ARCH PHARM
Arch. Pharm. Chem. Life Sci. 2015, 348, 1–24
Arch iv d e r Ph a rm a zie
Review Article Recent Advances in the Chemistry and Biology of Benzothiazoles Rupinder K. Gill1,2, Ravindra K. Rawal1, and Jitender Bariwal1 1 2
Department of Pharmaceutical Sciences, ISF College of Pharmacy, Moga, Punjab, India 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, anthelmintic, 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 Benzothiazole belongs to the family of bicyclic heterocyclic compounds having benzene nucleus fused with five-membered ring comprising nitrogen and sulfur atoms. Benzothiazole is an important scaffold with a wide array of interesting biological activities and therapeutic functions including antitubercular [1– 2], antimicrobial [3–4], antimalarial [5], anticonvulsant [6–7], anthelmintic [8], analgesic [9], anti-inflammatory [10], antidiabetic [11] and antitumor [12] activities. Moreover, benzothiazoles are present in a range of marine or terrestrial natural compounds that have useful biological activities. Benzothiazoles have been therapeutically useful in the treatment of various diseases such as neurodegenerative disorders, local brain ischemia, central muscle relaxants and cancer [13]. Benzothiazoles have promising biological profile and are easy to access which makes this pharmacophore an interesting moiety for designing new benzothiazoles. Benzothiazole moiety has wide applications in dyes such as thioflavin [14]. Some of the marketed drugs comprising benzothiazole are shown in Fig. 1 [15–17]. Some reviews have been recently reported in literature, briefly describing the synthetic strategies and biological
activities of benzothiazole nucleus [18–21]. The main feature that was missing in the recently reported review [18] is the unexplained synthetic methodologies with reference to the scope of the functional group compatibility and SAR of the molecules under consideration. In the present review we discuss the effect of functional groups on yields of the product and robustness of the methodology along with the SAR studies. This makes this review distinguished and out of the league which will appeal the researches around the globe and serve as an ideal platform to synthesize new potent benzothiazoles. We have included detailed synthetic methodologies used to access benzothiazoles and special care has been taken to cover the most relevant and important literature reports.
Pharmacological profile
Correspondence: Dr. Jitender Bariwal, Department of Pharmaceutical Sciences, ISF College of Pharmacy, Moga-142001, Punjab, India. E-mail: [email protected] Fax: þ91 1636 239515
The benzothiazoles have shown wide range of pharmacological profile and accordingly they may be classified into the following categories. 1. Benzothiazole as antitubercular agent 2. Benzothiazole as antimicrobial agent 3. Benzothiazole as antimalarial agent 4. Benzothiazole as anticonvulsant agent 5. Benzothiazole as anthelmintic agent 6. Benzothiazole as analgesic, anti-inflammatory agent 7. Benzothiazole as antidiabetic agent 8. Benzothiazole as anticancer agent
ß 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
1
ARCH PHARM
Arch. Pharm. Chem. Life Sci. 2015, 348, 1–24 R. K. Gill et al.
O S O
NH N
F
H 2N S
O
Arch iv d e r Ph a rm a zie
O
Ph
S F F
O OH
R iluzole
HN
N H Sib enadet Hydr ochlor ide (Viozan )
S NH 2 N
Pr amipexole
Figure 1. Marketed drugs of benzothiazole.
Benzothiazole as antitubercular agent Tuberculosis (TB) is a fatal contagious disease caused by infection with Mycobacterium tuberculosis but also with M. bovis and M. africanum, which can affect almost any tissue or organ of the body, the most common site of infection of the disease being the lungs [22]. The lack of efficacy of antimycobacterial agents is due to the ability of M. tuberculosis to develop alternative metabolic routes and insufficient drug permeability through mycobacterial cell wall. The mycobacterial cell wall consists of three main components that form the mycolyl-arabinogalactan-peptidoglycan (mAGP) complex. Mycolic acid, which is the outermost layer of cell wall, consists of high-molecular-weight R-alkyl-b-hydroxy fatty acids and is mainly present as trehalose monomycolate (TMM), trehalose dimycolate (TDM or cord factor) and esters of arabinogalactan [23]. The first line chemotherapeutics for the treatment of TB include isoniazid and ethambutol which inhibit mycobacteria by distressing the synthesis of mycolic acids and arabinan, respectively. A range of multi-drug resistant strains of TB (MDRTB) and drug resistant tuberculosis (XDR-TB) have also emerged [24, 25]. Thus, there is a need to develop novel, nontoxic, cell permeable, multidrug resistant antitubercular agent. In spite of numerous attempts for synthesis of novel anti-TB agents, benzothiazole always displayed a most versatile class of compounds against microbes [26–30]. Some prominent reports from recent literature have been discussed in this section. A series of novel, 2-(2-(4-aryloxybenzylidene)hydrazinyl)benzothiazoles have been designed on the basis of molecular hybridization approach by combining the 2-hydrazinylbenzothiazole and 4-(aryloxy)benzaldehyde. Almost all the synthesized compounds displayed significant activity (MIC ¼ 1.5–29.00 mg/mL against M. tuberculosis H37Rv). Among them, five of the tested compounds exhibit MIC value of
Arch. Pharm. Chem. Life Sci. 2015, 348, 1–24
Arch iv d e r Ph a rm a zie
Review Article Recent Advances in the Chemistry and Biology of Benzothiazoles Rupinder K. Gill1,2, Ravindra K. Rawal1, and Jitender Bariwal1 1 2
Department of Pharmaceutical Sciences, ISF College of Pharmacy, Moga, Punjab, India 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, anthelmintic, 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 Benzothiazole belongs to the family of bicyclic heterocyclic compounds having benzene nucleus fused with five-membered ring comprising nitrogen and sulfur atoms. Benzothiazole is an important scaffold with a wide array of interesting biological activities and therapeutic functions including antitubercular [1– 2], antimicrobial [3–4], antimalarial [5], anticonvulsant [6–7], anthelmintic [8], analgesic [9], anti-inflammatory [10], antidiabetic [11] and antitumor [12] activities. Moreover, benzothiazoles are present in a range of marine or terrestrial natural compounds that have useful biological activities. Benzothiazoles have been therapeutically useful in the treatment of various diseases such as neurodegenerative disorders, local brain ischemia, central muscle relaxants and cancer [13]. Benzothiazoles have promising biological profile and are easy to access which makes this pharmacophore an interesting moiety for designing new benzothiazoles. Benzothiazole moiety has wide applications in dyes such as thioflavin [14]. Some of the marketed drugs comprising benzothiazole are shown in Fig. 1 [15–17]. Some reviews have been recently reported in literature, briefly describing the synthetic strategies and biological
activities of benzothiazole nucleus [18–21]. The main feature that was missing in the recently reported review [18] is the unexplained synthetic methodologies with reference to the scope of the functional group compatibility and SAR of the molecules under consideration. In the present review we discuss the effect of functional groups on yields of the product and robustness of the methodology along with the SAR studies. This makes this review distinguished and out of the league which will appeal the researches around the globe and serve as an ideal platform to synthesize new potent benzothiazoles. We have included detailed synthetic methodologies used to access benzothiazoles and special care has been taken to cover the most relevant and important literature reports.
Pharmacological profile
Correspondence: Dr. Jitender Bariwal, Department of Pharmaceutical Sciences, ISF College of Pharmacy, Moga-142001, Punjab, India. E-mail: [email protected] Fax: þ91 1636 239515
The benzothiazoles have shown wide range of pharmacological profile and accordingly they may be classified into the following categories. 1. Benzothiazole as antitubercular agent 2. Benzothiazole as antimicrobial agent 3. Benzothiazole as antimalarial agent 4. Benzothiazole as anticonvulsant agent 5. Benzothiazole as anthelmintic agent 6. Benzothiazole as analgesic, anti-inflammatory agent 7. Benzothiazole as antidiabetic agent 8. Benzothiazole as anticancer agent
ß 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
1
ARCH PHARM
Arch. Pharm. Chem. Life Sci. 2015, 348, 1–24 R. K. Gill et al.
O S O
NH N
F
H 2N S
O
Arch iv d e r Ph a rm a zie
O
Ph
S F F
O OH
R iluzole
HN
N H Sib enadet Hydr ochlor ide (Viozan )
S NH 2 N
Pr amipexole
Figure 1. Marketed drugs of benzothiazole.
Benzothiazole as antitubercular agent Tuberculosis (TB) is a fatal contagious disease caused by infection with Mycobacterium tuberculosis but also with M. bovis and M. africanum, which can affect almost any tissue or organ of the body, the most common site of infection of the disease being the lungs [22]. The lack of efficacy of antimycobacterial agents is due to the ability of M. tuberculosis to develop alternative metabolic routes and insufficient drug permeability through mycobacterial cell wall. The mycobacterial cell wall consists of three main components that form the mycolyl-arabinogalactan-peptidoglycan (mAGP) complex. Mycolic acid, which is the outermost layer of cell wall, consists of high-molecular-weight R-alkyl-b-hydroxy fatty acids and is mainly present as trehalose monomycolate (TMM), trehalose dimycolate (TDM or cord factor) and esters of arabinogalactan [23]. The first line chemotherapeutics for the treatment of TB include isoniazid and ethambutol which inhibit mycobacteria by distressing the synthesis of mycolic acids and arabinan, respectively. A range of multi-drug resistant strains of TB (MDRTB) and drug resistant tuberculosis (XDR-TB) have also emerged [24, 25]. Thus, there is a need to develop novel, nontoxic, cell permeable, multidrug resistant antitubercular agent. In spite of numerous attempts for synthesis of novel anti-TB agents, benzothiazole always displayed a most versatile class of compounds against microbes [26–30]. Some prominent reports from recent literature have been discussed in this section. A series of novel, 2-(2-(4-aryloxybenzylidene)hydrazinyl)benzothiazoles have been designed on the basis of molecular hybridization approach by combining the 2-hydrazinylbenzothiazole and 4-(aryloxy)benzaldehyde. Almost all the synthesized compounds displayed significant activity (MIC ¼ 1.5–29.00 mg/mL against M. tuberculosis H37Rv). Among them, five of the tested compounds exhibit MIC value of
