Corresponding Author:
N. Siddiqui
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi-110 062, India.
E-mail: [email protected]
Date of Submission 10 October 2005
Date of Revision 2 September 2006
Date of Acceptance 8 January 2007
Indian J Pharm Sci, 2007, 69 (1): 10-17  

Abstract

The small and simple benzothiazole nucleus is present in compounds involved in research aimed at evaluating new products that possess interesting biological activities, such as antitumor, antimicrobial, anthelmintic, antileishmanial, anticonvulsant and antiinflammatory. The present review focuses on the benzothiazoles with potential activities that are now in development.

Benzothiazoles are bicyclic ring system with multiple applications. In the 1950s, a number of 2-aminobenzothiazoles were intensively studied as central muscle relaxants. Since then medicinal chemists have not taken active interest in this chemical family. Biologist’s attention was drawn to this series when the pharmacological profile of Riluzole [1] was discovered. Riluzole (6-trifluoromethoxy-2-benzothiazolamine, PK-26124, RP-25279, Rilutek) was found to interfere with glutamate neurotransmission in biochemical, electrophysiological biphasicand behavioral experiments. After that benzothiazole derivatives have been studied extensively and found to have diverse chemical reactivity and broad spectrum of biological activity.

Although they have been known from long ago to be biologically active [2-4], their varied biological features are still of great scientific interest. Benzothiazoles show antitumor activity, especially the phenyl-substituted benzothiazoles [5-7], while condensed pyrimido benzothiazoles and benzothiazolo quinazolines exert antiviral activity [8]. Recently, Racane et al. [9] have described the synthesis of bis-substituted amidino benzothiazoles as potential anti HIV agents. Substituted 6-nitro-and 6-aminobenzothiazoles [10] show antimicrobial activity. Given below is a brief account of various alterations conducted on benzothiazole ring and their associated biological activities.

Antitumor activity

A series of potent and selective antitumor agents mostly from substituted 2-(4-aminophenyl) benzothiazoles were developed and examined, in vitro, their antitumor activity in ovarian, breast, lung, renal and colon carnicoma human cell lines [11-21]. Pyrimido benzothiazole and benzothiazolo quinoline derivatives [22], imidazo benzothiazoles [23,24] as well as, polymerized benzothiazoles [25] showed antitumor activity.

2-(4-Aminophenyl) benzothiazoles [26,27] (1) comprise a novel mechanistic class of antitumor agents. Their unusual activity was first recognized from the distinctive biphasic-dose response relationship shown in in vitro assays against sensitive breast tumor cell lines, e.g., MCF-7 and MDA-468. Potency against these breast lines and others was independent of the estrogen or growth factor receptor status of the cells. Introduction of methyl or halogen substituent into the 3’-position of the 2-phenyl group enhances potency and extends the spectrum of action to certain colon, lung, melanoma, renal and ovarianc cell lines.

6-Amidino-substituted-2-aminobenzothiazoles (2), N-methyl-2-(4-cyanostyryl) benzothiazolium, cyano-substituted-2-styryl benzothiazoles (3) and amidino and bis-amidino-Caleta et al [28]. All new compounds were tested on cytostatic activities against malignant cell lines. The compounds exerted a different inhibitory effect, depended on concentration and type of the cells. The best inhibitory effect was achieved with compounds (3) and (4) with slight differences among them. All of them inhibited the growth of examined tumor cell lines and also normal fibroblasts. Other examined compounds exhibited a moderate inhibitory effect, depending on type of the cells.

Fluorinated analogues of 2-(4-aminophenyl) benzothiazoles have been synthesized which successfully block C-oxidation by Hutchinson et al17. 2-(4-Amino-3-methylphenyl)-5fluorobenzothiazoles (5) is the favored analogue for clinical consideration possessing enhanced efficacy in vitro and superior potencies against human breast and ovarian tumor xenografts implanted in nude mice.

Quinol esters and ethers [29] (6) derived from the oxidation of 2-(4-hydroxyphenyl) benzothiazoles and quinine monoketals (7) from the oxidation of 2-(3-hydroxyphenyl benzothiazoles, respectively, have significantly improved and extended antitumor potency in vitro against pairs of breast and colon human tumor cell lines.

The oxidation reactions of 2-(4-hydroxy-3-methoxyphenyl) benzothiazole (8) were studied by Wells et al [30]. In in vitro growth inhibition tests against the human breast cancer cell lines MCF-7 and MDA-468 (over 7 and 10 d, respectively) determined by MTT 2assay, the phenolic benzothiazole gave IC50 values (dose to inhibit cell growth by 50%) of 0.62 and 0.06 μM, respectively. Beneteau et al. [31] have described the synthesis of 2-cyano-4,7-dimethoxybenzothoiazoles (9). The 2-cyano derivatives exhibit interesting in vitro antitumor activity. As for the 4,7-dimethoxybenzothiazoles, removal of the cyano substituent present in the 2-position of the dioxino-benzothiazole ring involved the lost of activity (IC50 >100 μM).

Antimicrobial activity

Benzothiazoles show a wide spectrum of chemotherapeutic activity and a considerable amount of work has been done on the synthesis of new potent antibacterial and antifungal benzothiazoles. Bhusari et a1 [32], prepared some new 2-(substituted phenylsulfonamido)-6-substituted benzothiazoles (10) and screened them for their antibacterial activity against Bacillus subtilis, Salmonella typhi and S. dysentery. Compounds with R=Br and R’=CH3, NH2 and I were found more active and others were less or moderately active.

Various benzothiazolo triazole derivatives (11) were prepared by Sreenivasa et al [33] and found to possess good activity against S. aureus, E. coli and C. ablicans. Some 6-fluoro-7-(substituted)-(2-N-p-anilinosulfonamido) benzothiazoles (12) (R =o-nitroanilino, m-nitroanilino, pnitroanilino, o-chloroanilino, m-chloroanilino, pchloroanilino, anilino, morpholino, piperazino, dimethylamino) were synthesized and studied for their antibacterial and antifungal activities. All compounds showed moderate activity against S. aureus, S. albus and C.ablicans [34].

Ojha et al. [35], reported various benzothiazolyl carboxamido pyrazoline derivatives (13) and studied their antimicrobial activity. They found that when R=CH3 and R1=o-OCH3 C6H4, compound showed no activity and when R = Cl and R1 = p-OCH3 C6H4, the compound was active against S. aureus. The rest of the compounds showed activity against, S. aureus, E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus mirabilis.

Some 8-[(6’-substituted-1’,3’-benzothiazol-2’-yl)aminomethyl] substituted hydroxy coumarins (14) were screened for antibacterial activity against S. aureus and E. coli and also antifungal activity against Alternaria brassicicola and Fusarium udam. All these compounds showed moderate activity [36].

Barede et al. [37] worked on a few 5,6-disubstituted -2- (substituted phenyl carboxamido) benzothiazoles (15) and found them active against M. tuberculosis, S. typhi, S. aureus, C. ablicans, Trichophyton rubrum and Trychophyton mentagrophyles. The compounds were also active against some helmenths like Hymenolepis nana. A few 2-[(4-amino/2, 4-diaminophenyl) sulfonyl derivatives of benzothiazoles (16) have been found to possess good activity against E. coli [38] .

Yilidiz-Oren et al. [39] has synthesized a series of multisubstituted benzoxazoles, benzimidazoles and benzothiazoles (17) as non-nucleoside fused isosteric heterocyclic compounds and tested for their antibacterial activities against Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis as gram positive and E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa as gram negative bacteria and yeast Candida albicans using twofold serial dilution technique. The synthesized compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 100 and 3.12 μg/ml. Benzothiazole ring system enhanced the antimicrobial activity against Staphylococcus aureus.

Latrofa et al. [40] prepared a series of N-cycloalkylidene2,3-dihydro-1,3-benzothiazoles (18), N-cycloalkyl-2acylalkylidene-2,3-dihyro-1,3-benzothiazoles (19), and N-alkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles (20) and tested for in vitro antibacterial and antifungal activities against four gram positive and five gram negative bacteria. The findings obtained showed that some of the tested compounds were effective against bacterial strains, whereas, only few compounds exhibited a moderate antifungal activity against the yeast strains evaluated.

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The series of 2-benzylsulfanyl derivatives of benzoxazole and benzothiazoles (21) were synthesized by Koci et al, [41] and evaluated for their in vitro antimycobaterial activity against Mycobaterium tuberculosis and non tuberculous mycobateria, and the activity was expressed as the minimum inhibitory concentration (MIC) in μMl/l. The substances bearing two nitro groups or a thioamide group exhibited appreciable activity particularly against non-tuberculous strains.

Various substituted 2-(4-acetamidophenylsulfonamido) benzothiazoles and 2-(4-amino phenyl sulfonamido) benzothiazoles (22) containing different functional groups have been synthesized and all the compounds have been screened for their antitubercular activity in vitro and compared with standards (Streptomycin and isoniazid). Among the compounds tested, compounds with R1 =CH3 and R2 = Br, were found to be most potent. Overall the compounds having electron-with drawing substituents (NO2, COOH and halogens) showed better activity than unsubstituted one [42].

Anthelmintic activity

Recent reports of resistance to benzimidazoles have now forced the researchers to urgently develop new drugs with anthelmintic activity, to fight helminthiasis, which is vcausing untold misery to the infected individuals. This prompted synthesis of benzothiazole derivatives, which is sulfur isostere of benzimidazole, in the hope of achieving better anthelmintic activity.

In the search of new anthelmintic agents of benzothiazole series, Nargund,43 synthesized few novel 8-fluoro-9-substituted(l,3)benzothiazolo (5, 1-b)-1,3,4triazoles (23). All these compounds were studied for their anthelmintic activity against earthworm, Perituma posthuma. The compound with R= o-nitroanilino substituent was found to possess markedly higher anthelmintic activity, than other compounds compared with standard. But all the other compounds are found to possess interestingly low level of activity, whereas 8- bromo-9-substituted (1, 3) benzothiazolo [5, 1-b]-1, 3, 4- triazoles (23) have been synthesized and screened for their anthelmintic activity against earthworm, Perituma posthuma. Among the compounds tested, compounds with 4substituent R=4-carboxyanilino and morpholino were found to be the most potent in the series [44]. Some substituted imidazobenzothiazoles (24) were tested for in vivo anthelmintic activity against H. nana infection and were found to show good to moderate activity [45].

Antileishmanial activity

Delmas et al. [46] synthesized (1,3-benzothiazol-2-yl) amino-9- (10H)-acridinone derivatives (25) and were assessed for their in vitro antileishmanial and anti HIV activities 1-(6- amino-benzothiazol-2-ylamino)- 10H-acridin-9-one, revealed a selective antileishmanial activity, mainly due to amastigote-specific toxicity. Results suggested that the addition of a benzothiazoles group on a parent amino-9- (10H)-acridinone ring could enhance antileshmanial abilities, the presence of a 6-amino-benzothiazole group on position 2 amino chain or a 6-nitro-benzothiazole group. On position 4 amino chain was essential for specific antiamastigote properties.

Florence Delmas et al, [47] has synthesized position 2 substitution-bearing 6-nitro and 6-amino benzothiazoles and their corresponding anthranilic acids and assessed the in vitro antiparastic activity of each derivative against the parasites of the genus Leishmania infantum and Trichomonas vaginalis compared to their toxicity towards human monocytes. The antiprotozal properties depended greatly on the chemical structure of the position 2 substitution-bearing group.

2-[(2-Chloro-benzothiazol-6-yl) amino] benzoic acid, demonstrated an interesting antiproliferative activity towards parasites of the species Trichomonas vaginalis, while compound.

2-({2-[(2-Hydroxyethyl) amino]-benzothiazol-6-yl} amino) benzoic acid exhibited a promising activity against parasites of the species Leishmania infantum in their intracellular amastigote form.

Anticonvulsant activity

A large number of benzothiazole derivatives were evaluated for anticonvulsant activity and found to possess significant activity against various types of seizures. In the search of new anticonvulsant agents having benzothiazole nucleus, Jimonet et al. [48] have synthesized a lot of substituted-2-benzothiazolamines (26). All these compounds were found to possess significant activity.

A series of benzothiazolyl guanidines (27) were synthesized by Siddiqui et al. [49] The compounds with R=4-CH3 and 4-Cl were found to be equipotent (100%) in activity to phenobarbitone in maximal electroshock seizure test and blocked subcutaneous pentylenetetrazole and strychnine induced seizures to some extent. All other compounds also had significant anticonvulsant activity.

Singh et al, [50] synthesized some 2-(4-arylthiosemicarbazidocarbonylthio) benzothiazoles (28). The compounds were screened for their anticonvulsant activity against pentylenetetrazole induced convulsions in mice and found that all the compounds possess measurable anticonvulsant activity. A large number of 2-(3H)-benzothiazolone derivatives (29) have been synthesized and evaluated for their anticonvulsant activity in mice and were found to be significantly active [51].

Antiinflammatory activity

Pyrazolones and pyrazolinones rank among the more venerable non-steroidal antiinflammatory agents. Phenylbutazone and its congeners incorporating a pyrazoline-3,5-dione structure are more potent antiinflammatory agents. In the recent years a number of Benzothiazole derivatives have been synthesized and found to display antiinflammatory activity.

In vitro pharmacological profiles of E3040 (30), 6hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazoles were investigated by Oketani et al. [52] against the 5-lipooxygenase activity of rat basophilic leukaemia cells, E 3040 and Zileuton (a-5-lipooxygenase inhibitor) had an IC50 of 0.23 and 0.93 μM, respectively. This result indicates that E 3040 potently inhibited 51 lipooxygegnase and thromboxane A2 synthetase and blocked leukotriene B4 and thromboxane B2 production in rat peritoneal and human blood cells. Sawhney et al. [53] have prepared some novel 2-(2-benzothiazolyl)-6-aryl-4,5dihydro-3(2H)-pyridazinone (31) and found that they possessed low to moderate antiinflammatory activity.

Singh et al. [54] prepared some new 2-(4’-butyl-3’,5’ dimethylpyrazol-1’-yl)-6-substituted benzothiazoles (32) and 4-butyl-1-(6’-susbtituted-2’-benzothiazolyl)-3-methylpyrazol-5-ones (33) and were found to display significant antiinflammatory activity. Paramshivappa et al.55 prepared a series of 2-[(2-alkoxy-6-pentadecylphenyl) methyl] thio]- 1H-benimidazoles/ benzothiazoles and benzoxazoles from an anacardic acid and investigated their ability to inhibit human cycloxygenase-2-enzyme (COX-2). The active compounds were screened for cyclooxygenase-1 (COX- 1) inhibition. Compound (34a) is 384 fold and (34b) is more than 470 fold selective towards COX-2 compared to BMSCOX-1. Dogruer et al.[56] synthesized sixteen (2- benzothiazolone-3-yl and 2-benzoxazolone-3yl) acetic acid derivatives (35) and tested them for antinociceptive and antiinflammatory activity. 4-[2-(6-Benzoyl-2-benzoxazolone-3-yl) acetyl] morpholino, 4-{2-[6-(2-chloro-benzoyl)-2-benzoxazolone-3-yl] acetyl} morpholino, 4-{2- [6-(2-chloro-benzoyl)-2-benzoxazolone-3yl] acetyl} morpholine, 1-[2-(5-chloro-2-benzoxazolone-3-yl) acetyl] pyrrolidine, methyl ((6-methyl-2-benzoxazolone-3-yl) acetate and N, N-diethyl-2- (2-benzothiazolone-3-yl) acetamide have shown more potent antinonciceptive activity than others.

Miscellaneous

Diouf et al. [57] synthesized original derivatives of 2-piperazinyl benzothiazoles (36) and studied as mixed ligands for serotoninergic 5-HT1A and 5-HT3 receptors. The studied compounds exhibited significant affinities for these two serotoninergic receptor subtypes. The pharmacological profile of these ligands was agonist for 5-HT1A receptors and antagonist for 5-HT3 receptor sub sites. Compounds with such a pharmacological profile are of clinical relevance in the treatment of psychotropic diseases. e.g., anxiety, depression and schizophrenia.

Brown et al, [58] reported a series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents and screened against human rhinovirus (HRV). HRV cause approximately one-half of all cases of respiratory tract infection (colds). Several 2-alkoxy and 2-akylthiobenzoxazole and benzothiazoles derivatives (37) showed excellent anti HRV activity. When tested against a panel of 16 representatives HRV types, the 2-ethxoybenzooxazole derivatives, 13 was found to have superior HRV activity (median EC50 3.88 ng/mL) to known capsid-binders pleconaril and pirodavir.

Das et al, [59] prepared a series of structurally novel benzothiazoles based small molecule inhibitors of p56lck was prepared to elucidate their structure-activity relationships (SAR), respectively and cell activity in the T-cell proliferation assay. p56lck (Lck), a member of the Src family of non-receptor protein tyrosine kinase is expressed primarily in T-lymphocytes and natural killer cells.

Selective inhibitors of Lck may have potential therapeutic utility in the treatment of T-cell mediated disorders such as autoimmune and inflammatory diseases and in the prevention of solid organ transplant rejection [60]. BMS-243117 [61] (38) is identified as a potent and selective Lck inhibitor with good cellular activity (IC50=1.1 μM), whereas BMS-350751 (39) and BMS-358233 (40) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.

Srinivasan et al. [62] have shown that the replacement of the urea moiety by benzothiazolesulfonamide provided inhibitors of HIV-1 protease with improved potency and antiviral activities. Certain members of the class showed good oral bioavailability in rats; most notably compounds are shown in (41).

Conclusions

The reviewed new class of 2-substituted aminobenzothiazoles has shown a wide spectrum of biological activities. The substituted benzothiazolylimino dithiazolidines and the 2-(2’-aryl-1,3,4-oxadiazol -yl)mercaptomethyl benzothiazoles are having significant antibacterial activity. Significant antiinflammatory activity is displayed by some new 2-(4’-butyl-3’-5’-dimethylpyrazol-1yl)-6-substituted benzothiazoles and 4-butyl-1-(6’substituted -2’-benzothiazolyl)-3-methylpyrazol-5-ones.

In search of new anticonvulsants, riluzole and benzothiazolylguanidines are found to have potent activity. Potent antitumor activity was demonstrated by a number of 2-(4-aminophenyl) benzothiazoles. The 2-(4-acetamido-2bromo-5-methylphenyl sulfonamide) benzothiazole is found to be effective as antituberculor agents, whereas ethoxazolamide and o-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamides are found to show the carbonic anhydrase inhibitory action. The biological profiles of these new generation of benzothiazoles represents much progress with regard to the older compounds.

References