Importance of Benzothiazole Nucleus in Medicinal

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.

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 against P. posthuma by 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 against S. aureus (Gram positive) and E. coli (Gram negative) bacteria. Among the compounds tested compound (4a) was found to be the most potent in the series against S. aureus where as the compound (4b) was found to be the most potent against E. 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 species S. aureus and B. substilis and gram-negative species E. coli and S. typhi respectively.

                                                 (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 genus Candida in vitro was 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-aminobenzothiazole N-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 evaluated in vitro against 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 tested in vitro against 3 Gram-positive (S. aureus, S. faecalis and B. subtilis), 3 Gram-negative (E. coli, K. pneumoniae and C. albicans) and a fungus Candida albicans. The benzothiazole derivatives (10a and 10b) were found to be more active than others.

(10a)

(10b)

A series of N-cycloalkenyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles (11a-j),  N -cycloalkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles (12a-e), and N-alkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles (12f-g), were synthesized by Latrofa et al (2005)7 and tested for in vitro antibacterial and antifungal activities against four gram-negative bacteria (Bacillus subtilis 6633, Enterococcus faecalis 29212, Staphylococcus aureus 6538, Staphylococcus aureus 25923, Escherichia coli 25922, Acinetobacter calcoaceticus a1, Acinetobacter calcoaceticus a2, Pseudomonas aeruginosa 27835, Klebsiella oxytoca 49131), four yeast-like fungi and one fungus (Candida tropicalis 750, Candida albicans 14053, Candida albicans 10231, Criptococcus laurentii 18803, and Saccharomyces 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)

                                                  (16d)                              -CH=CH-(2-furyl)

                                                  (16e)                              -CH=CH-CH=CH2

                                                  (16f)                                 -O-C6H5

Benzothiazole with cyclooxygenase (COX-1&2) inhibitor activity:

Paramashivappa et al (2003)25 have synthesized a series of 2-[[2-alkoxy- 6-pentadecylphenyl) methyl]thio]-1H-benzimidazoles/benzothiazoles and benzoxazoles and investigated their ability to inhibit human Cyclooxygenase-2-enzyme (COX-2). Compound (17) was found to be 470-fold selective towards COX-2 compared to COX-1.

(17)

Benzothiazole with H1- & H3- antagonist activity:

New 2-(1-Piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl) benzothiazoles were prepared and tested as H1- and H3-receptor antagonists by Walczynski et al (1999).26 The simple alkyl substituted, 2-[1-(4-methyl and 4-ethyl)piperazinyl] analogues (18a and 18b) show increasing, moderate H3-antagonistic activity (pA2=6.0, and  pA2= 7.0).

                                                                   (18a)    R = CH3

(18b)     R = CH2CH3

Benzothiazole with human 11?-hydroxysteroids dehydrogenase type 1 inhibitor activity:

Selective inhibitors of 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) have considerable potential as treatments for metabolic deseases, such as diabetic mellitus type 2 or obesity. Su et al (2006)27 reported the discovery and synthesis of a series of novel benzothiazole derivatives and their inhibitory activities against 11?-HSD1 from human hepatic microsomes measured using a radioimmunoassay (RIA) method. The benzothiazole derivatives (19a and 19b) showed greater than 80% inhibition at 10 mM and exhibited IC50 value in the low micromolar range.

                                                      Compound              Ar

(19a)                  2,5-Dichlorophenyl

                                                      (19b)                  4-n-Propylphenyl

Benzothiazole with mutagenic activity:

The potential initiation activities of a novel monoamine oxidase type-A (MAO-A) inhibitor E2011(20), which induced preneoplastic foci in the rat liver, were investigated by comparing the mutagenic activity of E2011, 6-aminobenzothiazole (a structure scaffold of E2011) and its derivatives by Sato et al (2000).28 The results strongly suggest that E2011 has potential activities in the rat liver in vivo after undergoing decarbonation, one of the metabolic pathways, at the carbonyl moiety of oxazolidine ring to form mutagenic amine(s).

(20)

Benzothiazole with p56lck inhibitor activity:

A series of structurally novel benzothiazole based small molecule inhibitors of p56lck was prepared to elucidate their structure-activity relationships (SAR), selectivity and cell activity in the T-cell prolifiration assay by Das et al (2003).29 BMS-350751(21a) (IC50 = 475 nM) and BMS-358233 (21b) (IC50 = 262 nM) was identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.

(21a)

(21b)

Benzothiazole with topoisomerase II inhibitor activity:

To investigate one possible mechanism of action of the cytotoxic activities of benzothiazoles, Choi et al (2006)30 synthesized 2-(substituted-phenyl)benzothiazoles and evaluate their ability to inhibit topoisomerase II activities. The results showed that 2-(3-Amino-4-methylphenyl) benzothiazole (22) has high activity (IC50=71.7 mM).

(22)

Benzothiazole with anticancer/antitumour activity:

Novel benzothiazole derivatives have been synthesized via the corresponding imino-1,2,3-dithiazoles by Beneteau et al (1999)1 and the cytotoxicity of some of these polyheterocyclic compounds was studied. The 2-cyno-4,7-dimethoxybenzothiazole derivatives (23a) and (23b) were found practically equipotent on cell proliferation with IC50’s of, respectively, 20.6µM and 25.2µM.

(23a)

(23b)

The synthesis of a series of new antitumour agents, the benzothiazole substituted quinol ether and esters, is reported via hypervalent iodine mediated oxidation of hydroxylated 2- phenylbenzothiazoles by Wells et al (2000).2 The products were found to be active in vitro against human colon and breast cancer cell lines with IC50 values in the nanomolar range. In both colon cell lines tested quinol ester compound (24) was the most potent (0.24µM for HCT-116).

(24)

A series of sulfamate salt derivatives of the potent and selective 2-(4-aminophenyl) benzothiazole antitumour agents has been prepared and their evaluation as potent prodrugs for parentral administration carried out by Shi et al (2001).3 The salts were sparingly soluble in aqueous media (pH 4-9), and degradation to the active free amines was shown to occur under strongly acidic conditions. Studies focused on sulfamate salts (25a) and (25b) revealed that neither was particularly soluble in water over the pH range 4-9 and, furthermore, decomposition of salt (25b) to the active free base was evident only at acidic pH at 50°C. Since no degradation of these compounds were found in biological matrices conducted as part of this study. 

(25a)

(25b)

The synthesis of  a new series of antitumour 2-(4-aminophenyl)benzothiazole analogues, substituted in the 3´-position by cyano or alkynyl groups, was described by Hutchinson et al (2003).4 Several of the analogues, notably the 5-fluorinated compounds (26) and (27), were found to possess potent in vitro activity against MCF-7 and MDA 468 human cancer cell lines. More comprehensive in vitro analysis (NCI 60-cell line) establish compound (26) as a particular potent and selective 2-(4- aminophenyl) benzothiazole analogue.

(26)

(27)

The title compounds 2-[2-(bis-(2-chloroethyl)amino)-methyl]-benzothiazoles were synthesized by Murugan et al (2004)31 by the reactions of corresponding 2-[2-(bis-(2-hydroxyethyl)amino)methyl] benzothiazole with phosphorous trichloride and phosphorus oxychloride. The biological evaluation of the compounds was carried out by various methods such as short-term in vitro cytotoxic activity and

in vitro anticancer screening. Compounds (28a) and (28b) showed significant anticancer activity.

(28a)

(28b)

Based on 2-methyl-4-nitro-2H-pyrazole-3-carboxylicacid [2-(cyclohexanecarbonylamino) benzothiazole-6-yl]amide, which shows selective cytotoxicity against tumorigenic cell lines, 2,6-dichloro-N-[2-(cyclopropanecarbonylamino)benzothiazole-6-yl]benzamide was designed and synthesized by Yoshida et al (2005)32 as a biologically derivative containing no nitro group. The highly potent derivative (29) exhibited excellent in vivo inhibitory effect on tumour growth.

(29)

The 2-arylsubstituted benzothiazole derivatives were synthesized by Kini et al (2007)33 by refluxing

o-aminothiophenol with substituted benzoic acids in the presence of polyphosphoric acid at 220°C. The screening for antitumour activity was done and three compounds (30a), (30b) and (30c) were found to be significantly cytotoxic as compared to other derivatives.

(30a)

(30b)

(30c)

 Drugs with Benzothiazole nucleus34

1-Diamthazole dihydrochloride:

          6-[2-(Diethylamino)ethoxy]-N,N-dimethyl-2-benzothiazolamine dihydrochloride

Therapeutic category: Antifungal

2- Ethoxzolamide:

6-Ethoxy-2-benzothiazolesulfonamide

Therapeutic category: Diuretic (Carbonic anhydrase inhibitor)

3-Pramipexole:

(S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole diamine

Therapeutic category: Antiparkinsonian (Dopaminergic agonist)

4-Riluzole35:

6-Trifluoromethoxy-2-benzothiazolamine

Therapeutic category: Antiparkinsonian (Sodium channel blocker)

                                    Anticonvulsant (NMDA receptor antagonist)

            Modifications on the benzothiazole nucleus have resulted in a large number of compounds having diverse pharmacological activities. The synthesis, structures and biological activities of benzothiazole derivatives have long been focused of research interest in the field of medicine, due to potential activities exhibited by them. The biological profiles of these new generations of benzothiazoles represent much progress with regards to older compounds. Looking into the medicinal importance of benzothiazole moiety, it was thought worthwhile to synthesize certain newer derivatives of benzothiazole and screen them for their biological activities.

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