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. (A β ) 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- [ 11 C]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 benzo thiazole 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; R 2 = Me) ( 1 ) 20.3 ± 3.0 successfully demonstrated to bind A β plaques in the 6-Me-BTA-0 (R 1 = 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-substituted benzothiazoles using

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