Importance of Benzothiazole Nucleus in Medicinal

INTRODUCTION				Selective inhibitors of 11?-hydroxysteroid
The small and simple benzothiazole nucleus is present				dehydrogenase type 1 (11?-HSD1) have considerable
in compounds involved in research aimed at evaluating				potential as treatments for metabolic deseases, such
new products that possess interesting biological				as diabetic mellitus type 2 or obesity. Su et al (2006)27
activities like- antitumour1-4, antimicrobial5-7,,				reported the discovery and synthesis of a series of
antitubercular8, antimalarial9, anticonvulsant10,11,				novel benzothiazole derivatives and their inhibitory
anthelmintic12, analgesic and anti-inflammatory				activities against 11?-HSD1 from human hepatic
activity.13,14 The benzothiazole ring is present in various				microsomes measured using a radioimmunoassay
marine or terrestrial natural compounds, which have				(RIA) method. The benzothiazole derivatives (19a and
useful biological activities. Heterocycles containing the				19b) showed greater than 80% inhibition at 10 mM and
thiazole moiety are present in many natural products				exhibited IC50 value in the low micromolar range.
such as bleomycin, epothilone A, lyngbyabellin A &				Compound Ar
dolastatin 10.15 Benzothiazole is a privileged bicyclic ring				(19a) 2,5-Dichlorophenyl
system. Due to their important pharmaceutical utilities,				(19b) 4-n-Propylphenyl
the synthesis of these compounds is of considerable				Benzothiazole with mutagenic activity:
interests. Chemistry of benzothiazole nucleus				The potential initiation activities of a novel monoamine
Being a heterocyclic compound, benzothiazole finds				oxidase type-A (MAO-A) inhibitor E2011(20), which
use in research as a starting material for the synthesis				induced preneoplastic foci in the rat liver, were
of larger, usually bioactive structures. Its aromaticity				investigated by comparing the mutagenic activity of
makes it relatively stable, although as a heterocycle, it				E2011, 6-aminobenzothiazole (a structure scaffold of
has reactive sites, which allow for functionalization.				E2011) and its derivatives by Sato et al (2000).28 The
Benzothiazole is a colorless, slightly viscous liquid with a				results strongly suggest that E2011 has potential
melting point of 2°C, and a boiling point of 227-228				activities in the rat liver in vivo after undergoing
°C. The density of benzothiazole is 1.644 gm/ml,				decarbonation, one of the metabolic pathways, at the
and molecular mass is 139.19 gmol-1. Benzothiazole has				carbonyl moiety of oxazolidine ring to form mutagenic
no household use. It is used in industry and research.				amine(s).
Structure of benzothiazole (C7H5NS):				(20)
1-thia-3-azaindene				Benzothiazole with p56lck inhibitor activity:
MEDICINAL IMPORTANCE of Benzothiazole				A series of structurally novel benzothiazole based
NUCLEUS				small molecule inhibitors of p56lck was prepared to
A large number of therapeutic agents are synthesized				elucidate their structure-activity relationships (SAR),
with the help of Benzothiazole nucleus. During recent				selectivity and cell activity in the T-cell prolifiration
years there have been some interesting developments				assay by Das et al (2003).29 BMS-350751(21a) (IC50 =
in the biological activities of benzothiazole derivatives.				475 nM) and BMS-358233 (21b) (IC50 = 262 nM) was
These compounds have special significance in the field				identified as potent Lck inhibitors with excellent cellular
of medicinal chemistry due to their remarkable				activities against T-cell proliferation.
pharmacological potentialities.				(21a)
Benzothiazole with analgesic activity:				(21b)
Series of sulphonamide derivatives were prepared by				Benzothiazole with topoisomerase II inhibitor activity:
condensation of 2-(4-aminophenyl				To investigate one possible mechanism of action of
sulphonamido)-6-substituted benzothiazoles with alkyl				the cytotoxic activities of benzothiazoles, Choi et al
isothiocynates by Siddiqui et al (2004).13 The				(2006)30 synthesized
compound (1) with methoxy substitution showed				2-(substituted-phenyl)benzothiazoles and evaluate their
maximum analgesic activity in the series.				ability to inhibit topoisomerase II activities. The results
(1)				showed that 2-(3-Amino-4-methylphenyl)
mino) benzothiazoles and				benzothiazole (22) has high activity (IC50=71.7 mM).
6-fluoro-7-substituted-2-(1,3-thiazolo[3,2-b] [1,2,4]				(22)
triazol-3-amino) benzothiazoles were synthesized by				Benzothiazole with anticancer/antitumour activity:
Gurupadayya et al (2005).14 The compounds (2a and				Novel benzothiazole derivatives have been
2b) exhibited 60% and 71.79% analgesic activity.				synthesized via the corresponding imino-1,2,3-dithiazoles
Compound X R				by Beneteau et al (1999)1 and the cytotoxicity of some
(2a) O NHC6H4-4-NO2				of these polyheterocyclic compounds was studied.
(2b) S NHC6H4-4-NO2				The 2-cyno-4,7-dimethoxybenzothiazole derivatives
Benzothiazole with anthelmintic activity:				(23a) and (23b) were found practically equipotent on
2-[3-amino, 5-methylthio, 4-carboxamido pyrazol-1-yl]				cell proliferation with IC50’s of, respectively,
6-fluoro, 7-chloro (1,3) benzothiazoles were synthesized				20.6µM and 25.2µM.
and tested for anthelmintic activity against P. posthuma				(23a)
by Jayachandran et al (2003).16 The compound (3)				(23b)
was found to possess markedly higher anthelmintic				The synthesis of a series of new antitumour agents,
activity.				the benzothiazole substituted quinol ether and esters, is
(3)				reported via hypervalent iodine mediated oxidation of
Benzothiazole with antibacterial activity:				hydroxylated 2- phenylbenzothiazoles by Wells et al
A number of new- 2-[(4?-halophenyl)				(2000).2 The products were found to be active in vitro
thioureido]-6-substituted benzothiazoles were prepared				against human colon and breast cancer cell lines with
by refluxing equimolar quantity of 2-amino-6-substituted				IC50 values in the nanomolar range. In both colon cell
benzothiazoles by Javed et al (2004).17 The				lines tested quinol ester compound (24) was the most
synthesized compounds have been screened for their				potent (0.24µM for HCT-116).
antibacterial activity against S. aureus (Gram positive)				(24)
and E. coli (Gram negative) bacteria. Among the				A series of sulfamate salt derivatives of the potent
compounds tested compound (4a) was found to be				and selective 2-(4-aminophenyl) benzothiazole
the most potent in the series against S. aureus where				antitumour agents has been prepared and their
as the compound (4b) was found to be the most				evaluation as potent prodrugs for parentral
potent against E. coli.				administration carried out by Shi et al (2001).3 The salts
(4a) R =Br				were sparingly soluble in aqueous media (pH 4-9), and
(4b) R = Cl				degradation to the active free amines was shown to
Novel heterocyclic compound				occur under strongly acidic conditions. Studies focused
15-iminobenzothiazolo[2,3-b]pyrimido[5,6-e]pyrimido[2,3-b]				on sulfamate salts (25a) and (25b) revealed that
benzothiazol-14-(H)-one and its 3,10-disubstituted				neither was particularly soluble in water over the pH
derivatives have been synthesized by Baheti et al				range 4-9 and, furthermore, decomposition of salt (25b)
(2005).18 Amongst the synthesized compounds,				to the active free base was evident only at acidic pH
compound (5a) and (5b) showed higher zone of				at 50°C. Since no degradation of these
inhibition against gram-positive species S. aureus and B.				compounds were found in biological matrices
substilis and gram-negative species E. coli and S. typhi				conducted as part of this study.
respectively.				(25a)
(5a) R = NO2				(25b)
(5b) R = Cl				The synthesis of a new series of antitumour
Benzothiazole with anticonvulsant activity:				2-(4-aminophenyl)benzothiazole analogues, substituted
A series of new sulphonamide derivatives 2-[4-{(alkyl				in the 3´-position by cyano or alkynyl groups,
thioureido) phenyl} sulphonamido]-6-halo/alkyl				was described by Hutchinson et al (2003).4 Several of
benzothiazoles) having benzothiazole nucleus were				the analogues, notably the 5-fluorinated compounds
synthesized by Alam et al (2004).10 The compounds				(26) and (27), were found to possess potent in vitro
(6a, 6b, and 6c) showed most potent anticounvulsant				activity against MCF-7 and MDA 468 human cancer
activity.				cell lines. More comprehensive in vitro analysis (NCI
Compound R1 R2				60-cell line) establish compound (26) as a particular
(6a) Cl C2H5				potent and selective 2-(4- aminophenyl) benzothiazole
(6b) F CH3				analogue.
(6c) Br C2H5				(26)
Various substituted 2-amino-N-(2-benzothiazolyl)				(27)
benzamides and				The title compounds
2-thio-3-(2-benzothiazolyl)-4-(3H)-quinazolinones				2-[2-(bis-(2-chloroethyl)amino)-methyl]-benzothiazoles
containing different functional groups have been				were synthesized by Murugan et al (2004)31 by the
synthesized by Chakole et al (2005).11 The				reactions of corresponding
anticonvulsant activity of compounds (7a-e) were				2-[2-(bis-(2-hydroxyethyl)amino)methyl] benzothiazole
carried out by maximal electroshock method and and				with phosphorous trichloride and phosphorus
activity ranges from 72-89%.				oxychloride. The biological evaluation of the
Compound R1 R 2 R3 R4				compounds was carried out by various methods such
(7a) H H H H				as short-term in vitro cytotoxic activity andin vitro
(7b) H H Cl H				anticancer screening. Compounds (28a) and (28b)
(7c) Br H Cl H				showed significant anticancer activity.
(7d) Br H H NO2				(28a)
(7e) Br Br OCH3 H				(28b)
Benzothiazole with antifungal activity:				Based on
The antifungal activity of				2-methyl-4-nitro-2H-pyrazole-3-carboxylicacid
6-amino-2-n-pentylthiobenzothiazole (APB) against 26				[2-(cyclohexanecarbonylamino)
strains of genus Candida in vitro was studied by				benzothiazole-6-yl]amide, which shows selective
Bujdakova et al (1994).19 Susceptibility of 17 strains				cytotoxicity against tumorigenic cell lines,
was IC50 < 40 mmol/ml, of 7 strains IC50 =				ole-6-yl]benzamide was designed and synthesized by
40-80mmol/ml and of 2 strains IC50 = 80-200mmol/ml.				Yoshida et al (2005)32 as a biologically derivative
(APB)				containing no nitro group. The highly potent derivative
The synthesis and optimization of a series of				(29) exhibited excellent in vivo inhibitory effect on
2-aminobenzothiazole N-myristoyltransferases inhibitors				tumour growth.
using solution phase combinatorial chemistry were				(29)
described by Yamazaki et al (2005).20 The antifungal				The 2-arylsubstituted benzothiazole derivatives were
activity seems to be associated with CaNmt inhibitory				synthesized by Kini et al (2007)33 by
activity only in the cycloalkyl linker series. The (1R, S)				refluxingo-aminothiophenol with substituted benzoic
enantiomer (8) exhibited the most potent CaNmt				acids in the presence of polyphosphoric acid at
inhibitory activity (IC50:0.49µM) with an excellent				220°C. The screening for antitumour activity was
selectivity.				done and three compounds (30a), (30b) and (30c)
(8)				were found to be significantly cytotoxic as compared
Benzothiazole with anti-HIV activity:				to other derivatives.
Three new series of benzo[d]isothiazole, benzothiazole				(30a)
and thiazole schiff bases were synthesized by Vicini				(30b)
et al (2003).21These compounds were evaluated in				(30c)
vitro against representatives of different virus classes,				Drugs with Benzothiazole nucleus34
such as HIV-1 (Retrovirus), a HBV (Hepadnavirus) and				1-Diamthazole dihydrochloride:
single-stranded RNA+ viruses, Yellow fever virus				ine dihydrochloride
(YFV) and Bovine viral diarrhoea virus (BVDV). The				Therapeutic category: Antifungal
compounds				2- Ethoxzolamide:
(9a-g) showed potent anti-HIV activity.				6-Ethoxy-2-benzothiazolesulfonamide
Compound R R1				Therapeutic category: Diuretic (Carbonic anhydrase
(9a) H C6H5				inhibitor)
(9b) H 2-ClC6H4				3-Pramipexole:
(9c) H 2-NO2C6H4				(S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole
(9d) H 3- NO2C6H4				diamine
(9e) F 3-ClC6H4				Therapeutic category: Antiparkinsonian (Dopaminergic
(9f) F 4- NO2C6H4				agonist)
(9g) OC2H5 4-OHC6H4				4-Riluzole35:
Benzothiazole with antimicrobial activity:				6-Trifluoromethoxy-2-benzothiazolamine
The synthesis of a new series of 2,5-disubstituted				Therapeutic category: Antiparkinsonian (Sodium
benzoxazoles, 2-substituted oxazolo(4,5-b)pyridines,				channel blocker)
benzothiazoles and benzimidazoles was described in				Anticonvulsant (NMDA receptor antagonist)
order to determine their antimicrobial activities and				CONCLUSION
feasible structure-activity relationships(SAR) by Yacin				Modifications on the benzothiazole nucleus have
et al (1992).5 The synthesized compounds were				resulted in a large number of compounds having
tested in vitro against 3 Gram-positive (S. aureus, S.				diverse pharmacological activities. The synthesis,
faecalis and B. subtilis), 3 Gram-negative (E. coli, K.				structures and biological activities of benzothiazole
pneumoniae and C. albicans) and a fungus Candida				derivatives have long been focused of research
albicans. The benzothiazole derivatives (10a and 10b)				interest in the field of medicine, due to potential
were found to be more active than others.				activities exhibited by them. The biological profiles of
(10a)				these new generations of benzothiazoles represent
(10b)				much progress with regards to older compounds.
A series of				Looking into the medicinal importance of benzothiazole
oles (11a-j), N				moiety, it was thought worthwhile to synthesize certain
(12a-e), and				newer derivatives of benzothiazole and screen them
N-alkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles				for their biological activities.
(12f-g), were synthesized by Latrofa et al (2005)7 and				REFERENCES
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prepared and tested as H1- and H3-receptor				34. The Merck Index An Encyclopedia of Chemicals,
antagonists by Walczynski et al (1999).26 The simple				Drugs, and Biologicals. 12th Ed. New Jersey: Merck
alkyl substituted, 2-[1-(4-methyl and 4-ethyl)piperazinyl]				Research Laboratories, Division of MERCK & CO,
analogues (18a and 18b) show increasing, moderate				Inc.; 1996.
H3-antagonistic activity (pA2=6.0, and pA2= 7.0).				35. Abraham DJ. BURGER’S Medicinal
(18a) R = CH3				Chemistry and Drug Discovery Vol. 6 Nervous System
(18b) R = CH2CH3				Agents. 6th Ed. United States of America: A John
Benzothiazole with human 11?-hydroxysteroids				Wiley and Sons, Inc. Publication; © 2003.
dehydrogenase type 1 inhibitor activity:

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