142 employing ionic liquid, 1,3-di-n-butylimidazolium tribromide [bbim][Br3] under mild reactionconditions [116]. The starting material benzothiazolyl thio-carbamides 142 was obtained by reacting substituted 2-aminobenzothiazole 140 and phenyl isothiocyanate 141 inpresence of 4-dimethylamino-pyridine (5mol%) in DMF. Thebenzothiazolyl thiocarbamides 142 undergo oxidative cycli-zation in presence of tribromide-based ionic liquid at 70°C tofurnish N-bis-benzothiazole 143 via C–S bond formationreaction. Substitution of electron donating or electron

NH

NR1 R2

S Pd(PPh3)4 (3 mol%)MnO2 (10 mol%)

CH3CN, O2, 80°C N

SN

NR1R2 =N NN

NO

ON

,

,

R1

R2

101

4 examples

100Yield: 90-93%

Scheme 14. Synthesis of 2-aminobenzothiazoles via palladium-catalyzed oxidative intramolecular reaction.

I

NH

SR1

R2

Pd/C

DMF, r.t., 6-36 h S

N R2

R1

102 103

Scheme 15. Synthesis of 2-substituted benzothiazoles using Pd/C mediated reaction.

NH2

X+

X = I, BrY = H, CH3, Cl, Br, OCH3

CHH,=Z 3Z1 = H, 4-CH3, 4-OCH3, 4-NO2, 2-NO2,

4-NHAc,3-Cl,2-COOCH3

CS2X

HN S-M+

SL / CuI

K2CO3, DMSO S

NS-M+

CuI /

H2N NH2

K2CO3, L =S

NS

Y

Z

Y

Z Z

Y

Y

ZI

Z1

Z1

110

triethylamine

THF, 12 h, r.t.

DMSO,90°C, 4 h examples20

104105 106 107

108

109 Yield: 65-92%

Scheme 16. Synthesis of 2-arylthiobenzothiazoles by ligand-assisted Cu(I)-catalyzed sequential intra- and intermolecular S-arylation.


ARCHRCH PHARMHARM


withdrawing groups on 2-aminobenzothiazole and phenylisothiocyanates produces N-bis-benzothiazoles 143 in excel-lent yield (Scheme 24).

Synthesis of benzothiazoles by utilizingthioformanilidesAn efficient photochemical cyclization of thioformanilides144 has been reported by Penenory and co-workers utilizingchloranil as catalyst for the synthesis of 2-substitutedbenzothiazoles 145 [117]. The optimization reaction con-ditions utilize 1,2-dichloroethane and toluene as co-solventsat 80°C to provide excellent yield of the product. It has beenobserved that unsubstituted benzenoid ring provides betteryield as compared to electron donating benzenoid ring,whereas electron withdrawing group substituted benzenoid

ring of benzothiazole has no effect on the reaction outcome.Beside this, phenyl ring at 2-position on benzothiazoleprovides better yield while aliphatic groups such as t-butyland methyl group do not favor the reaction (Scheme 25).

Besides chloranil, thioformanilides were also converted to2-substituted benzothiazoles in presence of catalytic amountsof CuI (5mol%) and 1,10-phenanthroline (10mol%) usingCs2CO3 as base in dimethoxyethane under refluxing con-ditions within 24h [118] and also in the presence ofmanganese triacetate under MW [119].

Additionally, an exclusive, economical, metal free and base-promoted synthesis has been reported for the synthesis of 2-substituted benzothiazoles 147 from N0-substituted-N-(2-halophenyl) thioureas 146 in dioxane [120] (Scheme 26). Ithas been observed that both electron donating and electron

NH2

X

R1

+80-100°C, h16-24 S

NSH

R1

111 112

DBU, toluene

NH

X SS

_DBUH+

113

DBU

DBUH+S C S

step-a 15 examplesYield: 43-89%

BrI,X =

105

CS2

step-b

DBU.HX

Scheme 17. Synthesis of benzothiazoles by utiliz-ing anilines.

NH2

R

pyridine,a)2 hreflux,

reagent,Lawesson'sb)chlorobenzene,

3 hreflux,

NHS

NO2

R

114

R = H, OCH3, F

116

K3[Fe(CN)6], aq. NaOH,

SnCl2.2H2O, ethanol,

S

NNH2

118

NO2

O Cl

+reflux, 30 min

S

NNO2

ref lux, 4 h

Yield: 64-90%11 examples117

115

R1

R1

R1 R1

R = 4-F, 6-F, 4,5-di-F, 4,6-di-F,5,7-di-F, 5-F, 7-F, 5,6-di-F,6,7-di-F

R1 = H, CH3

RR

Scheme 18. Synthesis of benzothiazoles by utilizing anilines and 4-nitrobenzoyl chloride.


ARCHRCH PHARMHARM


withdrawing benzyl amine provide satisfactory yield, whereas1-(2-iodophenyl)-3-phenyl-thiourea prolongs the reactiontime by about 10h to give a moderate yield of 2-amino-substituted benzothiazole. In addition, N0-heterocyclic ringsgave moderate yields and N,N0,N0-trisubstituted thioureasgave excellent yield under the same reaction conditions.

Although, ester group at position 4 of heterocyclic ring alsofavors the reaction and provides excellent yields. However,ortho-bromoaryl precursors gave lower yields than the ortho-iodoaryl precursors. Moreover, both the electron-donatingmethoxy substituent and the electron-withdrawing fluoro ortrifluoromethyl groups on the aryl ring of N0-substituted N-(2-

NH2

R1R2

119

CSCl2

CH2Cl2

NCS

R1R2

120

H2N

R3

R3

R3 = CH3, Cl

CH3OH, ref lux, 1 hR1

R2

NH NH

S R3

R3

122

Br2 / CHCl3

S

NNH

R3

R3

R1

R2 R1 = H, Br, CH3, NO2R2 = H, Cl, NO2123

r.t., 3 h

0°C, 1 h


121

Scheme 19. Synthesis of benzothiazoles from substituted isothiocyanates.

NH2

NH2.HCl NH4SCN

H2O

NH CS

NH2R

R R

liq NH3 S

NNH2

R

R2

R1

R1

R2

R1

R2

R1

R2

HCl / H2O Br2/CHCl3

Br

K2CO3, DMF

S

N HN

RR1

R2

124 125 126 127

128Brn

Brn


Scheme 20. Synthesis of substituted N-alkylbromo-benzothiazoles using substituted aniline and ammonium thiocyanate.

H2N

O

O

KSCN, CuSO4.5H2O

CH3OH, ref lux, 6 h, 79%

N

SH2N

O

O129

13079%Yield:

example1Scheme 21. Synthesis of benzothiazole utilizingethyl 4-aminobenzoate.


ARCHRCH PHARMHARM


halophenyl)thioureas provide good yields of 2-substitutedbenzothiazoles.

An organocatalytic synthesis of benzothiazoles 149 hasbeen reported by Punniyamurthy and co-workers throughcyclization of arylthioanilides 148 using 1-iodo-4-nitroben-zene as catalyst and oxone as an oxidant at room temperature[121]. The advantage of this method resides in broad

substrate compatibility, mild reaction conditions and excel-lent yield. Wide variety of substrates and functional groupsare compatible under these reaction conditions as electronwithdrawing as well as electron donating groups at variouspositions of aryl ring afforded moderate to excellent yieldexcept nitro substituted phenyl ring. Heterocyclic rings alsoyielded desired compounds in excellent yield (Scheme 27).

O + H2N NH2

S

131 132

I2

110°C, 12 h N

SNH2. HI

Na2CO3

N

SNH2

133 134Yield: 57%1 example

Scheme 22. Synthesis of benzothiazole by using thioureas.

RR1

NH2H CSCl2

CH2Cl2R

R1

NHC S +

135 136

H2N

Cl

F

137

CH3OH

reflux, 1 h

HN S

HN

F

Cl

R1

RH

Br2/ CHCl3

139

r.t., 3 h

HNS

N Cl

F

RR1

H

138

0°C, 1 h

R = Ph, 4-OCH3-C6H4, 4-F-C6H4, 4-Cl-C6H4,cycloalkyl, (CH2)5-CH3

R1 = CH3, CH2CH3

Scheme 23. Syntheses of optically active 2-aminobenzothiazoles utilizing optically active isothiocyanates.

S

NNH2 +

R2

NC

S

140 141

R1 = H, 6-F, 6-OMe,6-OC2H5, 4-Cl

R2 = H, F, Cl

4-DMAP (5 mol%)

DMF, r.t. 2-4 h

S

NNH

NHS

R2

[bbim][Br3]

70°C min30-40, S

N

NH

S

N

R2

143

142


R1

R1

R1

Scheme 24. Synthesis of benzothiazole via oxidative cyclization of thiourea employing ionic liquid, 1,3-di-n-butylimidazoliumtribromide [bbim][Br3].


ARCHRCH PHARMHARM


Synthesis of benzothiazole by employingWeinreb amide reagentThere are some reagents that have been exclusively used forthe synthesis of benzothiazoles. One of such reagents isWeinreb amide reagent. An efficient one pot syntheticprotocol for the synthesis of 2-substituted benzothiazoles151 has been reported by Sadashiva and co-workers through

condensation and cyclization of Weinreb amide 151 with o-aminothiophenol 150 [122]. Chemically, Weinreb amide is N-methoxy-N-methylamide and it is very easy to prepare andhas good stability and selectivity. In this particular reaction,Weinrab amide 151 has been proved to be an effectivereagent for the synthesis of 2-substituted benzothiazoles 152in the presence of boron trifluoride etherate using 1,4-dioxane as solvent at 100°C which provided excellent yield of75–94% within 60min. Interestingly, only the amide functionparticipates in cyclization even in presence of other activefunctional groups like carboxyl, halogens, cyano andmethoxyon the carbon skeleton of the Weinreb amide. Phenyl ringsubstituted at 2-position with electron withdrawing andelectron donating groups gave high yield of the product 152.Similarly, aliphatic as well as heterocyclic substitutions at2-position also provides high yield of the 2-substitutedbenzothiazoles 152 (Scheme 28).

Conclusion

Benzothiazole is an important class of heterocyclic com-pounds and exhibits a variety of biological activities. In thisreview, we have emphasized on the biological diversity ofbenzothiazoles, their synthetic methodology and recentdevelopments in this field during the last few years. Varietyof benzothiazoles have been developed in recent yearspossessing appreciable antitubercular, antimicrobial, antima-larial, anticonvulsant, anthelmintic, analgesic, anti-inflamma-tory, antidiabetic and anticancer activities. In addition, arange of synthetic methodologies have been elaborated to

Z

NH

R

S chloranil

N

SR

Z

Z = H, OCH3; R = t-Bu, Ph, 4-C6H4-Y (Y = CH3, t-Bu)

80°C, 3 h

144 145

Scheme 25. Synthesis of benzothiazoles by utilizingthioformanilides.

XR

HN N

SR2 Cs2CO3, dioxane

S

NN

R1

R

X = I, Br

146 147

130°C, 2 h

R1

R2

R = 4-F, 5-Cl, 5-OCH3,4-CF3, 5-CF3

Scheme 26. Synthesis of benzothiazole utilizing N0-substituted-N-(2-halophenyl)thioureas.

HN R2

SR1

4-NO2C6H4I, oxone

h5-48r.t.,HFIP,TfOH, S

NR2R1

yield95%up toYield:29 examples

148 149

R1 = 2-CH3, 3-CH3, 3-OCH3, 3-NO2, 4-Br, 4-CN, 4-CO2C2H4, 4-Cl, 4-F, 4-OCH3, 4-CH3, 4-NO2, 4-CF3, 2,4-(CH3)2, etc.

R2 = Ph, 2-CH3C6H4, 3-CH3C6H4, 4-FC6H44-OCH3C6H4, 4-CH3C6H4, 4-NO2C6H4 etc.

Scheme 27. Organocatalytic synthesis ofbenzothiazoles.

NH2

SH

R1

+ NO

O

R BF3.OEt2

1,4-dioxane100°C

S

NR

R1

R1 = H, CH3, BrR = Alkyl, Alkenyl, Aryl, HeteroarylYield: 75-94%9 examples

150 151152

Scheme 28. Synthesis of benzothiazolesemploying Weinreb amide reagent.


ARCHRCH PHARMHARM


obtain benzothiazoles in excellent yield and mild reactionconditions. 2-Aminothiophenols were predominantly usedfor the synthesis of benzothiazoles. Various methods havebeen described for synthesis of benzothiazoles by treating 2-aminothiophenol with aldehydes, carboxylic acids, alcoholsand diones. Other approaches are also described for synthesisof benzothiazoles such as metal-catalyzed reactions, utilizinganilines, thioformanilides and Weinreb amide reagent.

It is worthwile to point out that one pot synthesis of 2-substituted benzothiazole using Weinreb amide reagent ando-aminothiophenol is an efficient method as it is less timeconsuming, afforded excellent yields and reactants can bepreparedwith ease. Alongwith this, organocatalytic synthesisof benzothiazole using 1-iodo-4-nitrobenzene is another highyielding method and has broad substrate compatibility andmild reaction conditions. This review would assist medicinalchemists to furthermodify this important class of heterocyclesto enhance their biological activity profile.

The authors are thankful to Department of Sciences andTechnology (DST) to provide Junior Research fellowship toMs.Rupinder Kaur Gill through research grant to Dr. JitenderBariwal (Letter No. SR/FT/CS-59/2011). Authors are alsothankful to Mr. Praveen Garg, Chairman, ISF College ofPharmacy, Moga, Punjab for his continuous support andencouragement.

The authors have declared no conflict of interest.

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