ARCH PHHARMARM Arch. Pharm. Chem. Life Sci. 2015, 348, 155–178 Archiv der Pharmazie Review Article Recent Advances in the Chemistry and Biology of Benzothiazoles 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 benzene ring fused with a five-membered thiazole 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 benzothiazole 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 ß 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com 155 Arch. Pharm. Chem. Life Sci. 2015, 348, 155–178 ARCH PHHARMARM R. K. Gill et al. Archiv der Pharmazie 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]. Riluzole 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 – Pramipexole 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 triazoles 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-