Substituted Benzothiazoles: Synthesis and Medicinal Characteristics

DOI 10.1515/hc-2013-0026 Heterocycl. Commun. 2013; 19(2): 89–99

Review

Maged Henary* , Shirish Paranjpe and Eric A. Owens Substituted benzothiazoles: synthesis and medicinal characteristics

Abstract: The attractiveness of heterocyclic compounds in compounds. These types of compounds have shown sig- medicinal chemistry has increased significantly in the past nificant biological activities with a wide range of practi- few decades as they have been proven to be highly active for cal applications in the medical field. The following is a a number of purposes. More specifically, the benzothiazole- brief review of heterocyclic compounds containing the containing heterocyclic compounds have shown great prom- benzothiazole moiety and the corresponding advance- ise in the pharmaceutical industry. As continuation of our ments in the medical field utilizing this heterocyclic first review article of the synthesis and specific applications scaffold. Benzothiazole-containing heterocycles are of various benzothiazole cyanine dyes (Henary, M.; Paran- becoming ever more prevalent within pharmacological jpe, S.; Owens, E. A. Synthesis and application of benzothia- research due to their amenability for diverse modifica- zole containing cyanine dyes. Heterocycl. Commun. 2013, tions with the potential for structurally tailoring the het- 19, 1–11), we will focus in this review on the synthesis and erocycle towards exciting medical purposes. The broad medical applications of alternate compounds that utilize the spectrum of medical applications includes uses as benzothiazole scaffold as a part of their molecular structure. anti-inflammatory agents and therapeutic compounds Benzothiazole derivatives encompass an attractive hetero- for combating cancer at very effective nanomolar con- cyclic class that exhibits exciting medicinal properties. The centrations; to begin, we introduce thioflavin-T and the applicability of these heterocyclic structures includes posi- synthesis of corresponding analogs for radiolabeled tron emission tomography probes for monitoring Alzhei- imaging of β -amyloid plaques in Alzheimer ’ s disease mer ’ s disease progression; furthermore, these compounds patients for determining the presence, progression and exhibit antimicrobial, anti-inflammatory, anticancer, antidi- prognosis of the disease. abetic and anti-HIV activity. Benzothiazole-containing heterocyclic structures are prominent throughout the literature and it is very important to acknowledge their efficacy and Positron emission tomography (PET) probes applicability. Herein, we review the recent developments covering the past few years concerning the advancements Benzothiazole derivatives are recognized as a promis- in synthetic methodology for the preparation of medicinally ing class of compounds for the imaging of β -amyloid relevant benzothiazole-containing heterocyclic structures. (Aβ ) plaques. Thioflavin-T is a benzothiazole-containing imaging agent which shows fluorescence enhancement Keywords: benzothiazole; heterocyclic compounds; PET upon binding to aggregates of protein amyloids [ 1 , 2 ]. probes; review; synthesis. Patients with Alzheimer ’ s disease (AD) show the accumulation of β-amyloid fibrils in the brain [3 , 4 ] and *Corresponding author: Maged Henary, Department of Chemistry, these fragments are then converted into hard plaques Georgia State University, Atlanta, 30303 GA, USA, which directly contribute to the progression of AD. In e-mail: [email protected] recent studies, it has been suggested that by imaging Shirish Paranjpe and Eric A. Owens: Department of Chemistry, these plaques, the severity and prognosis of AD can be Georgia State University, Atlanta, 30303 GA, USA estimated [ 5 ]. Among the existing molecular imaging technologies, PET possesses several advantages such as high intrinsic sensitivity, increased penetration depth and Introduction excellent spatial resolution while being fully quantitative [ 5 ]. PET is a widely recognized nuclear imaging technique In the past few years, there has been an increas- employed to determine the severity of AD which makes ing interest in the chemistry of benzothiazole related use of nuclear probes containing positron emitters; 90 M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation

specifically, radiolabeled benzothiazole derivatives Me S Me are finding great applicability as potential PET probes. N N Me Several synthetic approaches have been explored for Cl Me synthesizing various derivatives of thioflavin-T (Figure 1), including uncharged derivatives [6 ]. The synthesis of an Figure 1 Structure of thioflavin-T. uncharged derivative, compound 1 , is shown in Equa- tion 1. Commercially available substrate 6-Me-BTA-0 is allowed to react with methyl iodide in the presence Me S R1 1 N of potassium carbonate to furnish compound in 18% N R2 yield (the acronym BTA refers to benzothiazole-aniline backbone). Figure 2 6-Me-BTA compounds.

Me Me S K CO , MeI, DMSO S Me 2 3 N (1) NH2 N 100°C, 16 h N H 1

The neutral derivatives of thioflavin-T exhibit higher the labile methoxymethyl group (product 6 ), which on affinity towards Aβ than the cationic thioflavin-T as reduction with sodium borohydride in the presence of 7 evident by the affinity for the inhibitor (K i ) values ( Table 1 ). cupric acetate yielded compound . The radiolabeling The 6-Me-BTA-1 was further radiolabeled with 11 C at the was then achieved by treatment with sodium hydride aniline nitrogen atom to form N -methyl-11 C analog of 6-Me- in N,N -dimethylformamide (DMF), then with 11 MeI fol- BTA-2 which demonstrated high uptake and improved lowed by hydrolysis of the methoxymethyl group to clearance from the rodent brain during animal experi- furnish final compound 8 in approximately 15% radio- mentation ( Figure 2 ). chemical yield. Klunk et al. at the University of Pittsburgh developed PIB retention in the brain of AD patients was found to another benzothiazole-based compound, N -methyl- be selectively higher than in non-AD patients. PIB is con- [ 11C]2-[4 ′-(methylamino)phenyl]-6-hydroxybenzothia- sidered as a popular choice as radiotracer for PET imaging zole (compound 8 in Scheme 1), more popularly of A β plaques in AD patients [ 7 ]. known as Pittsburgh compound B (PIB) that exhibits A new and improved route for the synthesis of [11 C] PIB high binding affinity towards Aβ plaques [ 5 ]. Commer- is shown in Equation 2 [ 8 ]. The reaction was carried out cially available 4-methoxyaniline (2 ) was treated with using [11 C] methyl triflate in the absence of base in acetone p -nitrobenzoyl chloride in the presensce of pyridine to on the unprotected hydroxybenzothiazole base. This reac- give compound 3 that was subsequently reacted with tion resulted in increasing radiochemical yield for the Lawesson ’ s reagent. The resulting compound 4 was compound to approximately 60% at the end of the syn- cyclized to the benzothiazole derivative 5 through the thesis; this important report is significant when designing Jacobsen synthesis using potassium ferricyanide and compounds for clinical use to maximize the radiolabeled aqueous sodium hydroxide. The methoxy group of com- output for imaging. pound 5 was demethylated in the subsequent step and the resultant hydroxy group was then protected by using HO S 11MeOTf 8 NH2 (2) N Acetone

Table 1 Ki values of various benzothiazole derivatives. As shown above, several PET probes containing the Compound K (n m ) i benzothiazole core structure have been developed in the Thioflavin-T 820 ± 92 past few years. These probes have been modified based 1 = 2 = ± 6-Me-BTA-2 (R R Me) 143 19 on the thioflavin-T structure and these derivatives were 6-Me-BTA-1 (R 1 = H; R2 = Me) (1 ) 20.3 ± 3.0 successfully demonstrated to bind A β plaques in the 6-Me-BTA-0 (R1 = R 2 = H) 30.3 ± 5.9 brain [ 9 , 10 ]. M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation 91

O MeO O N MeO MeO 2 O S Cl Lawesson's reagent NH N Chlorobenzene N 2 Pyridine H H

23NO2 4NO2

K3Fe(CN)6 MeO S MeOCH2O S NaOH 1. BBr3, DCM NO2 NO2 EtOH N 2. MeOCH2Cl, K2CO3 N 5 6

NaBH4 MeOCH O 1. NaH/DMF HO Cu(OAc) 2 S S H 2 NH N 2 2. 11MeI N N 11 EtOH 3. HCl, MeOH Me 7 8

Scheme 1

Pharmacological activities of benzothiazole inhibition properties towards Gram-positive bacteria compounds as well as displayed promising behavior against drug- resistant bacteria such as methicillin-resistant S. aureus The general benzothiazole structure is an important and vancomycin-resistant E. faecalis. Active compound scaffold for drug development, and the correspond- 13 was synthesized as shown in Scheme 2. Commercially ing derivatives have been extensively studied for their available propanediamine (9 ) was treated with Boc anhy- pharmacological applications. This idea of incorporat- dride in tetrahydrofuran (THF), and the resulting mono- ing benzothiazole in designing medicinal compounds Boc protected compound 10 was then allowed to react will be further expanded in the following sections, espe- with 2-chloro-5,6-difluorobenzothiazole in the presence cially nuanced towards the ability to combat danger- of potassium carbonate to afford compound 11. Com- ous microbes, reduce inflammation, fight diabetes and pound 11 in the next step was hydrolyzed with trifluoro- improve the prognosis of patients diagnosed with HIV [11 ]. acetic acid to the corresponding primary amine 12 which, using the coupling strategy shown, was transformed into compound 13 . Antimicrobial activity Bandyopadhyay et al. synthesized a series of 2-sub-

stituted benzothiazoles using an Al2 O3 -Fe2 O3 nanocatalyst Ouyang et al. (Scheme 2) reported the synthesis of various as shown in Equation 3 [ 13 ]. The antibacterial activity benzothiazole derivatives bearing secondary amine func- of the synthesized compounds was evaluated using the tionalities as potential antimicrobial agents [ 12 ]. The Kirby-Bauer disc diffusion method. Compound 14 exhi- synthesized compounds were evaluated for their antibac- bited enhanced inhibitory activity against Vibrio cholerae, terial activity against American Type Culture Collection Bacillus cereus and Shigella dysenteriae compared with (ATCC) strains of Staphylococcus aureus, Enterococcus the well-known antibacterial drug ciprofloxacin. Com- faecalis and Escherichia coli using the standard broth pound 15 showed complete bactericidal activity within dilution method. Compound 13 demonstrated exciting 24 h compared with 48 h for ciprofloxacin.

F S Cl Boc O F 2 F N S H H2N NH2 H2N NHBoc N NHBoc THF K CO 2 3 F N 91011DMF, 120°C

Cl Cl Cl F Cl CHO F S CF3COOH S H H H N NH N N 2 NaCNBH , MeOH, Δ DCM F N 3 F N 12 13

Scheme 2 92 M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation

NH 2 Al2O3 - Fe2O3 S compound 28 by treatment with an aqueous potassium R-CHO R (3) 60°C SH N hydroxide solution followed by acidification and air oxida- tion. The disulfide 28 was then treated with 3,4-dimethoxy- 14: R = 2-EtPh benzaldehyde in the presence of triphenylphosphine and 15: R = 4-HOPh a catalytic amount of p -toluenesulfonic acid in refluxing toluene to yield final compound 29 in 88% yield. Com- Anticancer properties pound 29 possesses antiproliferative activity against a < breast cancer cell line (GI50 0.1 nm ) and a colon cancer < Shi et al. reported the synthesis of benzothiazole-2-thiol cell line (GI50 0.25 n m ). derivatives as potential anticancer agents. These com- Activation of phosphoinositide 3-kinase (PI3K) is pounds were evaluated against various cancer cell lines assumed to be one of the major causes for tumor growth in [14 ]. Synthesis was carried out as shown in Scheme 3. Com- humans. PI3K signaling leads to activation of the mamma- mercially available amines 16 – 18 were reacted with 2-chlo- lian target of rapamycin (mTOR) which in turn promotes roacetyl chloride in the presence of potassium carbonate, uncontrollable cell growth. D ’ Angelo et al. reported the and the resulting compounds 19 – 21 were reacted with synthesis of aminobenzothiazole derivatives that have dual 6-aminobenzothiazole-2-thiol to afford compounds 22 – 24 . PI3K and mTOR inhibitory properties [16 ]. The synthesis of In the last step of the synthetic scheme, compounds 22 – 24 the most promising compound 32 is shown in Scheme 5. were treated with 2-chloroacetyl chloride in the presence The starting compound, 2-amino-6-bromobenzothiazole, of triethylamine to furnish final compounds 25 – 27 in 70 – was first acylated using acetic anhydride in the presence 90% yield. Compound 26 demonstrated promising activity of 4-dimethylaminopyridine (DMAP) and then the product = 30 against SKRB-3 human breast cancer cells (IC50 1.2 n m ), was converted to boronate . Commercially available = = SW620 colon cancer cells (IC 50 4.3 nm ), A549 (IC 50 44 5-bromo-2-chloropyridin-3-amine was reacted with com- = 30 n m ) and HepG2 hepatic carcinoma cells (IC50 48 nm ) as pound utilizing Suzuki coupling to furnish compound well as induced apoptosis in HepG2 cancer cells. 31. Compound 31 in the last step was reacted with 4-fluoro- A series of 2-phenylbenzothiazoles was synthesized sulfonyl chloride in the presence of pyridine and 4-dimeth- by Mortimer et al. and evaluated in vitro against breast ylaminopyridine to prepare the final compound 32 . and colon cancer cell lines [15 ]. The synthesis of the most Compound 32 not only displays potent inhibitory activ- α = ± = ± efficient compound 2-(3,4-dimethoxyphenyl)-5-fluoroben- ity against PI3K ( Ki 1.2 0.9) mTOR (K i 2.0 4.8) but also zothiazole (29 ) was performed as shown in Scheme 4; inhibits tumor growth in mouse xenograft models (tumor the 2-amino-5-fluoro-benzothiazole was converted to type: glioblastoma, lung adenocarcinoma and colorectal).

H N R O R 2 S R Cl O SH O Cl N Cl S S N NH2 N N N N K2CO3, DCM Et3N,THF H H N NH2 16–18 19–21 22–24

O R O Cl 16, 19, 22, 25: R = Cl Cl S S O Cl N N 17, 20, 23, 26: R = Br H 18, 21, 24, 27: R = Me Et3N N NH 25–27

Scheme 3

OMe F F O OMe OMe S aq. KOH H S NH OMe 2 Δ PPh , TsOH F N 3 F N H2NSS NH2 28 29

Scheme 4 M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation 93

Me NH Me 2 Cl Me O N Br B Br S 1. Ac2O, DMAP, DCM Me O S NH2 NH N 2. bis(pinacolato)diboron N Me Pd(dppf)Cl2, K2CO3 Pd(dppf)Cl /DCM, KOAc 2 O H2O, dioxane 30

F O NH2 O S Cl F S Cl HN O O Cl N S DMAP, pyridine, THF NH N S N Me NH 31 O 32 N Me O

Scheme 5

Anti-inflammatory activity synthesized compounds 34 – 37 displayed no gastric ulcer- ation which has been a major downside to the clinical use In addition to antimicrobial and chemotherapeutic prop- of ibuprofen. erties, benzothiazole-based compounds have shown Gilani et al. synthesized a series of N -(6-chlorobenzo[d ] promising activity towards the development of anti- thiazol-2-yl)hydrazine carboxamide benzothiazole deriva- inflammatory agents. Specifically, Shafi et al. reported tives and evaluated these compounds for corresponding the synthesis of 2-mercaptobenzothiazole and 1,2,3-tria- anti-inflammatory activity [18 ]. The synthetic scheme for zole based bis-heterocyclic compounds as potential the compound 41 with best activity is shown in Scheme 7 anti-inflammatory agents [ 17 ]. The synthetic scheme for beginning with the treatment of 4-chloroaniline with potas- the synthesis of bis-heterocyclic compounds is shown in sium thiocyanate in glacial acetic acid followed by the Scheme 6. Commercially available benzothiazole-2-thiol addition of a bromine solution to furnish compound 38 . was reacted with propargyl bromide in dioxane in the Compound 39 was furnished by heating precursor 38 with presence of triethylamine to obtain compound 33 which a solution of sodium cyanate in glacial acetic acid. Reac- was then treated with aromatic azides using click chemis- tion of compound 39 with a hydrazine hydrate solution in try to afford final compounds 34 – 37 . the presence of concentrated sodium hydroxide solution Compounds 34 – 37 were tested for anti-inflammatory afforded compound 40 . In the final step, compound 40 activity via biochemical cyclooxygenase (COX) activity was heated under reflux with 2,4-dichlorobenzoic acid in assays and carrageenan-induced hind paw edema. Com- phosphorus oxychloride to furnish product 41 in 67% yield. 35 α α pound exhibited selective COX-2 inhibition with an IC50 The tumor necrosis factor- (TNF- ) is associated ratio of 0.44 of COX-2/COX-1 and displayed a better in vivo with several inflammatory diseases, and designing small anti-inflammatory activity profile when compared with molecule inhibitors of TNF- α activity is considered a the industry standard, ibuprofen. Compound 35 showed potential target for developing anti-inflammatory thera- increased analgesic activity compared with ibuprofen peutics [ 19 ]. The mitogen-activated protein kinase acti- when tested using the Writhing method. Importantly, the vated protein kinase 2 (MAPKAP-K2) gene is associated

R2 R1

Br N R2 N S S 3 N 1 N R SH S S N Et N, dioxane N 3 N CuSO4 5H2O S Sodium ascorbate 33 t 34: R1 = Cl; R2 = H BuOH:H2O 35: R1 = H; R2 = F 36: R1 = H; R2 = Br 37: 1 2 R = H; R = NO2

Scheme 6 94 M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation

O N NH2 KSCN N NaOCN Cl NH NH2 NH 2 AcOH Br2, AcOH Cl S Cl S 38 39

Cl Cl Cl N O NH2 N N NH Cl COOH Cl S O NH2NH2 H2O NH NH NaOH/EtOH Cl S POCl3 N 40 41

Scheme 7 with inflammatory response as it regulates the TNF-α . combating diabetes. Van Zandt et al. synthesized a series A series of pyrazolo[1,5-a ]pyrimidine based compounds of conjugated indole-N -acetic acid with benzothiazoles was synthesized and evaluated as MAPKAP-K2 inhibi- and evaluated these compounds for antidiabetic activ- tors [19 ]. The most potent inhibitor 46 was synthesized as ity [ 20 ]. The synthetic scheme for various benzothiazole depicted in Scheme 8. Commercially available 3-amino- derivatives is shown in Scheme 9. The starting material, pyrazole was treated with diethyl methylmalonate in a 2,3,5,6-tetrafluoroaniline, was first acylated with acetic solution of sodium ethoxide in ethanol to yield compound anhydride in pyridine and then the product was treated 42. Compound 43 was obtained by refluxing a solution with phosphorus pentasulfide in benzene to yield thio- of 42 with N,N -dimethylaniline and phosphorus oxy- amide compound 48 . Thioamide was then cyclized in chloride. Compound 43 in the next step was treated with the presence of sodium hydride in toluene. The resulting 6-amino-2-methylbenzothiazole in tetrahydrofuran in the compound 49 was hydrolyzed using a sodium hydroxide presence of sodium hydride in DMF to afford compound solution followed by treatment with hydrochloric acid 44 . The amino group of 44 was protected using Boc anhy- to afford 2-aminothiophenol hydrochloride 50 . Indole-3- dride, and the resultant derivative 45 was coupled with acetonitrile and its 5-substituted analogs were alkylated ( S )-3-amino-1-Boc-piperidine. Removal of the Boc groups with ethyl bromoacetate in the presence of sodium hydride using trifluoroacetic acid furnished the final product 46 . to furnish compounds 51 –54 . Compound 50 , in the final step, was condensed with individual compounds 51 – 54 in the presence of trifluoroethanol followed by treatment Antidiabetic activity with aqueous sodium hydroxide to furnish final products 55– 58 . Estimates predict that over 150 million people suffer Compounds 55 – 58 inhibited aldose reductase with 55 from diabetes, and through synthetic efforts, medici- IC50 values in the range of 5– 13 nm . Compound was nally relevant heterocyclic compounds containing the the most potent aldose reductase inhibitor with IC50 benzothiazole moiety show promising activity towards of 5 n m and displayed promising features such as the

H N OH Cl 2 S Me Me-CH(COOEt) Me POCl , Me NPh N Me N NNH 2 N N 3 2 N NH EtONa, aq. HCl Δ NaH, DMF/THF 2 N OH N Cl 42 43

N N N 1. (S)-3-amino-1- Me Me Me Boc-piperidine S S BocN S HN HN Boc O, DMAP 2. CF COOH, DCM 2 3 Me Me N Me N N N N Dioxane N NH N Cl N N N Cl H 44 45 46

Scheme 8 M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation 95

S Me NH HCl NH Me NH N 2 2 S 30% NaOH HS F F F F F F 1. Ac2O, pyridine NaH ethylene glycol

2. P4S10, benzene Toluene then HCl F F F F F F F F 47 48 49 50

F 50 N F CN CN 1. , trifluoroethanol, cat. butylated R R R BrCH2COOEt hydroxytoluene S NaH, ACN N 2. aq. NaOH, EtOH F N O N H O 51–54OEt 55–58 OH

51, 55: R = H 52, 56: R = F 53, 57: R = Cl 54, 58: R = Br

Scheme 9 normalization of nerve sugars and prevention of diabetic Anti-HIV activity cataracts in STZ-induced diabetic rat models. The enzyme 11β -hydroxysteroid dehydrogenase type Towards the goal of designing novel anti-HIV agents, 1 (11 β -HSD1) is responsible for glucocorticoid activity at Massari et al. synthesized 1,8-naphthyridone benzothia- the tissue level primarily in adipose and liver tissues [ 21 ]. zole derivative 67 as a potential inhibitor of the HIV-1 Glucocorticoids are insulin action antagonists and are the Tat-mediated transcription and antiviral activity in HIV- possible cause for the commonly elevated blood sugar infected cells (Scheme 10) [22 ]. Acrylamide 63 was treated concentration in diabetes patients. Moreno-D í az et al. with methylamine in a diethyl ether/ethanol mixture to reported a series of benzothiazole benzenesulfonamides yield compound 64 . Compound 65 was obtained by cycli- as shown in Equation 4 as potential 11 β -HSD1 inhibitors zation of the precursor 64 in the presence of potassium for the treatment of noninsulin-dependent diabetes mel- carbonate in DMF. The intermediate product 65 was then litus [21 ]. Starting material 2-amino-6-methoxybenzothia- condensed with 1-(benzothiazol-2-yl)piperazine in DMF zole was condensed in dichloromethane with arylsulfonyl to furnish compound 66 which was then hydrolyzed to 67 67 = chlorides in the presence of triethylamine and a catalytic afford the final product . Compound displayed EC50 amount of DMAP to furnish compounds 59 –62 . Com- 0.03 μg/mL and 0.02 μg/mL with HIV-1 and HIV-2 metal- pounds 59 and 60 displayed effective inhibition activity lothionein 4 (MT-4) cells. of 11β -HSD1 in an in vitro cell-based assay with 38% and Jonckers et al. synthesized benzothiazole amides 74 53% inhibition, respectively. and 75 as shown in Scheme 11 [ 23 ]. Commercially available

O 2 O N Cl S R N S O O NH2 NH (4) 1 S 1 S R DMAP, DCM, Et3N, 40°C R

59: R1 = OMe; R2 = H 60: 1 2 R = OMe; R = NO2 61: R1 = Me; R2 = Cl 62: R1 = Me; R2 = NO 2

As shown above, benzothiazole-based heterocyclic epoxide 68 was treated with an excess of isobutylamine compounds are becoming prevalent when discussing active in isopropanol to yield compound 69 . Compound 69 was drugs that combat various diseased states; however, discov- coupled with a benzothiazole-6-carboxylic acid using ering antiviral agents, specifically anti-HIV agents, remains O -(7-azabenzotriazol-1-yl)- N,N,N ′ ,N′ -tetramethyluronium of paramount importance in pharmaceutical research. hexafluorophosphate (HATU) as an activating agent in the 96 M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation

O O O S N NH CO Et CO Et K CO CO Et 2 MeNH2 2 2 3 2 N Me Et O/EtOH DMF DMF Cl N Cl N 2 Cl N Cl NH Cl N N Me Me Me 63 64 65

O O

CO2Et CO2H

N N N 4% NaOH N N N S N Me S N Me

N 66 N 67

Scheme 10

presence of triethylamine to afford compounds 70 and 71 , the with 4-methyl-3-methoxybenzaldehyde to yield compound subsequent treatment of which with trimethylsilyl chloride 78. Compound 79 was obtained by treatment of 78 with and sodium iodide furnished derivatives 72 and 73 . In the iodoxybenzoic acid in anhydrous THF. Demethylation of 79 final step, a triethylamine-mediated coupling of compounds to the final product 80 in the next step was accomplished 72 and 73 with 2,5-dioxopyrrolidin-1-yl thiazol-5-ylmethyl by heating with pyridinium hydrochloride. Compound 80 carbonate furnished final products 74 and 75 in approxi- inhibits 17β -hydroxysteroid dehydrogenase 1 (17β -HSD1) 74 75 = β mately 85% yield. Compounds and were evaluated as with IC50 27 nm and shows selectivity towards 17 -HSD2. pharmaco kinetic enhancers of HIV protease inhibitors. Anzini et al. developed various amidine, guanidine and thiourea derivatives of 2-amino-(6-trifluoromethoxy) benzothiazole 83 – 89 that were structurally related to rilu- Miscellaneous activities zole, a neuroprotective drug, as illustrated in Scheme 13 [ 25 ]. These compounds were evaluated as neuroprotec- Spadaro et al. described a synthesis of various hydroxy- tive agents via an in vitro procedure of ischemia/reperfu- benzothiazole compounds and evaluated them as poten- sion injury. Condensation of 4-(trifluoromethoxy)aniline tial agents for the treatment of estrogen-related diseases (81 ) with ammonium thiocyanate and benzyltrimethyl- [ 24 ]. The synthesis of the most potent compound 80 is ammonium tribromide in acetonitrile yielded 2-amino- depicted in Scheme 12. 2-Amino-6-methoxybenzothiazole 6-(trifluoromethoxy)benzothiazole (82 ). Treatment of 82 (76 ) was deaminated in two steps to afford compound 77 . with N,N -dimethylacetamide and phosphorus oxychloride Compound 77 was treated with n -butyllithium and the in toluene furnished amidine 83 . The reaction of 82 with resulting in situ formyl anion was then allowed to react various isothiocyanates in the presence of triethylamine

N R O N R Isobutylamine HOOC S H N N S H H N i-PrOH, Δ N NH HATU, Et N Boc OH Me O 3 Boc Boc OH Me Me 68 69 Me 70, 71

O O N Trimethylsilyl N N O O R O R N O O chloride/NaI S O S H N N S O N N 2 N H OH Me Et3N, Me-THF S OH Me

Me Me 72, 73 74, 75

70, 72, 74: 71, 73, 75: R = NH2 R = H

Scheme 11 M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation 97

OMe MeO MeO MeO S 1. NaNO2, H3PO4 S 1. n-BuLi, THF S NH 2 MeO 2. H3PO2, H3PO4 2. N N O N OH Me 76 77H 78

Me Me

OMe Pyridinium OH SIBX hydrochloride MeO S HO S THF N O N O 79 80

Scheme 12

F CO F CO F CO 3 NH4SCN, ACN 3 S POCl3, toluene 3 S Me NH2 N C PhCH2NMe3Br3 N CH3CONMe2 N NMe NH2 2 81 82 83

RNCS, Et3N toluene

F3CO S F3CO S NH 1. MeI, acetone NH N NH N NH 2. NH3(g), EtOH S R HN R

84: R = Et 88: R = Et 85: R = n-Pr 89: R = n-Pr 86: R = i-Pr 87: R = n-bu

Scheme 13 84 – 87 yielded various thiourea derivatives . Compounds NH2 84 and 85 were further treated with methyl iodide in KCNS N R-NCO N NH2 NH acetone followed by the reaction with gaseous ammonia Br2 S ACN S NH to afford guanidine derivatives 88 and 89 . Compounds O R 83 – 87 displayed a significant reduction in neuronal injury. 96 97: R = 2-MeOPh 98: R = 2,4-MeOPh Ugale et al. reported the synthesis of quinazoline- 99: R = 3,4,5-MeOPh 93 – 95 100: R = 2-furyl substituted benzothiazoles as shown in Equation 5. 101: R = 2-nitrophenyl These compounds were evaluated as anticonvulsant agents by maximal electroshock and PTZ-induced seizure Scheme 14 methods [26 ]. In the preparation of 93 – 95 , substrates 90 – 92 and 6-bromo-2-ethyl-4H -benzo[d ][1,3]oxazin-4-one compound 95 showed promising results against clonic in dry pyridine were heated under reflux. Compound 93 seizure. Significantly, none of the compounds exhibited showed remarkable activity against tonic seizure, whereas neurotoxicity or hepatotoxicity.

O Br Br O O 1 1 R N N Et N R NH N (5) 2 Dry pyridine, Δ R2 S N S R2 Et 90–92 93–95

90, 93: 1 R = H; R2 = H 91, 94: 1 R = Cl; R2 = H 92, 95: R1 = H; R = OMe 2 98 M. Henary et al.: Benzothiazole: synthesis and medicinal evaluation

H2N SH H2N SH R O O R HN R NaH, MeI R HN O S O S EtOHN DMF N EtOH N O H Me N O H Me 104: R = Me 102 103 107: R = Me 105: R = Cl 108: R = CF O 106: 3 R = NO2 109: R = Cl 110: R = Br 111: R = NO2

Scheme 15

Azam et al. synthesized a series of benzothiazole- As discussed above and in our other recent review urea derivatives as potential agents to combat Parkin- [1 ], benzothiazole-based compounds have widespread son’ s disease. The synthesis is shown in Scheme 14 medicinal applicability when conjugated with various [27 ]. The reaction of aniline with potassium thiocyanate heterocyclic and cyanine moieties. The extensive litera- and bromine afforded 2-aminobenzothiazole (96 ), the ture presentations in the preceding sections show that treatment of which with appropriate isocyanate furnished the benzothiazole heterocyclic structure is effective in the compounds 97 – 101. Compounds 97 – 101 exhi bited reduc- preparation of novel heterocyclic compounds and func- tion in catalepsy by more than 70% in a standard bar test. tions as the basic scaffold for determining the prognosis Karal ı et al. synthesized benzothiazole containing of patients suffering from AD through PET scans and gen- spiroindolinones and screened these compounds for anti- erating anti-HIV medication. We have previously shown oxidant activity [ 28 ]. The synthetic scheme is shown in that benzothiazole-containing cyanine dyes have exten- Scheme 15. 1H -Indole-2,3-dione (102 ) was alkylated with sive medicinal applications and as synthetic and medici- methyl iodide to furnish compound 103 . Compounds 102 nal chemists further develop these compounds, it is likely and 103 were then allowed to react with 2-aminothiophe- that the benzothiazole system will remain an integral nol in ethanol to afford final compounds 104 – 111 . The portion of the design of compounds in the future. methyl analog 107 was found to be the most potent antioxidant in the whole set of compounds compared with Received February 7, 2013; accepted February 23, 2013; previously α -tocopherol and ascorbic acid. published online March 25, 2013

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