INTRODUCTION
The small and simple benzothiazole nucleus is present in compounds involved in research aimed at evaluating new products that possess interesting biological activities like- antitumour1-4, antimicrobial5-7,, antitubercular8, antimalarial9, anticonvulsant10,11, anthelmintic12, analgesic and anti-inflammatory activity.13,14 The benzothiazole ring is present in various marine or terrestrial natural compounds, which have useful biological activities. Heterocycles containing the thiazole moiety are present in many natural products such as bleomycin, epothilone A, lyngbyabellin A & dolastatin 10.15 Benzothiazole is a privileged bicyclic ring system. Due to their important pharmaceutical utilities, the synthesis of these compounds is of considerable interests.
Chemistry of benzothiazole nucleus
Being a heterocyclic compound, benzothiazole finds use in research as a starting material for the synthesis of larger, usually bioactive structures. Its aromaticity makes it relatively stable, although as a heterocycle, it has reactive sites, which allow for functionalization. Benzothiazole is a colorless, slightly viscous liquid with a melting point of 2°C, and a boiling point of 227-228 °C. The density of benzothiazole is 1.644 gm/ml, and molecular mass is 139.19 gmol-1. Benzothiazole has no household use. It is used in industry and research.
Structure of benzothiazole (C7H5NS):
1-thia-3-azaindene
MEDICINAL IMPORTANCE of Benzothiazole NUCLEUS
A large number of therapeutic agents are synthesized with the help of Benzothiazole nucleus. During recent years there have been some interesting developments in the biological activities of benzothiazole derivatives. These compounds have special significance in the field of medicinal chemistry due to their remarkable pharmacological potentialities.
Benzothiazole with analgesic activity:
Series of sulphonamide derivatives were prepared by condensation of 2-(4-aminophenyl sulphonamido)-6-substituted benzothiazoles with alkyl isothiocynates by Siddiqui et al (2004).13 The compound (1) with methoxy substitution showed maximum analgesic activity in the series.
(1)
6-fluoro-7-substituted-2-(1,3-oxazolo[3,2-b][1,2,4]triazo-3-amino) benzothiazoles and 6-fluoro-7-substituted-2-(1,3-thiazolo[3,2-b] [1,2,4] triazol-3-amino) benzothiazoles were synthesized by Gurupadayya et al (2005).14 The compounds (2a and 2b) exhibited 60% and 71.79% analgesic activity.
Compound X R
(2a) O NHC6H4-4-NO2
(2b) S NHC6H4-4-NO2
Benzothiazole with anthelmintic activity:
2-[3-amino, 5-methylthio, 4-carboxamido pyrazol-1-yl] 6-fluoro, 7-chloro (1,3) benzothiazoles were synthesized and tested for anthelmintic activity againstP. posthumaby Jayachandran et al (2003).16 The compound (3) was found to possess markedly higher anthelmintic activity.
(3)
Benzothiazole with antibacterial activity:
A number of new- 2-[(4?-halophenyl) thioureido]-6-substituted benzothiazoles were prepared by refluxing equimolar quantity of 2-amino-6-substituted benzothiazoles by Javed et al (2004).17 The synthesized compounds have been screened for their antibacterial activity againstS.aureus(Gram positive) andE.coli(Gram negative) bacteria. Among the compounds tested compound (4a) was found to be the most potent in the series againstS.aureuswhere as the compound (4b) was found to be the most potent againstE.coli.
(4a) R =Br
(4b) R = Cl
Novel heterocyclic compound 15-iminobenzothiazolo[2,3-b]pyrimido[5,6-e]pyrimido[2,3-b] benzothiazol-14-(H)-one and its 3,10-disubstituted derivatives have been synthesized by Baheti et al (2005).18 Amongst the synthesized compounds, compound (5a) and (5b) showed higher zone of inhibition against gram-positive speciesS. aureusandB. substilisand gram-negative speciesE. coliandS. typhirespectively.
(5a) R = NO2
(5b) R = Cl
Benzothiazole with anticonvulsant activity:
A series of new sulphonamide derivatives 2-[4-{(alkyl thioureido) phenyl} sulphonamido]-6-halo/alkyl benzothiazoles) having benzothiazole nucleus were synthesized by Alam et al (2004).10 The compounds (6a, 6b, and 6c) showed most potent anticounvulsant activity.
Compound R1 R2
(6a) Cl C2H5
(6b) F CH3
(6c) Br C2H5
Various substituted 2-amino-N-(2-benzothiazolyl) benzamides and 2-thio-3-(2-benzothiazolyl)-4-(3H)-quinazolinones containing different functional groups have been synthesized by Chakole et al (2005).11 The anticonvulsant activity of compounds (7a-e) were carried out by maximal electroshock method and and activity ranges from 72-89%.
Compound R1 R 2 R3 R4
(7a) H H H H
(7b) H H Cl H
(7c) Br H Cl H
(7d) Br H H NO2
(7e) Br Br OCH3 H
Benzothiazole with antifungal activity:
The antifungal activity of 6-amino-2-n-pentylthiobenzothiazole (APB) against 26 strains of genusCandidain vitrowas studied by Bujdakova et al (1994).19 Susceptibility of 17 strains was IC50 < 40 mmol/ml, of 7 strains IC50 = 40-80mmol/ml and of 2 strains IC50 = 80-200mmol/ml.
(APB)
The synthesis and optimization of a series of 2-aminobenzothiazoleN-myristoyltransferases inhibitors using solution phase combinatorial chemistry were described by Yamazaki et al (2005).20 The antifungal activity seems to be associated with CaNmt inhibitory activity only in the cycloalkyl linker series. The (1R, S) enantiomer (8) exhibited the most potent CaNmt inhibitory activity (IC50:0.49µM) with an excellent selectivity.
(8)
Benzothiazole with anti-HIV activity:
Three new series of benzo[d]isothiazole, benzothiazole and thiazole schiff bases were synthesized by Vicini et al (2003).21These compounds were evaluatedin vitroagainst representatives of different virus classes, such as HIV-1 (Retrovirus), a HBV (Hepadnavirus) and single-stranded RNA+ viruses, Yellow fever virus (YFV) and Bovine viral diarrhoea virus (BVDV). The compounds
(9a-g) showed potent anti-HIV activity.
Compound R R1
(9a) H C6H5
(9b) H 2-ClC6H4
(9c) H 2-NO2C6H4
(9d) H 3- NO2C6H4
(9e) F 3-ClC6H4
(9f) F 4- NO2C6H4
(9g) OC2H5 4-OHC6H4
Benzothiazole with antimicrobial activity:
The synthesis of a new series of 2,5-disubstituted benzoxazoles, 2-substituted oxazolo(4,5-b)pyridines, benzothiazoles and benzimidazoles was described in order to determine their antimicrobial activities and feasible structure-activity relationships(SAR) by Yacin et al (1992).5 The synthesized compounds were testedin vitroagainst 3 Gram-positive (S. aureus, S. faecalisandB. subtilis), 3 Gram-negative (E. coli, K. pneumoniaeandC. albicans) and a fungusCandida albicans.The benzothiazole derivatives (10a and 10b) were found to be more active than others.
(10a)
(10b)
A series ofN-cycloalkenyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles (11a-j), N-cycloalkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles (12a-e), andN-alkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles (12f-g), were synthesized by Latrofa et al (2005)7 and tested forin vitroantibacterial and antifungal activities against four gram-negative bacteria (Bacillus subtilis6633,Enterococcus faecalis29212,Staphylococcus aureus6538,Staphylococcus aureus25923,Escherichia coli25922,Acinetobacter calcoaceticusa1,Acinetobacter calcoaceticusa2,Pseudomonas aeruginosa27835,Klebsiella oxytoca49131), four yeast-like fungi and one fungus (Candida tropicalis750,Candida albicans14053,Candida albicans10231,Criptococcus laurentii18803, andSaccharomyces cerevisiae). The findings obtained showed that some of the tested compounds (11) and (12) were effective against some of the bacterial strains used, whereas, only compounds (12b-g) exhibited a moderate antifungal activity against the yeast strains evaluated.
Compound
X
n
R'
(11a)
H
8
CH3
(11b)
H
8
C2H5
(11c)
H
8
C3H7
(11d)
H
8
i-C3H7
(11e)
H
3
C6H13
(11f)
F
3
C3H7
(11g)
OCH3
3
C3H7
(11h)
OCH3
3
i-C3H7
(11i)
CH3
3
i-C3H7
(11j)
CH3
3
C4H9
Compound
N
R2
R3
(12a)
4
C2H5
H
(12b)
3
C2H5
H
(12c)
3
CH3
H
(12d)
3
-(CH2)3-
(12e)
3
C6H5
H
Compound
R2
R3
(12f)
C6H5
H
(12g)
-CH2-N(CH2C6H5)-(CH2)2-
Benzothiazole with antiproliferative activity:
The multistep synthesis of a series of new substituted-benzothiazoles as hydrochloride or quaternary salts was synthesized by Caleta et al (2004).22 The best antiproliferative effect was achieved with compounds (13a-d) with slight differences among them.
Compound R1 R2 n
(13a) X H 1
(13b) Y H 2
(13c) H X 1
(13d) H Y 2
Where;
Benzothiazole with benzodiazepine receptor binding activity:
A series of substituted imidazo[2,1-b]benzothiazoles and pyrimido[2,1-b]benzothiazoles were synthesized by Trapani et al (1996)23 and the compounds evaluated for their affinity at the central benzodiazepine receptors. Efficacies towards benzodiazepine receptors were found that, the imidazobenzothiazoles (14a-c) possess inverse-agonist profiles and the pyrimidobenzothiazoles (15a and 15b) possess partial-agonist properties.
Compound R1 R2
(14a) OC2H5 Cl
(14b) OC2H5 OCH3
(14c) OCH3 CH3
(15a) R= -OCH3
(15b) R= -Cl
Benzothiazole with bradykinin B2 receptor antagonist activity:
The synthesis and the SAR study of novel O-substituted 8-quinolines and 4-benzothiazoles as highly potent non-peptide bradykinin B2 receptor antagonists was described by Heitsch et al (1999).24 The potent antagonists (16a-f) were derived from benzothiazole series.
Compound R1
(16a) -CH=CH-C6H5-(p-CH3)
(16b) -CH=CH-C6H5-(p-CF3)
(16c) -CH=CH-C6H5-(m-OCH3)
&
