ARCH PHHARMARM Arch. Pharm. Chem. Life Sci. 2015, 348, 155–178 Archiv der Pharmazie

Review Article

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

1 Department of Pharmaceutical Sciences, ISF College of Pharmacy, Moga, Punjab, India 2 Research Scholar, Punjab Technical University, Jalandhar, Punjab, India

Benzothiazole is a privileged heterocyclic scaffold having a ring fused with a five-membered ring. This moiety has attracted considerable attention because of its wide range of pharmacological activities such as antitubercular, antimicrobial, antimalarial, anticonvulsant, anthel- mintic, analgesic, anti-inflammatory, antidiabetic, antitumor activity, etc. In the last few years, some novel benzothiazoles have been developed with varied biological activities. To access this scaffold in high yield and to introduce diversity, a variety of new synthetic methods have been invented. In this review, we highlight the development of novel benzothiazoles for various biological activities along with the best synthetic 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 activities of nucleus [18–21]. The main feature that was missing in the recently reported review [18] is the Benzothiazole belongs to the family of bicyclic heterocyclic unexplained synthetic methodologies with reference to compounds havingbenzenenucleusfused withfive-membered the scope of the functional group compatibility and SAR of ring comprising nitrogen and sulfur atoms. Benzothiazole is an the molecules under consideration. In the present review we important scaffold with a wide array of interesting biological discuss the effect of functional groups on yields of the product activitiesandtherapeuticfunctionsincludingantitubercular [1– and robustness of the methodology along with the SAR 2], antimicrobial [3–4], antimalarial [5], anticonvulsant [6–7], studies. This makes this review distinguished and out of the anthelmintic [8], analgesic [9], anti-inflammatory [10], antidia- league which will appeal the researches around the globe betic [11] and antitumor [12] activities. Moreover, benzothia- and serve as an ideal platform to synthesize new potent zoles are present in a range of marine or terrestrial natural benzothiazoles. We have included detailed synthetic meth- compounds that have useful biological activities. Benzothia- odologies used to access benzothiazoles and special care has zoles have been therapeutically useful in the treatment of been taken to cover the most relevant and important various diseases such as neurodegenerative disorders, local literature reports. brain ischemia, central muscle relaxants and cancer [13]. Benzothiazoles have promising biological profile and are easy to access which makes this pharmacophore an interesting Pharmacological profile moiety for designing new benzothiazoles. Benzothiazole moiety has wide applications in dyes such as thioflavin [14]. The benzothiazoles have shown wide range of pharmacolog- Some of the marketed drugs comprising benzothiazole are ical profile and accordingly they may be classified into the shown in Fig. 1 [15–17]. following categories. Some reviews have been recently reported in literature, 1. Benzothiazole as antitubercular agent briefly describing the synthetic strategies and biological 2. Benzothiazole as antimicrobial agent 3. Benzothiazole as antimalarial agent 4. Benzothiazole as anticonvulsant agent Correspondence: Dr. Jitender Bariwal, Department of Pharma- 5. Benzothiazole as anthelmintic agent ceutical Sciences, ISF College of Pharmacy, Moga-142001, Punjab, fl India. 6. Benzothiazole as analgesic, anti-in ammatory agent E-mail: [email protected] 7. Benzothiazole as antidiabetic agent Fax: þ91 1636 239515 8. Benzothiazole as anticancer agent

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O byPatelandco-workersfor their activity againstM. tuberculosis S O Ph H37Rv. In this series, 2-(5-((1H-benzo[d]imidazole1-yl)methyl)- NH O 1,3,4-oxadiazole-2-ylthio)-N-(6-fluorobenzo[d]thiazole-2-yl)- N S F acetamide 2a and 2-(5-((1H-benzo[d]imidazole1-yl)methyl)- H2N F O S O F N 1,3,4-oxadiazole-2-ylthio)-N-(6-methoxybenzo[d]thiazole-2- H OH yl)acetamide 2b were found to be most potent [2]. Sibenadet Hydrochloride (Viozan) Silver(I) and gold(I) complexes of 2-(2-thienyl)benzothia- zole (BTT) 3 with metal/ligand composition of 1:2 and 1:1, HN respectively have been evaluated by Cuin and co-workers S which shows good activity against M. tuberculosis. The ligand NH2 N has been treated with silver(I) nitrate or gold(I) chloride in – methanol to afford silver ([Ag(BTT)2NO3] AgBTT2) and gold 1 ([Au(BTT)Cl]. /2H2O–AuBTT) complex, respectively. Interesting- Figure 1. Marketed drugs of benzothiazole. ly, silver(I) complex has been found to be more effective as compared to commercial drug silver sulfadiazine. However, BTT has been found to be less active against M. tuberculosis Benzothiazole as antitubercular agent [31]. Tuberculosis (TB) is a fatal contagious disease caused by Mannich bases of sulfadiazine, sulfamethoxazole, sulfacet- infection with Mycobacterium tuberculosis but also with M. amide with 2-amino-3-methyl-benzothiazole, 2-amino-5- bovis and M. africanum, which can affect almost any tissue or chloro-benzothiazole and 2-amino-5-chloro-6-fluoro-benzo- organ of the body, the most common site of infection of the thiazole have been reported to determine their efficacy against disease being the lungs [22]. The lack of efficacy of Mycobacterium. From this series, compound 4a (N0-(benzo[d]- antimycobacterial agents is due to the ability of M. thiazol-2-ylaminomethyl)sulfanilamide), 4b (N0-(5-chlorobenzo- tuberculosis to develop alternative metabolic routes and [d]thiazol-2-ylaminomethyl)sulfanilamide), 4c (N0-(5-chloro-6- insufficient drug permeability through mycobacterial cell fluorobenzo[d]thiazol-2-ylaminomethyl)sulfanilamide), 4d (N0- wall. (5-chlorobenzo[d]thiazol-2-ylaminomethyl)-N0-(pyramidin-4-yl)- The mycobacterial cell wall consists of three main compo- sulfanilamide) were found potent inhibitors of M. tuberculosis nents that form the mycolyl-arabinogalactan-peptidoglycan H37 RV strains [32] (Fig. 2). (mAGP) complex. Mycolic acid, which is the outermost layer of cell wall, consists of high-molecular-weight R-alkyl-b-hydroxy Benzothiazoles as antimicrobial agents fatty acids and is mainly present as trehalose monomycolate An antimicrobial agent reduces/blocks the growth and (TMM), trehalose dimycolate (TDM or cord factor) and esters multiplication of bacteria [33]. These agents are among the of arabinogalactan [23]. The first line chemotherapeutics for most common and often injudiciously used therapeutic drugs the treatment of TB include isoniazid and ethambutol which worldwide [34], and consequently resulted in emergence of inhibit mycobacteria by distressing the synthesis of mycolic antibiotic-resistant pathogens. Regardless of considerable acids and arabinan, respectively. A range of multi-drug advancement in the field of antimicrobial therapy, infectious resistant strains of TB (MDRTB) and drug resistant tuberculosis diseases caused by bacteria or fungi remain a major challenge. (XDR-TB) have also emerged [24, 25]. Thus, there is a need to Thus, there is an ever-increasing need to develop new develop novel, nontoxic, cell permeable, multidrug resistant molecules with better antimicrobial profile. For this, different antitubercular agent. In spite of numerous attempts for approaches have been employed by modifying the benzo- synthesis of novel anti-TB agents, benzothiazole always thiazole or by synthesizing hybrid molecules having synergis- displayed a most versatile class of compounds against tic effect through the combination of different microbes [26–30]. Some prominent reports from recent pharmacophores to enhance the antibacterial and antifungal literature have been discussed in this section. potential. Few of such examples have been summarized here. A series of novel, 2-(2-(4-aryloxybenzylidene)hydrazinyl)- Thiourea derivatives of benzothiazoles 5 have been found benzothiazoles have been designed on the basis of molecular to possess significant antimicrobial activity. In vitro study hybridization approach by combining the 2-hydrazinylben- revealed that higher activity is exhibited against fungi than zothiazole and 4-(aryloxy)benzaldehyde. Almost all the bacteria, while compounds bearing NO2 at position-5 of synthesized compounds displayed significant activity (MIC ¼ benzothiazole nucleus displayed significant activity against 1.5–29.00 mg/mL against M. tuberculosis H37Rv). Among both the bacteria and fungi [35]. them, five of the tested compounds exhibit MIC value of A series of Schiff bases of benzothiazole, 5-[2-(1,3-benzothia- <3.0 mg/mL, whereas, chloro substituted (E)-6-chloro-2-(2-(4- zol-2-yl-amino)ethyl]-4-(arylideneamino)-3-mercapto-(4H)-1,2,4- (2,4-dichlorophenoxy)benzylidene)hydrazinyl)benzothiazole 6 have been investigated for antibacterial and antifun- 1 displayed most potent activity (MIC of 1.5 mg/mL) [1]. gal activity by Soni and co-workers. Compound 6a, 5-[2-(1,3- Several derivatives of benzimidazolyl-1,3,4-oxadiazol-2-yl- benzothiazol-2-yl-amino)ethyl]-4-(4-dimethylaminobenzyli- thio-N-phenyl-(benzothiazolyl)acetamides have been screened deneamino)-3-mercapto-(4H)-1,2,4- possesses highest

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N N N N N H NH N N N Cl S Cl O S O S O Cl 2 R 1 2a:R=F 2b:R=OCH3 O 1 N R N S S N N O H S R3 S R2 H2N BTT 3 4 4a:R1 =H,R2 =H,R3 =H 4b:R1 =Cl,R2 =H,R3 =H 4c:R1 =Cl,R2 =F,R3 =H 1 2 3 4d:R =Cl,R =H,R =C4H3N2 Figure 2. Benzothiazoles as antitubercular agents antibacterial activity, while compound 6b, 5-[2-(1,3-benzo- (MIC 3.125 and Cp MIC 19.5 mg/mL). In addition, Schiff bases of thiazol-2-yl-amino)ethyl]-4-(3,4-dimethoxybenzylideneamino)- benzothiazole and quinazolinone linked through imine 3-mercapto-(4H)-1,2,4-triazole exhibits excellent activity linkage, 6-bromo-2-(2-methyl-2-phenyl-1,2,3,4-tetrahydro- against both the C. albicans and A. niger [36]. quinazolin-4-imino)benzo[d]thiazol-2-amine, 13, exhibited Amide linkage of 2-amino with 2-aminobenzo- highest activity against Salmonella paratyphyi (MIC ¼ 3.125 thiazole as in compound 7 displayed comparable activity with and ciprofloxacin MIC ¼ 43.4 mg/mL) [38]. Another compound chloroamphenicol against S. aureus (MIC ¼ 3.125 mg/mL), 14, exhibited moderate inhibitory activity against few whereas about 50% decrease in activity has been observed bacterial strains (Escherichia coli, Staphylococcus aureus) against S. pyogenes than chloroamphenicol [3]. In another and fungal strains (Candida albicans, Aspergillus niger) [4] series, 8 and pyrazolo[1,5-a] 9 were (Fig. 4). found to be most active against A. fumigatus and F. Further, thiazolidines 15 and azetidin-2-ones 16 have been oxysporum (MIC ¼ 6.25 mg/mL) [3] (Fig. 3). investigated for their antimicrobial activity. Among them, Further, imidazo[2,1-b][1,3]benzothiazoles 10 and 11 have compounds 15c, 15d, 15g, 16c and 16f were found as most been reported for their strong inhibitory activity against active antibacterial agents whereas compounds 15c, 15d, 15f, bacterial and fungal strains compared to standard antibacte- 16e and 16g were found to be potent antifungal agents [39]. rial (amoxicillin and cefixime) and antifungal (fluconazole) Afterward, more thiazolidinone incorporated benzothiazoles [37]. Substitution on side chain with guanidine propanoic acid have been synthesized and evaluated for antimicrobial as in compound 3-(3-(6-bromobenzo[d]thiazol-2-yl)guani- activity. The most active compounds identified from the dino)propanoic acid 12 displayed better activity profile than above series was 3-(4-(benzo[d]thiazol-2-yl)phenyl)-2-(4- the standard ciprofloxacin against Pseudomonas aeruginosa methoxyphenyl)thiazolidin-4-one 17a and 3-(4-(benzo[d]-

O2N N N N S O N SH N N O NH N R S S N R H NH H S N HN 2 5 6 O R=4-NO -Ph, thiophen-2-yl, Ph, HN S 2 6a:R=4-N(CH3)2 n-butyl, morpholin-2-yl O 6b:R=3,4-OCH3

N O 7 CN S N N H O N SN N N NH S HN

8 9

Figure 3. Benzothiazoles as antimicrobial agents.

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F S O F S R OH N N N HN N NH R N NH NH NH N Br S F H F N 12 10 11 R=Br,F R=Br,F S O N N N HN N N N NH N S Br S O N 13 14

Figure 4. Benzothiazoles as antimicrobial agents. thiazole-2-yl)phenyl-2-(4-hydroxy-phenyl)thiazolidin-4-one their target at different stages of the life cycle of the parasite. 17b, which exhibited significant activity against E. coli and However, some of the mosquitoes are reported to be resistant C. albicans (MIC ¼ 15.6–125 mg/mL) [40]. Another compound, to the commercial antimalarial drugs that are used in the 4-(4-hydroxyphenyl)-4H-pyrimido-[2,1-b]-[1,3]benzothiazole treatment of malaria [45] and also to insecticides used in curcumin 18, has been identified as a potent antibacterial vector control [46]. Thus, there is a need to develop new drugs agent against many species (Pseudomonas aeruginosa, Salmo- that should aid in resistance management. New benzothia- nella typhi, Escherichia coli, Bacillus cereus and Providencia zoles having broad antimalarial potential are discussed in this rettgeri), particularly it has equipotent activity with ciproflox- section. acin against S. aureus [41]. A series of amodiaquine analogues 22–24 of benzothiazoles In another comparative study of some heterocyclic com- have been screened for antiplasmodial activity against W2 pounds containing 19a and benzothiazole 19b and K1 chloroquine resistant strains of Plasmodium falcipa- nucleus, it has been observed that benzothiazoles are more rum. These compounds also block the formation of toxic active than the oxazole bearing derivatives in antimicrobial quinone imine and aldehyde metabolites as benzo-heterocy- assay [42]. Several benzothiazoles bearing 1,2,3-triazole clic ring system is attached to the 4-amino-7-chloroquinoline nucleus have been screened for antimicrobial activity and ring, without affecting antiplasmodial activity. From this compound 20a was found as most potent compound against series, compounds 22, 23, and 24 possess excellent ability to S. aureus, E. faecalis, S. typhi, E. coli, K. pneumonia, P. inhibit W2 and K1 chloroquine resistant strains of Plasmodium aeruginosa, with MIC value 3.12 mg/mL. Whereas, compound falciparum [47]. 20b displayed maximal potency against all the fungal strains Further, several derivatives of 2,6-substituted and 2,4- such as C. tropicalis, C. albicans, C. krusei, Cryptococcus substituted-benzo[d]thiazoles 25 have been screened for neoformans, A. niger, A. fumigatus [43] (Fig. 5). mosquito repellent activity against Anopheles arabiensis. Recently, a series of 6-(benzothiazol-2-yl)pyrido[2,3-d]- Among them, compounds 25b, 25c and 25d displayed highest 21 has been evaluated for their antibacterial repellent activity equivalent to the positive control N,N- and antifungal activity by Lavanya and co-workers. Among diethyl-m-toluamide (DEET) [5] (Fig. 7). the newly synthesized compounds, most of the compounds exhibited significant antibacterial and antifungal activity Benzothiazoles as anticonvulsant agent against Staphylococcus aureus, Escherichia coli, Klebsiella Epilepsy is a central nervous system disorder in which the pneumoniae, Pseudomonas aeruginosa, Streptococcus pyo- normal neuronal activity is disturbed, causing strange genes, Aspergillus flavus, Aspergillus fumigatus, Candida sensations, emotions, abnormal behaviour or sometimes albicans, Penicillium marneffei and Mucor than the standard convulsions, muscle spasms and loss of consciousness. Epilepsy drugs ciprofloxacin and clotrimazole [44] (Fig. 6). may happen due to an imbalance of neurotransmitters, abnormality in brain wiring, change in ion channels or Benzothiazoles as antimalarial agent sometime combination of these and other factors [48]. Malaria is a parasitic disease caused by the bite of an infected Currently, various novel anticonvulsants have been used anopheles mosquito in tropical and subtropical zones of the clinically such as pregabalin, stiripentol, zonisamide, tiaga- world. The easiest way to prevent malaria is to take bine, lamotrigine, levetiracetam, topiramate and many antimalarial drugs prophylactically before entering in an others. However, these drugs have limited use because of endemic area. Antimalarial agents are classified according to their serious side effects such as headache, nausea,

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R R O S Cl O N N NH O N S NH N O S N Cl S Cl N H R S H N 15 16 17 O 15a:R=H 15e:R=2-OCOCH3 16a:R=H 16e:R=2-OCOCH3 15b:R=2-Cl 15f :R=2-OCH 16b:R=2-Cl 16f :R=2-OCH 17a: R = CH3 15c:R=2,4-Cl 3 3 17b:R=OH 15g:R=4-NO 16c :R=2,4-Cl 16g:R=4-NO2 15d:R=2-CH 2 3 16d:R=2-CH3

HO

O OH N O N N O S R O O N 19a N OH S R=CN,NO2,OCH3 18 O N N R N N N R N O S N N R1 N R1 OCnH2n+1 19b 20 20a:RR = F, 1 =F 20b: R = H, R1 =Br

Figure 5. Benzothiazoles as antimicrobial agents.

hepatotoxicity, anorexia, ataxia, drowsiness, gastrointestinal substitution have been tried at benzene ring, among these disturbances and hirsutism [49–53]. To overcome these side new derivatives, compounds 3-(benzo[d]thiazol-2-yl)-6-bro- effects, various efforts have been made by researchers to mo-2-ethylquinazolin-4(3H)-one 28a and 6-bromo-2-ethyl-3- develop new promising anticonvulsant agents. Here, we have (6-methoxybenzo[d]thiazol-2-yl)quinazolin-4(3H)-one 28b spotted some recent literature reports where new benzo- have shown excellent activity against tonic seizure in the thiazoles have been investigated for their potential anticon- maximal electroshock (MES) model and clonic seizure by PTZ- vulsant property. induced seizure model, respectively [6]. 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 evaluated O for neurotoxicity, hepatotoxicity and behavioural study by H2N NH Bhusari and co-workers. From this study, compound 6-methyl- N NH 2-[(1-acetyl-5-(4-chlorophenyl))-2-pyrazolin-3-yl]aminobenzo- N N thiazole 26 was found to be the most promising compound, S N equivalent to standard phenytoin [54]. A series of N-(substituted benzothiazol-2-yl)amides have been synthesized and evaluated for their anticonvulsant and R Cl neuroprotective effects. The N-(6-methoxybenzothiazol-2-yl)- 21 4-oxo-4-phenylbutanamide 27 displayed greatest neuropro- 21a:R=4-Cl 21b:R=4-NO tective effect by lowering the levels of MDA and LDH [55]. 2 21c :R=4-OCH3 21d:R=2,4-(CH3)2 Replacement of heterocyclic ring with quinazolin-4-one and 21e :R=4-F 21f :R=4-C2H5 subsequently derivatization on benzene ring of benzothia- zole gave some potent anticonvulsant compounds. Variety of Figure 6. Benzothiazoles as antimicrobial agents.

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N H N H N N N N HN S HN S

Cl N Cl N 22 23 R2 N H N S N HN S N 25a:X=CH,R1 =4-OH,R2 =6-Cl R1 NH 25b:X=CH,R1 =H,R2 =6-Cl 1 2 25c:X=CH,R =4-NO2,R =6-Cl Cl N OH 1 2 25d:X=N,R =4-OCH3,R =6-Br 25e:X=CH,R1 =4-OCH,R2 =4-CH 24 3 3 X 25

Figure 7. Benzothiazoles as antimalarial agents.

In an another series of N-(benzo[d]thiazol-2-ylcarbamoyl)-2- compounds from this series were found to be potent methyl-4-oxoquinazoline-3(4H)-carbothioamides, compound anticonvulsants. Interestingly, antiphenamine action was 29a, [2-methyl-4-oxoquinazoline-3(4H)-carbothio-N-(6-chlor- highly expressed for thiazolyl propanamide derivatives 30c obenzo[d]thiazol-2-ylcarbamoyl)amide, and 29b, [2-methyl-4- [7] (Fig. 8). oxoquinazoline-3(4H)-carbothio-N-(6-trifluoromethoxybenzo- [d]thiazol-2-ylcarbamoyl)amide were found very potent com- Benzothiazoles as anthelmintic agents pared with standard phenytoin and ethosuximide, in anticon- Anthelmintics are used to treat infections with parasitic vulsant assay. These compounds also exhibit anticonvulsant worms by either stunning or killing them. Recent reports on activity against (S)-2-amino-3-(3-hydroxyl-5-methyl-4-isoxa- development of resistance by parasites insist researchers to zolyl)propionic acid (AMPA) and g-amino butyric acid (GABA) search for newer drugs with more selectivity and lower induced seizures [56]. toxicity profile. Number of benzothiazoles has been synthe- A novel series of N-[(benzo)thiazol-2-yl]-2/3-[1,2,3,4-tetra- sized for better anthelmintic property. Benzothiazoles are hydroisoquinolin-2-yl]ethan/propanamides 30 have been considered as sulfur isosteres of and are well synthesized by Zablotskaya and co-workers. Most of the reported for anthelmintic activity.

Cl R

O S O O Br O N N N N N H N N N S O NH 28 S 26 27 28a:R=H 28b:R=OCH R 3

N O N O S HN S N n N S C H N N O H 30 N 30a: n=1 29 30b: n=2 29a:R=Cl 30c: n=3 29b:R=OCF3

Figure 8. Benzothiazoles as anticonvulsant agents.

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S N R N S N NH N Cl O NH2 N NH O O N S N 2 H 31 O 32 N H 32a:R=Cl 33 32b:R=NO2 Figure 9. Benzothiazoles as anthelmintic agents.

New series of substituted 2-amino-benzothiazoles 30 have are more potent as they are comparable with the standard been reported for anthelmintic activity against Eudrilus drug pentazocine [64]. eugeinae and Megascoplex konkanensis. Most of the new Further, 1,2,3-triazole has been attached to 2-mercapto- compounds have shown appreciable anthelmintic activity benzothiazole ring and investigated for their anti-inflamma- equivalent to standard mebendazole. Compound 31 has the tory activity. Compound 38b exhibited potent selective COX-2 better anthelmintic activity among 2-amino-substituted inhibition whereas compounds 38a–d possess excellent anti- benzothiazoles substituted with chloro, fluoro, bromo, inflammatory activity as compared to the standard drug methyl, ethyl, methoxy or dimethyl group at sixth position ibuprofen. Moreover, these compounds have no ulcerogenic of benzothiazole [57]. Substitution with heterocyclic systems potency [10]. at position-2 of benzothiazole provides some potent anthel- In an another study, some novel derivatives of 4H-pyrimido mintic compounds. Among other derivatives of 3-(2-hydrazi- [2,1-b][1,3]benzothiazole-3-carboxylates 39 have been evalu- nobenzothiazole)-substituted -2-one, compound 32a,b ated for their anti-inflammatory potential. Number of and 33 have shown the most potent activity comparable to compounds from this series showed significant activity. standard drug albendazole in in vitro assay [58] (Fig. 9). However, compound ethyl-(4R)-2-amino-6-chloro-4-(3,4,5-tri- Similarly, a series of 1-[2-(substituted phenyl)-4-oxothiazo- methoxyphenyl)-4H-pyrimido[2,1-b][1,3]-benzothiazole-3- lidin-3-yl]-3-(6-fluoro-7-chloro-1,3-benzothiazol-2-yl)ureas 34 carboxylate 39 has been found to possess the most promising have been reported for anthelmintic activity against Perituma anti-inflammatory activity for further studies [65] (Fig. 11). posthuma. Compounds 34a and 34b containing methyl and Recently, pyrazolo[3,4-d]pyrimidines 40 have been attached methoxy group at C-3 and C-2 position of phenyl ring have with benzothiazole and investigated for their in vivo been found to be the most potent compounds [8] (Fig. 10). acute toxicity, analgesic, anti-inflammatory, and ulcerogenic potential. Compound 1-(1,3-benzothiazol-2-yl)-4-(4-dimethyl- Benzothiazoles as analgesic and aminophenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine 40b anti-inflammatory agents showed the most potent analgesic and anti-inflammatory Non-steroidal anti-inflammatory drugs (NSAIDs) exert their activity. In addition, these compounds were found to have analgesic effect by peripheral inhibition of prostaglandin (PG) significant gastrointestinal protection activity [9] (Fig. 12). through inhibition of the cyclooxygenase (COX) enzyme, which catalyzes the conversion of arachidonic acid into PG Benzothiazoles as antidiabetic agents [59]. However, PG has a dual function, mediation of Diabetes is a group of metabolic diseases that leads to high inflammation [60] and cytoprotection against HCl [61] in blood glucose level. In type-1 diabetes, insulin production is the stomach and intestine. Long term use of NSAIDs for the inadequate, while in case of type-2 diabetes, body cells do not treatment of pain and inflammation may lead to gastrointes- tinal (GI) disorders and renal toxicity [62]. Hence, there is always a need to overcome ulcerogenic effect and improve- N ment in analgesic and anti-inflammatory activity by develop- NH ’ F S NH ment of NCE s. R Several derivatives of 2-amino-6-substituted benzothiazole Cl O N 35 and 2-chloro-acetyl-amino-6-substituted benzothiazole 36 O S 34 have been screened for anti-inflammatory activity. Most of 34a:R=3-CH the compounds have shown significant anti-inflammatory 3 34b:R=2-OCH3 activity in in vitro models [63]. It has been found that benzothiazoles bearing pyrazolyl system as in compound 37 Figure 10. Benzothiazoles as anthelmintic agents.

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N N N N O S N NH2 N H Cl R S R S 35 36

R=H,CH3,OCH3,F,Cl R=H,CH3,OCH3,F,Cl R 37 R=Br,OC H ,Cl,OCH N N 2 5 3 N S N S N S R N NH2 Cl 38 O 38a: R = o-Cl O O 38b: p-F 38c: p-Br p O O 38d: -NO 2 Figure 11. Benzothiazoles as analgesic and anti- 39 inflammatory agents.

respond properly to insulin (insulin resistance). This results in hence, increase in release of intracellular calcium in the beta disorders such as polyuria (frequent urination), polydipsia cell and subsequent stimulation of insulin release. (increasingly thirsty) and polyphagia (hungry) [66]. Excess of Several derivatives of novel (E)-3-(benzo[d]thiazol-2-yl- glucose level in blood may also lead to serious health amino)phenylprop-2-en-1-ones 42 have been evaluated for problems such as damage to the eyes, kidneys, nerves, heart their antidiabetic activity, and majority of the compounds disease, stroke and even sometimes the need to remove a have shown appreciable antidiabetic activity [68]. limb. Pregnant women may also get diabetes, called In another study, various benzothiazoles have been gestational diabetes [67]. There are some reports in literature synthesized which enhance the rate of glucose uptake in L6 where benzothiazoles have been screened for their antidia- myotubes in AMPK-dependent manner. Among them, 6- betic property. ethoxy substituted benzothiazole as in compound 43 enhan- Substitution on side chain of 2-amino-benzothiazole with ces the rate of glucose uptake by up to 2.5-folds in comparison 2-(substituted amino)acetamide as in compound N-(6-chlor- with vehicle-treated cells and up to 1.1-fold, compared to 2- obenzo[d]thiazol-2-yl)-2-morpholinoacetamide 41, have chloro-5-((Z)-((E)-5-((5-(4,5-dimethyl-2-nitrophenyl)-2- shown maximum glucose lowering effects comparable to yl)-methylene)-4-oxothiazolidin-2-ylidene)amino)benzoic ac- the standard drug glibenclamide, when tested for its id (PT-1, 44). It has been observed that compound 43 fits in the hypoglycaemic activity by streptozotocin-induced diabetic three pharmacophoric features that are considered to be model in rat [11]. It is believed to act by activating the essential for the activity such as hydrophobic, aromatic and H- sulfonylurea receptor 1 (SUR1), the regulatory subunit of the bond acceptor [69] (Fig. 13). ATP-sensitive potassium channels (KATP) in pancreatic beta cells. This causes the depolarization of cell membrane and Benzothiazole as anticancer agents leads to opening of voltage-dependent calcium channel and, A large number of benzothiazole derivatives have shown potent anticancer activity. Some of the recent literature reports are summarized in this section. Novel derivatives of N-alkylbromo-benzothiazoles 45 have been evaluated for their anticancer potency. Most of the N N R fi N compoundsinthisserieshaveshownsigni cant cytotoxic activity. S However, compound 45, (3-bromo-propyl)-(6-methoxy-benzo- N thiazol-2-yl)amine has been found to be the most promising N anticancer agent against the PC-3 (IC ¼ 0.6 mM), THP-1 (IC ¼ 40 50 50 3 mM) and Caco-2 cell lines (IC ¼ 9.9 mM), respectively [70]. 40a:R=3-NO 50 2 Further, cadmium and indium complexes of benzothiazoles 40b:R=4-N(CH3)2 have been synthesized and tested for their anticancer activity Figure 12. Benzothiazoles as analgesic and anti-inflammatory by cell-based cytotoxicity assays. It has been found that agents. ligands (2-(pyridin-2-yl)benzo[d]thiazole and 2-(pyridin-4-yl)-

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R2

O 1 N R O N O HN S N CH2 NH S 1 R =H,CH3,OC2H5 Cl S 2 3 42 R =H,CH3 41 R 3 R =Br,Cl,F,CH3,OCH3

O HO N O Cl N S O S NO2 S S O N N Figure 13. Benzothiazoles as antidiabetic 43 H PT-1 , 44 agents. benzo[d]thiazole) are biologically inactive, while the cadmi- Substitution of pyrazolo[1,5-a]pyrimidine carboxylic acid at um complex 46 and 47 exhibits significant cytotoxic activity in position-2 of amino benzothiazole scaffold through an amide pancreatic cancer cell lines with IC50 values <16.0 mM [71]. functionality has been reported and the resulted compounds Further, new amidino derivatives of phenylene-bisbenzo- 52 have been screened for their anticancer activity against thiazoles 48 have been screened for their antiproliferative five human cancer cell lines; among these compounds, two activity against several human cancer cell lines, as well as DNA- compounds 52a and 52b were found to possess appreciable binding properties and all of new compounds exhibited anticancer activity. Both of these compounds also have significant antiproliferative effects on tumor cells in concen- potential to arrest G2/M cell cycle in A549 cancer cell line tration dependant manner. The most cytotoxic compound and cause reduction in Cdk1 expression level [75] (Fig. 15). was diimidazolinyl substituted phenylene-bisbenzothiazole These reports explain the importance of benzothiazoles for

48a with IC50 ¼ 5.3, 0.87, 6.19, 1.49, 6.63, 7.38 against MCF-7, their leading pharmacological activities. However, construction SK-BR-3, SW620, MiaPaCa-2, WI38 and HeLa cancer cell lines. of benzothiazole ring in high yield is still a challenging task. In addition, imidazolyl substituted phenylene-benzothiazole 48b has displayed highest selectivity towards tumor cells as it is devoid of cytotoxic effects on normal fibroblasts [72]. Synthetic methodology Substitution with heterocyclic ring systems at position-2 of 2- amino-benzothiazole provides new derivatives of . There are a number of methods that have been used to The 4-benzothiazole-amino- 49 were investigated synthesize benzothiazoles. Here, in this section we have for their in vitro cytotoxic activity. Among these derivatives, elaborated the most efficient and practically easy methods for compounds bearing 2,4,6-trimethylaniline as in compound 49 the synthesis of benzothiazoles. For better understanding and have shown the most potent anticancer activity. Further, depending on the starting material used, we have divided it compounds in the series 49a and 49b have been found to into six different sections. possess significant dual Src/Abl kinase inhibitory activity [12] (Fig. 14). Synthesis of benzothiazoles by utilizing A novel series of N-(-2-yl-methylene)benzo[d]thia- 2-aminothiophenol zol-2-amine and its Cu(II), Fe(III), Co(II), Ni(II) and Zn(II) Synthesis of benzothiazoles from different aldehydes, complexes have been synthesized and evaluated for their using aminothiophenol anticancer potential. Zn complex 50 has been found most An efficient synthesis of 2-substituted benzothiazoles 55 has active in human breast carcinoma (MCF-7), liver carcinoma been reported in high yield by condensation of 2-amino- (HEPG2), colon carcinoma (HCT116) and larynx carcinoma thiophenol 53 and substituted aromatic aldehydes 54 in N,N- (HEP2) cell lines [73]. dimethylformamide (DMF) and sodium metabisulfite

Another series of new benzothiazole- based con- (Na2S2O5) under reflux conditions of 2 h [76] (Scheme 1). jugates 51 have been reported for cytotoxic activity against Further, somewhat similar method has been utilized for MCF-7 cell line. Compounds 51a and 51b were found effective synthesis of benzothiazoles 57 by initially treating aromatic in inducing apoptosis in MCF-7 cells. Compound 51a has also aldehyde 56, (diethylamino)phenyl)-1,3,5--2,4-diyl)bis- shown down-regulation of oncogenic expression of Ras and (oxy))dibenzaldehyde (DIPOD) with solution of NaHSO3 in its downstream effector molecules such as MEK1, ERK1/2, ethanol at room temperature and then subsequently added p38MAPK and VEGF [74]. o-aminothiophenol 53 in DMF under reflux conditions for 3 h

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S N H N N O O N Br S O O N S O Cd N Cd N O 45 O S O N OH2 O H2O 46 47 R1 N N Cl- HN - N Cl S S N N HN S O HN NH O 49 48 N R N 49a: R=2-Cl,6-CH3 48a = 49b: R = 2,4,6-OCH3

48b = R1 N O , N O

N O , N O

O N O etc.

Figure 14. Benzothiazoles as anticancer agents. to afford targeted compound 57 in 74% yield [26]. Synthesis reaction of o-aminothiophenol 53 with aryl aldehyde 58 in of benzothiazole from o-aminothiophenol and substituted the presence of 30% H2O2 and cerium ammonium nitrate benzaldehyde with some modifications is common, as found in (NH4CeNO2) in acetonitrile at 50°C [79, 80] (Scheme 3). Beside many literature reports [77, 78] (Scheme 2). this, 2-substituted benzothiazoles 59 have also been synthe- In a quite similar approach, synthesis of benzothiazoles 59 sized from substituted aldehyde and o-aminothiophenol in from aryl aldehyde and o-aminothiophenol 53 involves the presence of various catalysts and reaction conditions such as

1 R N N 2 S SNN S R R3 6 N N R Zn 5 4 N R R N 51

1 3 2 4 5 6 50 51a:R =R =H,R =OCH3,R =R =R = 3,4,5-OCH3 1 2 3 4 5 51b:R =R =R = 3,4,5-OCH3,R =H,R =OCH3

N N N R4 H N R1 N S R5 O R2 R3 52 52a:R1 =R3 =R4 =R5 =H,R2 =F 52b:R1 =R2 =R3 =OCH,R4 =R5 =H 3 Figure 15. Benzothiazoles as anticancer agents.

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montmorillonite, SiO2/graphite; under MW and p-TsOH [81], Synthesis of benzothiazoles from carboxylic acids, using diethyl bromophosphonate/t-butyl hypochlorite; acetonitrile aminothiophenol

[82], H2O2/HCl in ethanol [83], AcOH/air; MW or thermal A peculiar method for synthesis of naphthyridine derivatives heating [84] and Baker’s yeast, dichloromethane [85], etc. of benzothiazole 71 has been described by You and co- Solid-phase synthesis of benzothiazoles from 2-amino- workers [88]. In this method, o-aminothiophenol 67 under- thiophenol has been reported using hydroxymethyl group goes cyclization on treatment with naphthyridine-3-carbox- of Wang resin or the R-amino group of an amino acid 60 ylic acid 68 in presence of polyphosphoric acid (PPA) at 170– bound to Wang resin as starting point [86]. 4-Fluoro-3- 250°C and affords compound 69 in moderate yield. Conse- nitrobenzoic acid 61 was attached to supporting resin by N,N0- quently, intermediate 69 was nitrated to give intermediate diisopropylcarbodiimide (DIPCDI) and 4-(dimethylamino)pyri- 70, which is followed by reduction of compound 70 with Pd/C dine (DMAP) (1.0 equiv) in DMF (Scheme 4). Thereafter, sulfur affording the final product 71 in 40–73% yield (Scheme 6). group has been introduced by nucleophilic aromatic substi- Recently, a robust method for the coupling of 2-amino- tution of aryl fluoride by triphenylmethyl mercaptan (Trt-SH) thiophenol 53 with amino acid (or ester) 72 has been in DMF, in the presence of N,N-diisopropylethylamine (DIEA) developed by Santos and co-workers to give access to 2- to afford intermediate 62, followed by reduction of nitro substituted benzothiazoles 73 [89]. In this reaction, 2-amino- group of 62 with SnCl2 in DMF to get access to the aniline thiophenol 53 was reacted with amino acid (or ester) such as intermediate. Then, thiol group was unmasked to obtain glycine ethyl ester and D-valine to give corresponding resin-bound 2-amino-4-carboxythiophenol 63 by treating benzothiazole 73, in the presence of dehydrating agent such with TFA-triethylsilane (TES)-CH2Cl2 (2:5:93). Finally, a series as PPA at 220°C within 4 h. It has been observed that of benzothiazoles have been synthesized by treating com- benzothiazoles are produced in high yield when ethyl ester of pound 63 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone amino acid has been used as starting material instead of (DDQ)-mediated oxidative cyclo-condensation with various amino acid (Scheme 7). aldehydes. Thereafter, resin-bound benzothiazoles were A convenient single step method for the synthesis of 2- cleaved from resin by utilizing TFA-H2O (19:1) to give access aryl benzothiazoles 75 has been reported by utilizing to substituted benzthiazoles 64 in good yield. It has been substituted aminobenzoic acid 74 and 2-aminothiophenol observed that substitution of aliphatic, cyclohexyl, thiophene 53 in the presence of PPA at higher temperatures [90, 91]. and unsubstituted phenyl ring at 2-position of benzothiazole Simultaneously, 4-nitrobenzoic acid 76 was employed for enhances the yield. However, phenyl ring substituted with synthesis of benzothiazole 77, subsequent reduction of 77 electron withdrawing or electron donating groups provides using Fe/NH4Cl gave access to compound 75 in 90% yield. It comparatively less yield. Bulky substitutions such as naphtha- has been observed that electron withdrawing groups on the lene ring also provides very low yield (Scheme 4). benzoic acid counterpart gave high yields of the product Recently, a facile method for the synthesis of benzothiazole (Scheme 8). has been described by Gulcan and co-workers using o- aminothiophenol 53 and 4-tert-butyl-2,6-diformylphenol 65 Synthesis of benzothiazoles from alcohols, using (2:1 ratio) under refluxing condition in ethanol for 24 h to aminothiophenol afford desired benzothiazole 66 in high yield [87] (Scheme 5). There are few reports in literature where alcohols have been used as starting material. One-pot tandem approach was reported by Rangappa and co-workers for synthesis of benzothiazoles 79 in excellent yields, using variety of alcohols 78 and o-aminothiophenol 53 without any oxidant [92]. This process includes oxidation of alcohols to aldehydes followed by cyclization with o-aminothiophenol 53 and finally propyl-

NH2 O N phosphonic anhydride (T3P) mediated dehydrogenation Na2S2O5 + R under mild reaction conditions (0–25°C). Closer look to the R SH DMF, reflux 2 h S scope of reaction depicts that the reaction of o-amino- 53 54 55 thiophenol 53 with variety of aromatic, aliphatic and 26 examples heterocyclic substituents reacts well under these optimized reaction conditions and provides access to high yield of the HO O HO O product (Scheme 9). , R= , OH Synthesis of benzothiazoles from diones, using aminothiophenol OH , etc. Guzel and co-workers have reported the synthesis of 3H-spiro- [1,3-benzothiazole-2,30-indol]-20(10H)-ones 83 and 10-methyl- 0 0 Scheme 1. Synthesis of benzothiazoles from substituted 3H-spiro[1,3-benzothiazole-2,3 -indol]-2 (10H)-ones 84 utiliz- aldehydes, using aminothiophenol. ing 5-substituted 1H-indole-2,3-diones 80 or 5-substituted 1-

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O H H O

S O O N O a) NaHSO3,C2H5OH, r.t. N N NN N N SH N S b) ,DMF,reflux,3 h O NH 2 N 53 57 N Yield: 74% 1example

56

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

HO HO NH N 2 H O /CAN + 2 2 neat, 50°C S SH O Scheme 3. Synthesis of benzothiazoles from dif- 59 53 58 ferent aldehydes, using aminothiophenol. methyl-1H-indole-2,3-diones 82 as starting material [93]. The diones82,respectivelyunderoptimizedconditionsingoodyield reaction sequence starts by generating carbanion on treating 5- (Scheme 10). substituted 1H-indole-2,3-diones 80 with NaH in DMF, followed by addition of iodomethane 81 to get access to 5-substituted 1- Synthesis of benzothiazoles from amines, using methyl-1H-indole-2,3-diones 82. Finally, 3H-spiro[1,3-benzo- aminothiophenol thiazole-2,30-indol]-20(10H)-ones 83 and 10-methyl-3H-spiro- Very recently, a very simple method has been adopted by [1,3-benzothiazole-2,30-indol]-20(10H)-ones 84 were obtained Narender and co-workers for the synthesis of 2-substituted by reacting 2-aminothiophenol 53 with 5-substituted-1H- benzothiazoles using molecular iodine [94]. The reaction of indole-2,3-diones 80 or 5-substituted 1-methyl-1H-indole-2,3- amine 85 with 2-mercaptoaniline 53 in the presence of

O OH O i) DIPCDI, DMAP, DMF, r.t., 4 h NO2 Y i) SnCl2 in DMF, r.t., 24 h ii) Trt-SH, DIEA, YH + ii) TFA-TES-CH Cl DMF, r.t., 24 h S-Trt 2 2 NO2 62 60 F 61 = polystyrene = Wang or Wang-CO-CH(R)-NH- Y O O i) R1-CHO, DDQ, CH Cl , 2 2 2 N NH 24 h, 25°C R 1 Y 3 R S ii) TFA-H2O(19:1),r.t.,1h S-H 64 63 1 R =Ph,4-OCH3-C6H4,4-Cl-C6H4,naphthyl, 4-NO2-C6H4, cycloalkyl, thiophen-3-yl, C7H15 2 R =OH, OH N H O

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

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NH2 Ethanol + O reflux, 24 h S S SH OH O N OH N 53 65 66 Yield: 77% Scheme 5. Synthesis of benzothiazole from 4-tert- 1example butyl-2,6-diformylphenol using o-amino-thiophenol.

1 O R N O NH2 HOOC F F PPA, N2 S + 170−250°C, 4 h 3 R1 SH N Y R N Y R3 Z Z 67 68 69 Yield: 15−51%

O N 2 N O H2N N O HNO ,H SO F 3 2 4 S 10% Pd/C F − S 35 40°C, 2 h r.t., 4 h 3 N Y R N Y R3 Z Z 70 71 Yield: 40−73% Y=C,N Z=H,F,(S)-CH(CH3)CH2O- 1 R =H,Cl,NO2,NH2

Scheme 6. Synthesis of benzothiazoles from carboxylic acids, using aminothiophenol. molecular iodine afforded the desired benzothiazole 86 at compound comprising disubstituted phenyl ring at 5, 7 room temperature. It has been observed that electron position of benzothiazole nucleus whereas compound com- withdrawing substitutent on the aromatic amines (at position prising monosubstituted phenyl ring at position 5 or 7 4 of phenyl ring) gave increased yields of the product than the provides low yield [95] (Scheme 12). electron donating substitutents. However, heterocyclic amines such as pyridin-2-yl-methanamine gave moderate Synthesis through metal catalyzed reaction yield (Scheme 11). Several methods have been reported for the synthesis of benzothiazoles using various metal catalyzed reactions. An By utilizing three-carbon synthon unprecedented palladium and copper-catalyzed procedure A 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 synthesized O NH by reacting chloroacetyl chloride 90 with trimethylsilylme- NH2 PPA N 2 X thylbenzotriazole 89. Compound 91 behaves as 1,2-dielec- + NH2 HO X 220°C, 4 h S R1 þ SH trophile and hence, undergoes [2 3]-type heterocyclization R1 73 with thiourea 92 to give intermediate N-[4-(1H-1,2,3-benzo- 53 72 1 R i X-R =CH2,CH-( )- Pr triazol-1-ylmethyl)-2-dimethylamino-1,3-thiazol 93 in 54% yield. Subsequently, intermediate 93 undergoes benzannela- Yield: 40-- 55% 2examples tion step by reacting with substituted chalcones 94 in ethanol in presence of sodium ethoxide to afford 2-aminobenzothia- Scheme 7. Synthesis of benzothiazoles from amino acids, using zole 95 in 25–74% yield. Highest yield was observed for the aminothiophenol.

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NH2 R1 NH 2 PPA N R1 + R R NH 220°C, 3 h 2 SH S COOH 75 53 73 Yield: 50-- 60%

R=H,2-Cl,3-CH3 Fe powder, NH4Cl 75% C2H5OH, reflux 2 h NO2 R1 NH2 N PPA R1 + R R NO 180°C, 5 h 2 SH S 77 COOH Scheme 8. Synthesis of benzothiazoles from 76 53 Yield: 90% aminobenzoic acid and aminothiophenol.

R NH T3P/ DMSO OH 2 Ethyl acetate N R + 0°C to r.t. 2-4 h SH S 78 53 79 R = H, 3-CN, 3-Cl, 2,4-F, 2-OCH3-4-F, 2-CH3-5-F Yield: 85-90% Scheme 9. Synthesis of benzothiazoles from alco- 7examples hols, using aminothiophenol.

O O NaH, CH3I R 81 R O O N DMF, 0.5 h ref lux, 4 h N H 80 82

NH NH2 EtOH, 2 EtOH, ref lux, 5 h ref lux, 5 h SH SH 53 53

HN HN R S R S O O N N H 83 84 R=CH3,CF3O, Cl, Br, NO2 R=CH3,Cl,NO2 Yield: 60-74% Yield: 39-75% 5examples Scheme 10. Synthesis of benzothiazoles 3examples from diones, using aminothiophenol.

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has been developed by Kundu and Nandi for the synthesis of provide benzothiazol-2-thiol 107. Further, the intermolecular (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles 99 C–S coupling reaction produces 2-arylthiobenzothiazoles 110 [96]. The 3-(2-aminophenylthio)prop-1-yne 96 has been in a single step. The optimized reaction condition that reacted with substituted aryl iodides 97 under palladium– provides high yield of 2-arylthiobenzothiazoles 110 utilizes copper catalyzed reaction condition at room temperature to CuI as precatalyst, K2CO3 as base, phenanthroline as ligand. afford disubstituted alkynes 98, within 24 h. Compound 98 However, use of less expensive cyclohexyl-1,2-diamine ligand after tosylation followed by cyclization with CuI in the 109 provides even higher yield in shorter reaction time (4 h). presence of triethylamine in THF gave access to (E)-2-(2- Superiority of this method is due to the use of inexpensive arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles 99 in 63– metal catalyst, ligand and requires low catalyst loading with 80% yield. Presence of 4-methyl and 2,4-dimethoxy group mild reaction conditions and shorter reaction times. Substitu- on aryl iodide gave targeted compounds in higher yield as tion of 4-nitrophenyl ring at 2-position of benzothiazole gave compared to 3-iodo and 1-naphthyl ring (Scheme 13). better yield while unsubstituted phenyl ring and 6-methoxy Another strategy has been reported by Batey and co- group provide lower yield (Scheme 16). workers for the synthesis of 2-aminobenzothiazoles 101 via palladium-catalyzed oxidative intramolecular C–S bond for- Synthesis of benzothiazoles by utilizing mation/C–H functionalization, utilizing an unusual co-cata- anilines lytic Pd(PPh3)4/MnO2 system under mild reaction conditions Various amines have also been used for the construction of [97]. It has been observed that MnO2 alone was not efficiently benzothiazoles, we present a few of such examples in this able to catalyze this reaction, hence a combination of Pd section. A simple and convenient base-promoted strategy has

(PPh3)4 and activated MnO2 has been used for oxidative been reported for the synthesis of a variety of 2-mercapto- cyclizations. Variety of N-arylthioureas 100 was used in this benzothiazoles 112. This tandem reaction utilizes commer- reaction and all of them provided high yield under these cially available o-haloanilines 111 and carbon disulfide 105 reaction conditions (Scheme 14). which were allowed to react in the presence of 1,8- A simple approach has been utilized by Li and co-workers diazabicyclo[5.4.0]undec-7-ene (DBU) to give corresponding through cyclization of o-iodothiobenzanilides 102 using Pd/C 2-mercaptobenzothiazoles 112 in good to excellent yields as a catalyst at room temperature for the construction of C–S [108]. Surprisingly, this intramolecular tandem condensation bond without using any ligand or additive [98]. This approach or S-arylation reaction has been achieved in absence of provides excellent yields under mild reaction conditions for transition metal catalyst. The optimal parameters for this varied substituents. Functional group and substrate compati- synthetic protocol to react aniline and carbon disulfide bility studies indicates that the electron withdrawing or utilizes DBU as a base, toluene as a solvent at 80°C for 16– donating groups at phenyl ring have very little effect on the 24 h. The plausible mechanism of this reaction involves the yields whereas substituents at o-position of phenyl ring gave nucleophilic attack of nitrogen from o-haloaniline 111 on the low product yield (Scheme 15). activated carbon disulfide 105 to afford the intermediate 113

In an another approach, synthesis of 2-arylthiobenzothia- (step a). Thereafter, via an intramolecular SNAr reaction zoles 110 has been reported by ligand-assisted Cu(I)-catalyzed intermediate 113 may possibly be converted into the product sequential intra- and intermolecular S-arylation in a one pot 112 (Step b). When o-iodoaniline was used as starting material protocol [99]. Despite of the Cu-catalyzed C–C, C–N and C–O both methyl and fluorine group on phenyl ring provides bond formation reactions [100–103], the chemistry of C–S excellent yield at 80°C. While, substitution of weak electron- bond formation [104–107] is less explored because of reduced withdrawing group, such as Br, strong electron-withdrawing catalytic efficiency due to higher affinity of thiol for metals group, such as CO2Me, CF3O and CN, along with an electron- and also possibility of thiol towards oxidative dimerization. In donating Me group at para position afforded corresponding this approach, synthesis of 2-arylthiobenzothiazoles 110 2-mercaptobenzothiazoles in satisfactory yields at 100°C. involves the intramolecular S-arylation of dithiocarbamate Interestingly, disubstituted compounds at para and ortho to salt 107 prepared from carbon disulfide 105 and aniline 104 to amino group also afforded high yield of 2-mercaptobenzo- thiazoles. However, o-chloroanilines are not favorable for this reaction even at higher temperature and longer reaction times (Scheme 17). NH 2 I , air N 2 R In another approach, synthesis of benzothiazole 118 has R NH + 2 S been reported from substituted anilines 114. Reaction of SH CH3CN, r.t. 30 min 85 86 anilines 114 with 4-nitrobenzoylchloride 115 gave access to 53 ’ Yield: 60-82% suitable benzanilides which upon treatment with Lawesson s R=Ph,4-OCH3C6H4,C7H5O2,4-ClC6H4, 11 examples reagent provided corresponding thiobenzanilides 116. Sub- 3,4-ClC H ,4-FC H ,4-CH C H ,4- 6 3 6 4 3 6 4 sequently through Jacobson’s cyclization, thiobenzanilides CF3C6H4,4-OCF3C6H4,C6H4N, etc. were converted to their respective 2-(4-nitrophenyl)-6-ben-

Scheme 11. Iodine mediated synthesis of benzothiazole using zothiazoles 117, by utilizing K3[Fe(CN)6] as reagent under 2-aminothiophenol. reflux condition for 30 min. Finally, the targeted

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O Cl N N NaH Cl N N + Cl Si N 90 N N DMF, 0°C to r.t. N r.t., 10-20 s N H O 87 88 89 Si 91 Cl S O 1 R N 4 NH R3 R 2 N 4 N R1 2 1 94 R N R N R 2 S R 92 N N C H ONa / C H OH 2 2 5 2 5 R ref lux, 12 h R3 C2H5OH, reflux, 12 h S 93 95 Yield: 25-74% 5examples 1 R =H,Ph,4-Cl-C6H4,4-NO2-C6H4 R2 =H,Ph 3 R =H,Ph,4-CH3-C6H4 4 R =Ph,4-CH3O-C6H4,4-NO2-C6H4, 4-Cl-C6H4

Scheme 12. Synthesis of 2-aminobenzothiazoles by utilizing three-carbon synthon. benzothiazoles 118 were obtained by reduction of nitro It was observed that benzothiazoles were obtained in high group using SnCl2 [74, 90, 109, 110] (Scheme 15). Using similar yield when reacted with 2,6-dichloro aniline instead of 2,6- strategy, Stevens and co-workers [111] have reported the dimethyl aniline. In addition, para substituted anilines synthesis of benzothiazoles employing fluorinated nitro- gave benzothiazoles in better yield as compared to meta benzanilides as starting material. All the fluoro substituted substituted aniline. Noticeably, anilines comprising electron nitro-benzanilides provide access to corresponding benzo- withdrawing group at para or meta position provide thiazoles in excellent yield except 4,6-difluoro and 5,7- benzothiazole in high yield as compared to electron donating difluoro nitro-benzanilides (Scheme 18). groups (Scheme 19). In another approach, synthesis of benzothiazoles 123 from In some other protocols, synthesis of benzothiazoles has variety of isothiocyanates 120 has been reported from been achieved using nearly the same procedure as described substituted anilines 119 [112, 113]. The isothiocyanates 120 in Scheme 16, however, a slight variation from the above were allowed to react with 2,6-dimethyl and 2,6-dichloro mentioned method lies in synthesizing the substituted aniline 121 in methanol to afford N,N0-disubstituted thioureas phenylthiourea which was achieved by treating substituted 122, followed by oxidative cyclization of 122 with bromine to anilines 124 with saturated solution of ammonium thiocya- give access to the targeted compounds 123 in moderate yield. nate in water. Subsequently, substituted phenylthioureas 126

Ar

NH p 2 (PPh ) PdCl ,CuI,Et N NH2 i) -TsCl, py, CH2Cl2,r.t.,10h + Ar I 3 2 2 3 CH3CN, r.t.24 h ii) CuI, Et3N, THF, reflux, 36 h S S 96 97 98 Ts N H H Ar = Ph, 1-naphthyl, 2-naphthyl, 3-Cl-C6H4,2-CH3-C6H4, S 4-CH3-C6H4,4-OCH3-C6H4,2-OCH3-CO-C6H4,2-thienyl, H Ar 2,4-OCH3-pyrimidin-5-yl, 5-iodo-2-thienyl, 3-iodophenyl, 4-iodophenyl 99 Yield: 63-80% 13 examples

Scheme 13. Synthesis through metal-catalyzed reaction.

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4,5,6,7-tetrahydrobenzothiazole 134 in moderate to good S Pd(PPh ) (3 mol%) 1 3 4 S R yield [115] (Scheme 22). MnO2 (10 mol%) N N NR1 R2 Syntheses of optically active 2-aminobenzothiazoles have H CH CN, O ,80°C N R2 3 2 been reported through optically active isothiocyanates 136 100 101 Yield: 90-93% [112]. The thiourea 138 has been prepared from optically 4examples active isothiocynates 136 by coupling with 4-fluoro-3-chloro- N , N N fi NR1R2 = aniline 137. The nal 2-amino substituted benzothiazole 139 O was obtained by oxidative cyclization with bromine in N , N O chloroform in high yield. It has been observed that unsubstituted phenyl and carbocyclic substituted 2-amino- Scheme 14. Synthesis of 2-aminobenzothiazoles via palladium- benzothiazole were obtained in better yield whereas catalyzed oxidative intramolecular reaction. aliphatic and substituted phenyl ring on 2-aminobenzothia- zole were obtained in poor to moderate yield irrespective of were cyclized in the presence of bromine in chloroform to give electron donating and electron withdrawing group at para- 2-aminobenzothiazoles 127 [25, 70, 114] (Scheme 20). position of phenyl ring (Scheme 23). Further, ethyl 4-aminobenzoate 129 has also been used as Chemoselective synthesis of benzothiazoles 143 has been starting material for the synthesis of substituted benzothia- reported by Kumbhare and co-workers through oxidative zole 130 by reacting with potassium thiocyanate, using cyclization of thiourea 142 employing ionic liquid, 1,3-di-n- copper sulfate as catalyst in methanol under reflux conditions butylimidazolium tribromide [bbim][Br3] under mild reaction for 6 h [72] (Scheme 21). conditions [116]. The starting material benzothiazolyl thio- carbamides 142 was obtained by reacting substituted 2- Synthesis of benzothiazole by using thioureas aminobenzothiazole 140 and phenyl isothiocyanate 141 in Substituted thioureas have proven to be important synthetic presence of 4-dimethylamino-pyridine (5 mol%) in DMF. The starting materials for the synthesis of substituted benzothia- benzothiazolyl thiocarbamides 142 undergo oxidative cycli- zoles. Cyclohexanone 131 when reacted with thiourea 132 in zation in presence of tribromide-based ionic liquid at 70°C to presence of molecular iodine, followed by neutralization of furnish N-bis-benzothiazole 143 via C–S bond formation hydroiodic salt 133 with NaHCO3 gave access to 2-amino- reaction. Substitution of electron donating or electron

R2 NH N R2 Pd/C 1 R1 R S I DMF, r.t., 6-36 h S 102 103

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

H Z NH Z N S-M+ Z 2 triethylamine L/CuI N - + + CS2 S M THF, 12 h, r.t. S Y X Y X K2CO3,DMSO Y S 105 107 104 106

Z1 CuI / I Z N 108 S 1 X=I,Br S Z Y Y=H,CH3, Cl, Br, OCH3 K2CO3,L= Z = H, CH3 H N 110 1 2 NH2 Z =H,4-CH3,4-OCH3,4-NO2,2-NO2, 109 Yield: 65-92% 4-NHAc,3-Cl,2-COOCH3 20 examples DMSO,90°C, 4 h

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

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R1 R1 NH N 2 DBU, toluene + CS SH 2 S X 80-100°C,16-24 h 111 105 112 X = I, Br step-a 15 examples step-b Yield: 43-89% DBU NH DBU.HX S + SCS DBUH X S _ DBUH+ 113 Scheme 17. Synthesis of benzothiazoles by utiliz- ing anilines.

withdrawing groups on 2-aminobenzothiazole and phenyl ring of benzothiazole has no effect on the reaction outcome. isothiocyanates produces N-bis-benzothiazoles 143 in excel- Beside this, phenyl ring at 2-position on benzothiazole lent yield (Scheme 24). provides better yield while aliphatic groups such as t-butyl and methyl group do not favor the reaction (Scheme 25). Synthesis of benzothiazoles by utilizing Besides chloranil, thioformanilides were also converted to thioformanilides 2-substituted benzothiazoles in presence of catalytic amounts An efficient photochemical cyclization of thioformanilides of CuI (5 mol%) and 1,10-phenanthroline (10 mol%) using

144 has been reported by Penenory and co-workers utilizing Cs2CO3 as base in dimethoxyethane under refluxing con- chloranil as catalyst for the synthesis of 2-substituted ditions within 24 h [118] and also in the presence of benzothiazoles 145 [117]. The optimization reaction con- manganese triacetate under MW [119]. ditions utilize 1,2-dichloroethane and toluene as co-solvents Additionally, an exclusive, economical, metal free and base- at 80°C to provide excellent yield of the product. It has been promoted synthesis has been reported for the synthesis of 2- observed that unsubstituted benzenoid ring provides better substituted benzothiazoles 147 from N0-substituted-N-(2- yield as compared to electron donating benzenoid ring, halophenyl) thioureas 146 in dioxane [120] (Scheme 26). It whereas electron withdrawing group substituted benzenoid has been observed that both electron donating and electron

NO2 O Cl R1 NH2 a) pyridine, K3[Fe(CN)6], aq. NaOH, + reflux, 2 h b) Lawesson's reagent, reflux, 30 min R1 S NH chlorobenzene, R NO2 reflux, 3 h 114 115

R=H,OCH3,F R 116 R1 R1 N N SnCl .2H O, ethanol, 2 2 R NH R NO 2 2 S S ref lux, 4 h 118 117 11 examples Yield: 64-90% 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 1 R =H,CH3

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

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R3

H2N

NH NCS R3 3 2 121 S R CSCl 3 2 R =CH3,Cl R1 NH NH CH Cl R2 2 2 R2 CH3OH, reflux, 1 h r.t., 3 h R2 R3 R1 R1 122 119 120

R3 Br2 /CHCl3 N 3 0°C, 1 h NH R R1 S 2 1 R R =H,Br,CH3,NO2 2 123 R =H,Cl,NO2 Yield: 23-44% 10 examples

Scheme 19. Synthesis of benzothiazoles from substituted isothiocyanates.

NH 2 R R S R R R NH HCl HCl / H O 1 2. NH SCN R1 NH C NH2 R1 N 2 4 Br2/CHCl3 N H2O R1 R liq NH3 S H 2 R2 R2 2 R2 126 127 124 125

R R K CO ,DMF 1 N H 2 3 N Br S n Br R2 Br n 128

Yield: 61-74% 20 examples

Scheme 20. Synthesis of substituted N-alkylbromo-benzothiazoles using substituted aniline and ammonium thiocyanate. withdrawing benzyl amine provide satisfactory yield, whereas Although, ester group at position 4 of heterocyclic ring also 1-(2-iodophenyl)-3-phenyl-thiourea prolongs the reaction favors the reaction and provides excellent yields. However, time by about 10 h to give a moderate yield of 2-amino- ortho-bromoaryl precursors gave lower yields than the ortho- substituted benzothiazole. In addition, N0-heterocyclic rings iodoaryl precursors. Moreover, both the electron-donating gave moderate yields and N,N0,N0-trisubstituted thioureas methoxy substituent and the electron-withdrawing fluoro or gave excellent yield under the same reaction conditions. trifluoromethyl groups on the aryl ring of N0-substituted N-(2-

H N 2 N KSCN, CuSO4.5H2O O H2N S O CH3OH, reflux, 6 h, 79% O 130 O 129 Yield: 79% Scheme 21. Synthesis of benzothiazole utilizing 1 example ethyl 4-aminobenzoate.

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S S S I2 Na2CO3 + NH . HI NH O H2N NH2 2 2 110°C, 12 h N N 131 132 133 134 Yield: 57% 1example

Scheme 22. Synthesis of benzothiazole by using thioureas.

R1 HN S Cl H HN Cl H H CH OH R NH2 CSCl N C 3 2 R S + H N F R 2 reflux, 1 h R1 CH2Cl2 R1 F r.t., 3 h 138 135 136 137 Br2/CHCl3 0°C,1h H R Cl R1 N R=Ph,4-OCH3-C6H4,4-F-C6H4,4-Cl-C6H4, HN cycloalkyl, (CH2)5-CH3 S F R1 =CH ,CH CH 3 2 3 139

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

halophenyl)thioureas provide good yields of 2-substituted substrate compatibility, mild reaction conditions and excel- benzothiazoles. lent yield. Wide variety of substrates and functional groups An organocatalytic synthesis of benzothiazoles 149 has are compatible under these reaction conditions as electron been reported by Punniyamurthy and co-workers through withdrawing as well as electron donating groups at various cyclization of arylthioanilides 148 using 1-iodo-4-nitroben- positions of aryl ring afforded moderate to excellent yield zene as catalyst and oxone as an oxidant at room temperature except nitro substituted phenyl ring. Heterocyclic rings also [121]. The advantage of this method resides in broad yielded desired compounds in excellent yield (Scheme 27).

R2

N N 1 C 4-DMAP (5 mol%) S R NH2 + S N NH S R2 DMF, r.t. 2-4 h R1 NH 140 141 S 142 R2 R1 N S R1 =H,6-F,6-OMe, [bbim][Br3] S N N 6-OC H ,4-Cl 70°C, 30-40 min 2 5 H R2 =H,F,Cl 143 Yield: 83-91% 12 examples

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

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Z condensation and cyclization of Weinreb amide 151 with o- Z S S chloranil aminothiophenol 150 [122]. Chemically, Weinreb amide is N- R methoxy-N-methylamide and it is very easy to prepare and N R 80°C, 3 h N H has good stability and selectivity. In this particular reaction, 144 145 Weinrab amide 151 has been proved to be an effective reagent for the synthesis of 2-substituted benzothiazoles 152 t t Z = H, OCH3;R= -Bu, Ph, 4-C6H4-Y (Y = CH3, -Bu) in the presence of boron trifluoride etherate using 1,4- dioxane as solvent at 100°C which provided excellent yield of Scheme 25. Synthesis of benzothiazoles by utilizing 75–94% within 60 min. Interestingly, only the amide function thioformanilides. participates in cyclization even in presence of other active functional groups like carboxyl, halogens, cyano and methoxy on the carbon skeleton of the Weinreb amide. Phenyl ring R1 substituted at 2-position with electron withdrawing and H 1 N N Cs CO ,dioxane N R electron donating groups gave high yield of the product 152. R2 2 3 N R R Similarly, aliphatic as well as heterocyclic substitutions at S 130°C, 2 h S R2 X 2-position also provides high yield of the 2-substituted 146 147 benzothiazoles 152 (Scheme 28). X=I,Br R=4-F,5-Cl,5-OCH3, 4-CF3,5-CF3

Scheme 26. Synthesis of benzothiazole utilizing N0-substituted- Conclusion N-(2-halophenyl)thioureas. Benzothiazole is an important class of heterocyclic com- pounds and exhibits a variety of biological activities. In this review, we have emphasized on the biological diversity of Synthesis of benzothiazole by employing benzothiazoles, their synthetic methodology and recent Weinreb amide reagent developments in this field during the last few years. Variety There are some reagents that have been exclusively used for of benzothiazoles have been developed in recent years the synthesis of benzothiazoles. One of such reagents is possessing appreciable antitubercular, antimicrobial, antima- Weinreb amide reagent. An efficient one pot synthetic larial, anticonvulsant, anthelmintic, analgesic, anti-inflamma- protocol for the synthesis of 2-substituted benzothiazoles tory, antidiabetic and anticancer activities. In addition, a 151 has been reported by Sadashiva and co-workers through range of synthetic methodologies have been elaborated to

H N R2 N 4-NO2C6H4I, oxone 1 2 R1 R R S TfOH, HFIP, r.t., 5-48 h S 148 149 Yield: up to 95% yield 29 examples 1 R =2-CH3,3-CH3,3-OCH3,3-NO2,4-Br,4- CN, 4-CO 2C2H4,4-Cl,4-F,4-OCH3,4-CH3,4- NO2,4-CF3,2,4-(CH3)2,etc. R2 =Ph,2-CH C H ,3-CH C H ,4-FCH 3 6 4 3 6 4 6 4 Scheme 27. Organocatalytic synthesis of 4-OCH C H ,4-CHC H ,4-NO C H etc. 3 6 4 3 6 4 2 6 4 benzothiazoles.

O 1 1 R N R NH2 BF3.OEt N R 2 R + O 1,4-dioxane S SH 100°C 152 151 1 150 R =H,CH3,Br R=Alkyl, Alkenyl, Aryl, Heteroaryl Yield: 75-94% Scheme 28. Synthesis of benzothiazoles 9examples employing Weinreb amide reagent.

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obtain benzothiazoles in excellent yield and mild reaction [11] G. Mariappan, P. Prabhat, L. Sutharson, J. Banerjee, U. conditions. 2-Aminothiophenols were predominantly used Patangia, S. Nath, J. Korean Chem. Soc. 2012, 56, 251– for the synthesis of benzothiazoles. Various methods have 256. been described for synthesis of benzothiazoles by treating 2- [12] J. Cai, M. Sun, X. Wu, J. Chen, P. Wang, X. Zong, M. Ji, aminothiophenol with aldehydes, carboxylic acids, alcohols Eur. J. Med. Chem. 2013, 63, 702–712. and diones. Other approaches are also described for synthesis [13] M. M. Choi, E. A. Kim, H. G. Hahn, K. D. Nam, S. J. Yang, of benzothiazoles such as metal-catalyzed reactions, utilizing S. Y. Choi, T. U. Kim, S. W. Cho, J. W. Huh, Toxicology anilines, thioformanilides and Weinreb amide reagent. 2007, 239, 156–166. It is worthwile to point out that one pot synthesis of 2- [14] W. E. Klunk, Y. Wang, G. Huang, M. L. Debnath, D. P. substituted benzothiazole using Weinreb amide reagent and Holt, L. Shao, R. L. Hamilton, M. D. Ikonomovic, S. T. o-aminothiophenol is an efficient method as it is less time DeKosky, C. A. Mathis, J. Neurosci. 2003, 23, 2086–2092. consuming, afforded excellent yields and reactants can be [15] C. Pittenger, V. Coric, M. Banasr, M. Bloch, J. H. Krystal, prepared with ease. Along with this, organocatalytic synthesis G. Sanacora, CNS Drugs 2008, 22, 761–786. of benzothiazole using 1-iodo-4-nitrobenzene is another high [16] M. E. Giles, C. Thomson, S. C. Eyley, A. J. Cole, C. J. yielding method and has broad substrate compatibility and Goodwin, P. A. Hurved, A. J. G. Morlin, J. Tornos, S. mild reaction conditions. This review would assist medicinal Atkinson, C. Just, J. C. Dean, J. T. Singleton, A. J. Longton, chemists to further modify this important class of heterocycles I. Woodland, A. Teasdale, B. Gregertsen, H. Else, M. S. to enhance their biological activity profile. Athwal, S. 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