ejbps, 2015, Volume 2, Issue 3, 149-162.
Review Article
SJIF Impact Factor 2.062
European European JournalJournal of Biomedicalof andBiomedical Pharmaceutical Sciences ISSN 2349-8870 Volume: 2 AND Issue: 3 149-162 Pharmaceutical sciences Year: 2015 http://www.ejbps.com
Raju et al
RECENT ADVANCES OF BENZOTHIAZOLE DERIVATIVES AS MARKER FOR VARIOUS BIOLOGICAL ACTIVITIES Gollapalli Naga Raju* and Rama Rao Nadendla Department of Pharmaceutical Analysis, Chalapathi Institute of Pharmaceutical Sciences, Guntur, India. Article Received on 18/03/2015
*Correspondence for
Article Revised on 09/04/2015
Article Accepted on 03/05/2015
ABSTRACT
Author
Benzothiazoles can serve as unique and versatile pharmacophore for
Gollapalli Naga Raju
experimental drug design. Benzothiazole moiety is very small but is
Department of
fascinated by scientists because of the different biological activities by
Pharmaceutical Analysis,
benzothiazole
and
their
derivatives.
The
small
and
simple
Chalapathi Institute of Pharmaceutical Sciences, Guntur, India.
benzothiazole nucleus possesses numerous pharmacological activities like antitumor, antimicrobial, anti-inflammatory, anticonvulsant, and antidiabetic activities. This review was focused on the benzothiazole
and its different derivatives that posses different biological activities. KEYWORDS: Benzothiazole, Antimicrobial, Anticancer, Anticonvulsant, Anti-oxidant, Anti-inflammatory. INTRODUCTION A heterocyclic compound is one which possesses a cyclic structure with at least two different kinds of hetero atoms in the ring. Nitrogen, oxygen, and sulphur are the most common heteroatoms. Benzothiazoles are bicyclic ring systems having S and N at 1 and 3 positions of the ring. Benzothiazole derivatives have been studied and found to have various chemical and biological activities. Benzothiazole ring is made from thiazole ring fused with benzene ring. In the 1950s, a number of Benzothiazole derivatives were intensively studied, as the benzothiazole pharmacophore is one of privileged structure in medicinal chemistry. Benzothiazole ring is found to be possessing pharmacological activities such as anti-tumor (Shailja Sachan et al, 2011), anti-microbial (Sekar. N et al, 2014), anti-tubercular (Priyadarsini. R et al, 2012), anti-convulsant (Nadeem Siddiqui et al, 2012), anthelmintic
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(Balaji.P.N et al, 2014), anti-oxidant (J. Joseph et al, 2014), anti-inflammatory (Velingkar et al, 2011), antifungal (Gaurav Alang et al, 2010), antileishmanial (Fazal Rahim et al, 2015), antipsychotic (Pankaj Arora et al, 2010), anti-ulcer (Arun Pareek et al, 2010), local anesthetic (Athina Geronikaki et al, 2009), schistosomicidal (Mona A. Mahran et al, 2007) and diuretic (Mohammad Shahar Yar et al, 2009) activities. Given below is a brief account of various biological activities of benzothiazole ring and its derivatives. BIOLOGICAL ACTIVITIES OF BENZOTHIAZOLE DERIVATIVES Anticancer activity Novel benzothiazole-2-thiol derivatives, was developed via computer-aided drug design and de novo synthesis (X Peng et al, 2014). MTT assay showed it had potent anti-proliferative activity on various human cancer cells. O
S
S N H
Cl
H N
N O
Design and Synthesis of Novel Pyrazole Derivatives Linking to Benzimidazole, Benzoxazole and Benzothiazole (Khaled RA Abdellatif et al, 2014) and found the anti-tumor cytotoxicity. N H2N
N
NH2
N NH
S N
A series of Coumarin substituted benzothiazoles were and all the compounds were tested for their anticancer activity against MCF-7 breast cancer cell line with MTT assay (Suvarna G. Kini et al, 2012). Most of the compounds showed moderate to good anti-breast cancer activity. O O H3CO
S N
H3CO
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A series of pyrimido[2,1-b][1,3]benzothiazole derivatives were synthesized by microwave irradiation methods through MCR Mechanism (Deshmukh Vinayak K et al, 2013). The newly synthesized compounds showed good inhibitory activity on non small cell lung cancer (NCI-H522) cell lineat a single concentration of 10μM. Cl
NC Cl H2N
N N S
2-Substituted derivatives of 3-cyano-4,14-diimino -2-methylthio -10- nitropyrimido [2,3-b] pyrazolo [3,4-e] pyrimido [2,3-b] [1,3] benzothiazole have been prepared (Anil B. Chidrawar et al, 2014). All these newly synthesized compounds exhibits remarkable anticancer activity against CCRF-CEM (Leukemia) and other cell lines NCI-H522, SK-MEL-5, OVCAR-3, UO31, MCF7. NH O2N
S
N
N
CN
R=
N
NH
N
O
N N N
R
N
NH
A novel series of benzothiazole derivatives were synthesized and are screened for in vitro cytotoxicity against mouse Ehrlich Ascites Carcinoma (EAC) and two human cancer cell lines (MCF-7 and HeLa) (Girish Bolakatti et al 2014). All the synthesized compounds exhibit potent anticancer activity. N NO2 S
F HN
R
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4a 4-Fluoro 4b 4-Chloro 4c 4-Bromo 4d Unsubstituted 4e 4-Methyl 4f 2,4-dimethyl
4g 4-Methoxy 4h 2,4-dichloro 4i 3,4-dimethyl 4j 2,5-dichloro 4k 2-Methyl 4l 3-Chloro-4-fluoro
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Anticonvulsant activity Anticonvulsant Property among Different Fluoro Substituted Synthesized Benzothiazole Derivatives (I. Shanmukha et al 2014), and observed the anticonvulsant action of SSBDs is better against strychnine induced seizures than MES seizures. O
O O
N NH S
F
S
H C
N
N
CH3 CH3
O N
NH
Cl
A series of 3-[2-(2-substituted benzylidene) hydrazinyl]-N-(6-substitutedbenzo[d]thiazol-2yl)propanamides were synthesized successfully and all compounds were tested for anticonvulsant activity using MES and scPTZ screens (Ruhi Ali and Nadeem Siddiqui, 2014). All the series of substituted benzothiazole derivatives may be promising for the development of potential anticonvulsant agents after further optimization. N NHCOCH2CH2NHNCH
OH
S
H3CO
Designing of Hybrid form of Benzothiazole-quinazoline were docked with GABA-A then all the designed molecules were found with the higher affinity values (more than double affinity value) as compared to the γ-aminobutyric acid, so it could be concluded that these hybrid derivatives may be proved the better inhibitors of GABA-A for the anticonvulsant activity. O N
N S N
Synthesis
of
new
series
of
CH3
2-amino-6-substituted
benzothiazoles
were
injected
intraperitoneally into mice and evaluated by the maximal electroshock (MES). Phenytoin was used as the standard. (Ranjana Singh et al, 2014). Thus it can be concluded that substitution of 6th position with fluoro, chloro, bromo and nitro groups at the terminal benzothiazole ring is beneficial for anticonvulsant activity.
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S R = Cl, F, Br, NO2
N
R
Computational parameters of newer substituted benzothiazole hydrazinecarboxamides, using pharmacophoric features with aromatic hydrophobic aryl (A), NH-C=O and NH-C=S as hydrogen bonding domains (HBD), Nitrogen atom as electron donor (D) and phenyl as distal aryl ring (C) (Nadeem Siddiqui et al, 2014). Results showed that these molecules possessed ideal computational profile and should be further synthesized and screened for anticonvulsant activity. H N R1
N H
S
BZ-1: BZ-2: BZ-3: BZ-4: BZ-5: BZ-6: BZ-7:
R F Cl NO2 CH3 OCH3 F Cl
O
H N
N N H
R S
R R1 BZ-8: NO 2 Phenyl BZ-9: CH3 Phenyl BZ-10: OCH3 Phenyl BZ-11: F Phenyl BZ-12: Cl Phenyl 2, 6-dimethylphenyl BZ-13: NO2 2, 6-dimethylphenyl BZ-14: CH3 BZ-15: OCH3
R1 2, 6-dimethylphenyl 2, 6-dimethylphenyl 2, 6-dimethylphenyl 3,4-dichlorophenyl 3,4-dichlorophenyl 3,4-dichlorophenyl 3,4-dichlorophenyl 3,4-dichlorophenyl
Anti-inflammatory activity 2-Amino-6-methoxy benzothiazole derivatives were synthesized and the compounds were screened for their anti-inflammatory activity (Vrushali Patil et al, 2015). In vitro antiinflammatory study reveals that the activity of the drugs under test was satisfactory as compared to that of standard DFS. O H N
S
HN NH2
N
OCH3
Bioactive Benzothiazole Derivatives were synthesized and they have been screened for their anti-inflammatory activities (Ashok Kumar KV et al 2014). The results are reveals that compounds promisingly inhibit albumin denaturation in comparison with standard drugs, ibuprofen exhibited 80% and diclofenac sodium exhibited 88% inhibition of albumin denaturation.
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HN
N S
N NH
O
C5H11
S
F Cl
2-(6-Acetamidobenzo[d]thiazol-2-ylcarbamoyl) benzoic acid derivatives were synthesized evaluated for their anti-inflammatory and analgesic activities (Verma et al, 2014). Some of the compounds exhibited potent activities when compared with the standards. CH3 O OH
HN
N O
S
N H
O
The novel 2-benzylbenzo[d] thiazole-6-sulfonamide derivatives were synthesized and compounds were screened for anti-inflammatory activity by carrageenan induced paw oedema method in rats at a dose of 100 mg/kg body weight (Reena Mahtab et al, 2014). All the newly synthesized benzothiazole derivatives have shown considerable anti-inflammatory activity. S O
R N
S
NH2
O
Rm1 Rm2 Rm3 Rm4 Rm5
H 2-OH 2-OCH3 3-Br 4-Br
Rm6 Rm7 Rm8 Rm9 Rm10
2-F 4-F 2,5-F -NO2 -Cl
Anti-oxidant activity Novel 6-fluorobenzothiazole substituted pyrazole analogues were synthesized and substituted with anisidine, pyrrolidine, o-phenylene diamine. Further, they were screened for antimicrobial, anti-oxidant and anti-convulsant activities. These derivatives showed potent activity when compared to the standard drug.
N
F
N R
NH
N
S
CH3
4a 4b 4c 4d 4e
C2H5 m- CH3 o- CH3 4-OCH3 3-OCH3
4g 4b 4c 4d 4e
Piperazine Pyrrolidine Anisidine o-Phenylene diamine p-Aminophenol
HO
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Novel 2-(4-amino-2-aryllaminothiazol-5-oyl)benzothiazole derivatives have been synthesized from amidinothioureas and 2-(2-bromoacetyl)benzothiazole with triethylamine (Yardily et al, 2014). The antioxidant activity of the synthesized compounds was determined by DPPH free radical scavenging activity. H2N
3a C6H53b 4-MeOC6H43c 4-EtOC6H43d 4-MeC6H43e 4-ClC6H4
N
N
S
S
NHR
O
Novel coumarin substituted derivatives of benzothiazole derivatives were synthesized and were evaluated for antioxidant activity by DPPH radical scavenging activity (Suvarna G. Kini et al, 2013). The present study revealed that newly synthesized coumarin substituted benzothiazole derivatives showed significant antioxidant activity in EAC bearing mice. R3
R2
R1 N O S O
2-(benzothiazol-2-ylthio)-N-butylacetamide,
SC1 H OCH3 SC2 H OC2H5 SC3 H OAc SC4 H OCH2CH=CH2 SC5 H H SC6 H H SC7 H H SC8 OCH3 OCH3 SC9 OAc OAc SC10 H N(C2H5)2
H H H H OCH3 OC2H5 OAc H H H
2-(benzo-thiazol-2-ylthio)-N-octyl-acetamide
and 2- (benzothiazol-2-ylthio)-N-dodecylacetamide were synthesized and screened for the antioxidant activity (Nessim, M. I et al, 2013). Results reveal that these prepared compounds have good antioxidant activity. O N S S
NH
R
R = C4H9, C8H17, C12H25
Anti-tubercular activity Mannich bases of sulphadiazine, sulphamethoxazole, sulphacetamide with 2- amino -3 methyl benzothiazole, 2 -amino chloro benzothiazole and 2 -amino 5 -chloro 6- fluro benzothiazole were synthesized (Naira Nayeem et al 2012). The synthesized compounds were screened for their anti tubercular activity using Lowenstein-Jensen (L.J) medium against Mycobacterium tuberculosis H37 RV strains.
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O S
N
O
R3
H2N
N
R1
S
R2
NH
Derv 6a 6b 6c 6d 6e 6f 6g 6h 6i
R1 H Cl Cl Cl H CH3 H Cl CH3
R2 H H F H H H H H H
R3 H H H C4H3N2 C4H3N2 COCH3 COCH3 COCH3 H
7-Chloro-2-(substituted)-3-(4-(6-methylbenzo[d]thiazol-2-yl) phenyl) quinazolin-4(3H)-ones have been prepared and careened in- vitro antitubercular activity was carried out against Mycobacterium tuberculosis H37Rv strain using Lowenstein-Jensen medium (Asif Shaik et.al, 2014). R N
S
CH3
N N
Cl O
3-[6'-fluoro-7'-chloro (1',3') benzo thiazol-2'-yl]-m-nitrophenyl (1,3) thiazolidine-4-one derivatives were synthesized (Sathe B.S et al 2010). Anti-tubercular activity was carried out against Mycobacterium tuberculosis. Some compounds showed promising antimycobacterial activity.
N
R = ortho, meta and para nitroanillines, ortho, meta, para chloroanillines, morpholino, Piperazine, diphenylamine NO2
N F
S R
Series
of
S
O
3-(3-pyridyl)-5-(4-nitrophenyl)-4-(N-substituted-1,3-benzothiazol-2-amino)-4H-
1,2,4-triazole derivatives were synthesized (Patel N.B. et al 2011). Anti-tubercular activity H37Rv using Lowenstein-Jensen agar method. It was also observed that the promising to be better antituberculars. N
N N
HN
N N
NO2 S
R = a. 6-F, d. 6-CH3, g. 4-CH3, j. 4-Cl b. 6-Br, e. 6-OCH3, h. 4-NO2, c. 6-NO2, f. 6-Cl, i. 5-Cl,6-Cl, R
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Antimicrobial activity A new series of benzothiazole derivatives were synthesized and the new compounds examined for antibacterial effects again different strain of bacteria and antifungal were high to lowest minimum inhibition concentration values (Jayesh Maru et al 2014). O H3C
S
C O
NH
S N
A parent benzothiazole nucleus was synthesized by p-amino acetanilide, and then it is subjected to treatment with various substituted aromatic aldehydes to get the corresponding Schiff’s bases followed by treatment with pthalic anhydride (Verma A.K et al 2014). The synthesized derivatives showed very good antibacterial activities against previously reported derivatives of benzothiazole. CH3 O
C OH
HN
N O
S
N H
O
A new series of heterocyclic compounds 9-chloro-10-fluoro-15-imino-14-oxo-14Hbenzothiazole [2, 3-b] pyrimido [5, 6-e] pyrimido [2, 3-b] benzothiazole and its substituted derivatives have been synthesized (P. Ravi Prasad et al 2014). The biological activity of the synthesized compounds was found to be good to moderate. Cl F
S
N
N
S R
N O
3a 3b 3c 3d 3e
H 1-Cl 3-NO2 1,4-dimethyl 2,3-dichloro
NH
New classes of structurally novel derivatives were synthesized by incorporating two bioactive structures, a benzothiazole and thiazolidin-4-one (Shikha Agarwal et al 2014). The antimicrobial properties of the synthesized compounds were investigated against bacteria and fungi by using serial plate dilution method.
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O O
N
S N
N N H H R = 2-Cl, 2,4-diCl, 2-CH3, 2-OCH3, 4-NO2, 2-OH, 2-Br S
H3C
R
Miscellaneous activities Several thiazolidinonyl benzothiazoles and thiazolinylbenzothiazoles were synthesized (M. A. Mahran et al 2003). Some of the prepared compounds were screened for their antiparasitic activity. Most of them showed reasonable antinematodal or schistosomicidal activity.
R
R1
N N
NH S
N S
a b c d e f g h i j
R C2H5 C6H5 C6H5 C6H5 4-C6H4(Br) 4-C6H4(Br) 4-C6H4(Br) 4-C6H4(Cl) 4-C6H4(Cl) 4-C6H4(Cl)
R1 4-C6H4(NO2) C6H5 4-C6H4(Br) 4-C6H4(NO2) C6H5 4-C6H4(Br) 4-C6H4(NO2) C6H5 4-C6H4(Br) 4-C6H4(NO2)
Some Substituted 2-Amino Benzothiazole Derivatives were tested on the germination of wheat seeds (R. S. Bendre et al, 2013). Almost all the compounds showed good activity at tested concentrations. The tested derivatives characterized as biologically active substances with auxin like growth promoting activity. O
R N
S
O N H
Ar R = H, 4-CH3, 6-CH3, 6-OCH3 Ar = 2-Cl-Ph, 4-Cl-Ph, 4-Cl, 3,5-diMe-Ph
N-(1H-benzimidazol-2-yl)-6-substituted-1,3-benzothiazol-2-amines and 6-substituted-N-(4,5dihydro- 1H-imidazol-2-yl)-1,3-benzothiazol-2-amines were synthesized (Manish Chaudhary et al 2011). Antifeedant activity, contact toxicity and stomach toxicity against Spodoptera litura and acaricidal activity against Tetranychus urticae were moderate for test compounds. R
NH
R1
N S
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N
NH2
4A: R=H, R1=Br 4B: R=H, R1=F 4C: R=CH3, R1=H 4D: R=H, R1=OC2H5 4E: R=H, R1=CH3
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CONCLUSION From the above literature review concluded that the Benzothiazole and their derivatives have shown a wide spectrum of biological activities. It is a versatile pharmacophore in the field of medicinal chemistry. Hence this unique molecule must serve as future therapeutic leads of developing various biological agents. The biological profiles of this new generation of Benzothiazoles represent much progress with regard to the older compounds. Thus this paper proves to be significant for further research work on the bioactive Benzothiazole derivatives. ACKNOWLEDGEMENT The authors are grateful to Department of Pharmaceutical Analysis, Chalapathi Institute of Pharmaceutical Sciences, Guntur and UGC for providing facilities to perform this review work. REFERENCES 1. Ajeet et al. Designing of Hybrid form of Benzothiazole-quinazoline as GABA-A Inhibitor with Anticonvulsant Profile: An in-silico Approach, American Journal of Pharmacological Sciences, 2013; 1(6): 116-120. 2. Anil B. Chidrawar et al, Novel Synthesis and In Vitro Anticancer Activity of 3-Cyano4,14-Diimino-2-Methylthio-10-Nitropyrimido[2,3-b]
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