INTRODUCTION:

Benzothiazole is a privileged bicyclic ring system. Due to their potent and significant biological activities it has great pharmaceutical importance; hence, synthesis of this compound is of considerable interest. The small and simple benzothiazole nucleus if present in compounds involved in research aimed at evaluating new products that possess interesting biological activities. Basically 2-substitued benzothiazole has emerged in its usage as a core structure in the diversified therapeutically applications. The studies of structure–activity relationship interestingly reveal that change of the structure of substituent group at C-2 position commonly results the change of its bioactivity. Among those 2-substituted benzothiazole derivatives with fluorine substituted molecules have already received considerable attention due to their potential bioactivities¹. Since benzothiazoles shows multiple therapeutic values, in 1950s, Since then the medicinal chemists have not taken active interest in this chemical family, although they have been known from ages to be biologically active² but as the Riluzole³ (6-trifluoro-2-benzothiazolamine) was discovered benzothiazole derivatives have been studied extensively and found to have diverse chemical reactivity and broad spectrum of biological activity viz antitumor, antitubercular, antimalarial, anticonvulsant anthelmintic, analgesic, anti-inflammatory, antifungal, a topical carbonic anhydrase inhibitor an antihypoxic, an anti-nematode, a dual inhibitor of thromboxan A-2 synthatase and selective and reversible inhibitor of monoamine oxidase type A (MAO-A)

Benzothiazoles of Therapeutic Interest

The 2-Substituted Benzothiazoles found to possess broad spectrum of pharmacological activity of clinical importance.

Anticancer agents:

Schnus., Rodney.C⁴., and co-workers synthesized N-(5-fluoro benzothiazol 2-yl)-2-guanidino thiazole 4-carboxamide (01, 02) as systematic antitumor agents against Lewis lung carcinoma. Jagabandhu Das⁵ and coworkers synthesized 2-{[(tert-butylamino) carbonyl] amino}-N-(2-chloro-6-methylphenyl)-1, 3-benzothiazole-6-carboxamide (03) for anti cancer activity. Hutchinson Ian⁶, reported 3′-cyano and 3′-alkynyl-substituted 2-(4′-aminophenyl) benzothiazole (04) for anticancer activity. Linhong Jin⁷, reported synthesis of N-(benzothiazole-2-yl)-1-(fluorophenyl)-O, O-dialkyl-α-aminophosphonate (05) for anticancer activity. Stanton Hon⁸ and coworkers reported synthesis of 2-[6-(trifluoromethoxy)-1, 3-benzothiazol-2-yl]-1H-isoindole-1, 3(2H)-dione (06) and screened for anticancer activity. Eun Young Song⁹ synthesized a series of amide and urea derivatives of benzothiazole (07, 08) and initially evaluated for their antiproliferative profile in a panel of cancer cell lines. Further potent compounds were investigated for their ability to inhibit Raf-1 activity. Richard B¹⁰ and coworkers reported synthesis of novel benzothiazole derivatives (09) for anticancer activity. Dong-Fang Shi¹¹ synthesized 2-(4-Aminophenyl) benzothiazole Sulfamate Salt (10) for antitumor activity.

Masao Yoshida¹² and coworkers reported synthesis of 2-methyl-4-nitro-2H-pyrazole-3-carboxylicacid [2-(cyclohexanecarbonylamino) benzothiazol-6-l] amide (11) for anticancer activity. Cedric J¹³ reported synthesis and pharmacological activity of 4-(5/6/7-fluoro-1,3-benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-one (12) against tumor cell lines. Chunjian Liu¹⁴ synthesized a series of benzothiazole derivatives (13) and evaluated for their antiproliferative profile. Shu-Ting Huang¹⁵, reported synthesis and screening of 4-methyl-2'-(2-methylphenyl)-3a', 7a’-dihydro-2, 4’-bi-1, 3-benzothiazole (14) derivatives against carcinoma cells. Wells G.¹⁶ studied the oxidation reactions of 2-(4-hydroxy-3-methoxyphenyl) benzothiazole (15) against the human breast cancer cell lines. 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 assay, the phenolic benzothiazole gave IC₅₀ values (dose to inhibit cell growth by 50%) of 0.62 and 0.06 µM, respectively. Bradshaw, T.D¹⁷ reported Quinol esters and ethers derived from the oxidation of 2-(4-hydroxyphenyl) benzothiazoles (16) and quinine monoketals (17) 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. Caleta¹⁸ and coworkers synthesized 6-Amidino- substituted -2-aminobenzothiazoles, N-methyl- 2- (4-cyanostyryl) benzothiazolium, cyano-substituted-2-styryl benzothiazoles and amidino and bis-amidino-substituted 2-styryl benzothiazoles (18, 19, and 20). All new compounds were tested on cytostatic activities against malignant cell lines. Hutchinson I¹⁹, reported synthesis of fluorinated analogues of 2-(4-aminophenyl) benzothiazole (21) derivatives which successfully block C-oxidation and screened invitro against human breast and ovarian tumor xenografts implanted in nude mice. Shi, D.F.²⁰ and coworkers synthesized 2-(4-Aminophenyl) benzothiazoles (22) comprise a novel mechanistic class of antitumor agents. All the compounds screened for certain colon, lung, melanoma, renal and ovarian cell lines. Shu-Ting Huang²¹ reported synthesis of novel benzothiazole (23, 24) derivatives and screened for anti-tumor activity. Min Wang²², reported preparation of 4-fluorinated 2-arylbenzothiazoles (25, 26) by a modification of Jacobson thioanilide radical cyclization and screened as new potential antitumor drugs, which show potent and selective inhibitory activity against breast, lung, and colon cancer cell lines. Suk-June Choi²³ synthesized 2-(4-aminophenyl) benzothiazole (27) derivatives which display potent and selective antitumor activity against breast, ovarian, colon, and renal cell lines.Beneteau, V.²⁴ and coworkers synthesized series of novel 2-cyano-4,7-dimethoxybenzothoiazole (28) derivatives as anticancer drugs.

Antimicrobial agents:

Osceigyimah Peter.²⁵, synthesized (4-isothiazolin-3-one-5-thio) benzothiazole (29) as antimicrobial agents. Trivedi P.²⁶ et al synthesised 2(substituted benzal hydrazino carbomyl methyl thio) benzothiazoles (30) for antimicrobial activity. Mohrram. H.H.²⁷ synthesised some benzothiazole derivatives (31) with potential antibacterial activity.

Charlecek. P.²⁸, synthesised 2-styryl benzothiazolinium salts (32) for antibacterial and fungicidal activity. Sutoris V.²⁹, synthesized 3 and 2,3 substituted benzothiazolinium salts (33) and investigated antimicrobial activity. Sutoris. V.³⁰, synthesised 3,4,6-substituted benzothiazolium salts (34) for antimicrobial activity. Lipthay T³¹, reported synthesis of arenazo (benzylthio) benzothiazoles (35) for fungicidal activity.Sutoris. V³², synthesized 2-alkyl and 2-alkyl-sulphonyl benzothiazoles (36) for antimicrobial property.

Sangal. S. K³³., synthesized 2-hydrazino benzothiazoles (37) as possible anti-inflammatory agents. S.P. Singh³⁴ reported synthesis of novel 2-(4’-butyl-3^’,5’-dimethyl pyrazol-1’-yl)-6-substituted benzothiazole (38) as antiinflammatory agents. Ahmad M.³⁵, synthesized 4-benzothiazol-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (39) for anti microbial activity. Ricardo A. Tapia³⁶, synthesized 6,7-Dihydrobenzothiazolo[6,5-h]pyrrolo[1,2,3-de]quinoxaline-11-one (40) for antiprotozoal activity.Seckin Ozden³⁷, reported synthesis of series of novel benzothiazole (41) derivatives for antimicrobial activity Marian Zarian³⁸, reported 2-substituted benzothiazole (42, 43) derivatives as antimicrobial agent. Petra Marinko³⁹, synthesized 4-aminomethyl-4, 5, 6, 7-tetrahydro-1,3-benzothiazole (44, 45) for antimicrobial activity.

Bondock Samir⁴⁰and coworkers synthesized pyrazoles [3,2-a]pyrimidine, tetrazolo[1,5-a]pyrimidine, pyrido[1,2-a]pyrimidine, 1,5-benzodiazepine, benzothiazole (46) and screened for antimicrobial activity. Kazuo Yamazaki⁴¹, reported synthesis of 2 and 6 substitutes benzothiazole (47) derivatives as antifungal agent.Wei Huang⁴² synthesized 5-Chloro-2-(2-fluoro-benzylsulfanyl)-6-trifluoromethyl-benzothiazole (48) for fungicidal activity. Bhusari S. R.⁴³ prepared some new 2-(substituted phenylsulfonamido)-6-substituted benzothiazoles (49) and screened them for their antibacterial activity. Sreenivasa M.V.⁴⁴ reported synthesis of fluoro-benzothiazolr (50) derivatives which found to possess good activity against S. aureus, E. coli and C. ablicans. Ojha K. G.⁴⁵ reported various benzothiazolyl carboxamido pyrazoline (51) derivatives and studied their antimicrobial activity. Gopkumar. P.⁴⁶ synthesized some 6-fluoro-7-(substituted)-(2-N-p- anilinosulfonamido) benzothiazoles (52) for antimicrobial activity. Bhawsar, S.B.⁴⁷, synthesized some 8-[(6'-substituted-1',3'-benzothiazol-2'-yl)aminomethyl] substituted hydroxy coumarins (53) were screened for antibacterial activity.

Barede A.R.⁴⁸ worked on a few 5,6-disubstituted-2-(substituted phenyl carboxamido) benzothiazoles (54) for antimicrobial activity. Ghoneim K.M⁴⁹, synthesized 2-[(4-amino/2, 4-diaminophenyl) sulfonyl derivatives of benzothiazoles (55) and found to possess good activity against E. coli. Yilidiz-Oren⁵⁰, synthesized a series of multisubstituted benzoxazoles, benzimidazoles and benzothiazoles (56) as non-nucleoside fused isosteric heterocyclic compounds and tested for their antibacterial activities. Latrofa A.⁵¹ prepared a series of N -cycloalkylidene-2,3-dihydro-1,3-benzothiazoles (57) as antimicrobial agent.

Antitubercular agents:

Shieke. V.G.⁵², synthesised 2(Substituted aryl amino)-5,6-disubstituted/6-substituted (1,3) benzothiazoles (58) for anti-tubercular activity. Sidoova⁵³ and his associates reported synthesis of series of novel 2-Alkylthio-6-(4-nitrobenzylidene amino) benzothiazoles (59) for antimycobacterial activity. Sidoova.E.⁵⁴, synthesized 6-acetamido-2-alkylthio benzothiazoles (60) for antimycobacterial activity. Panday, Anil. V.⁵⁵, synthesised 2-substituted alkyl/-aryl amino-6-methyl benzothizoles (61) for antitubercular activity. Gogh.T⁵⁶, synthesized derivatives of 2-benzothizolo-dithiocarbamic acid (62) for tuberculostatic activity.

Cardiovascular agents:

Mouysset Genevieve.⁵⁷, reported various substituted 2-phenyl benzothizoles (63) for calcium channel blocking activity. Rose Ulrich⁵⁸., synthesized 2-aryl substituted benzannulated ring heterocycles (64) as potential cardiovascular agents. Millard⁵⁹, reported synthesis of amino derivatives of 4, 5, 6, 7-tetrahydro benzothiazoles (65) for cardiovascular activity. Otsuka⁶⁰ pharmaceutical company Ltd., reported benzothiazolinones (66) showed cardiotonic and coronary vasodialatory activity. Foscolos. G.⁶¹ prepared new benzothiazole (67) derivatives as vasodilating agents.

Enzyme inhibitors:

Greco Micheal. N⁶², reported benzothiazole hydroxy ureas (68) as inhibitors of 5-lipoxygenase enzyme. Sutoris.V.⁶³, and Co-Workers synthesized 3-(2-alkoxy carbomyl-ethyl) 2-benzothiazolinones (69) and their regulating activity on the growth of Triticum Oestivum. Woltersdrof O.W.⁶⁴, synthesized 1-o-acyl derivatives of hydroxy benzothiazole 2-Sulfonamide (70) as topically active carbonic-anhydrase inhibitors. Scholewald, Ronald D.⁶⁵, also reported sulfanamido benzothiazole derivatives as topical carbonic anhydrase inhibitors.

Local anesthetics

Costakes. E.⁶⁶, synthesized 2-(alkylamino acyl imino) 3-methyl benzothiazolines (71) exhibited local anaesthetic activity. Mehra S.C.⁶⁷, synthesised alkyl/arylamino propionyl 2-amino benzothiazole and 2-amino (substituted) benzothiazole (72) as potential local anaesthetics.

Hypoglycemic agents:

Chernykh. V.P.⁶⁸, synthesised ethyl N-[6-substituted benzo-(tetrahydrobenzo) 2-thiazolyl] oxamates (73) for hypoglycemic activity. Hermenegilda Moreno-Díaz⁶⁹, synthesized N-(6-Substituted-1,3-benzothiazol-2-yl)benzenesulfonamide (74) derivatives for antidiabitic activity. Hiroki Fujieda⁷⁰, synthesized chloro benzothiazole (75) derivatives and screened for antidiabitic activity. Hermenegilda⁷¹ synthesized N-(6-Substituted-1,3-benzothiazol-2-yl)benzenesulfonamide (76) derivatives and evaluated for their invivo antidiabetic activity in a non-insulin-dependent diabetes mellitus rat model.

Chloerectic agents:

Strielets. L.N.⁷² synthesised benzothiazolyl-2-mercaptoacetic acid hydrazide hydrazone (77) for choleretic activity in rats.

Central dopaminergic agents:

Millard.⁷³, synthesized amino derivatives of 4,5,6,7-tetrahydro benzothiazoles and N-Methyl amino derivatives (78) showed central dopaminergic activity.

Anticonvulsent

Jimonet P.⁷⁴ synthesized a lot of substituted-2-benzothiazolamines (79). All these compounds were found to possess significant activity. Siddiqui⁷⁵ et al reported a series of benzothiazolyl guanidines (80). 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. Singh⁷⁶ synthesized some 2-(4-arylthiosemicarbazidocarbonylthio) benzothiazoles (81). The compounds were screened for their anticonvulsant activity against pentylenetetrazole induced convulsions in mice and found that all the compounds possess measurable anticonvulsant activity. Huseyin U.A⁷⁷, reported large number of 2-(3 H )-benzothiazolone derivatives (82) and evaluated for their anticonvulsant activity in mice.

Antiinflammatory activity:

Oketani⁷⁸ investigated Invitro pharmacological profiles of E3040, 6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazoles (83) against the 5-lipooxygenase. Sawhney⁷⁹ et al. prepared some novel 2-(2-benzothiazolyl)-6-aryl-4,5-dihydro-3(2 H )-pyridazinone (84) and found that they possessed low to moderate anti-inflammatory activity. Singh⁸⁰ et al. prepared some new 2-(4'-butyl-3',5'-dimethylpyrazol-1'-yl)-6-substituted benzothiazole (85) and 4-butyl-1-(6'-susbtituted-2'-benzothiazolyl)-3-methylpyrazol-5-ones (86) and were found to display significant anti-inflammatory activity. Paramshivappa⁸¹ et al prepared a series of 2-[(2-alkoxy-6-pentadecylphenyl) methyl] thio]-1 H -benimidazoles/ benzothiazoles and benzoxazoles (87, 88) from an anacardic acid and investigated their ability to inhibit human cycloxygenase-2-enzyme (COX-2). Dogruer⁸² et al synthesized sixteen (2-benzothiazolone-3-yl and 2-benzoxazolone-3yl) acetic acid derivatives (89) and tested them for antiinflammatory activity.

Alzemier

K. Serdons⁸³ reported a 6-hydroxy-2-(40-aminophenyl)-1,3-benzothiazole (90, 91, 92, 93) performed radiolabelling with carbon-11 and investigated their in vivo and in vitro properties. Specific binding to amyloid plaques was demonstrated in vitro using post-mortem brain homogenates of AD patients; transgenic AD mice brain sections and postmortem human AD brain sections. The three structural analogues have a high potential as tracer agents for invivo visualization of amyloid plaques in AD patients. Yuli Xie⁸⁴ studies the interaction of benzothiazole derivatives (94, 95) with amyloid beta peptide (Ab) and Ab-binding alcohol dehydrogenase (ABAD) and it recently implicated in the pathogenesis of Alzheimer’s disease (AD).

Antileishmanial activity

Delmas⁸⁵ et al synthesized (1,3-benzothiazol-2-yl) amino-9- (10 H )-acridinone derivatives (96) and were assessed for their in vitro antileishmanial.

Anthelmintic

Nargund⁸⁶ synthesized few novel 8-fluoro-9-substituted (l,3)benzothiazolo (5, 1-b)-1, 3, 4-triazoles (97). All these compounds were studied for their anthelmintic activity against earthworm, Perituma posthuma. Amit⁸⁷and coworkers reported some substituted imidazobenzothiazoles (98) and tested for in vivo anthelmintic activity against H. nana infection and found to show good to moderate activity.

Miscellaneous

Caryolle.R.⁸⁸, synthesized 2-aryl benzothiazoles (99) and reported anti-parasitic properties. Nagarajan Srinivasan R⁸⁹ synthesized and rported benzothiazole derivatives (100, 101)) as Protease inhibitors for anti HIV activity. Takeda⁹⁰ chemical industries Ltd. reported benzothiazole derivatives (102, 103) as appetite suppressants. Obbe P. Zuiderveld⁹¹, prepared a 1-[(2-benzothiazole)-4-n-propyl]piperazine (104) and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). Diouf⁹² et al, synthesized original derivatives of 2-piperazinyl benzothiazoles (105) and studied as mixed ligands for serotoninergic 5-HT_1A and 5-HT₃ receptors.

CONCLUSION:

Benzothiazole belongs to an important class of heterocyclic compounds and exhibits a wide range of biological properties due to its potent biological activities.

Since, various marketed preparations are available which having benzoheterocyclic nucleus viz Riluzole (neuroprotective drug), Ethoxolamide (Diuretic drug), Pramipexole (Antiparkinson’s drug) and Thioflavine (Used to visualize amyloid plaques in Alzeimer‘s disease). Thus based on potent activities, benzothiazole nucleus mainly consider as a leading molecule and various derivatives have been synthesized through the structure modification and reported for diversified activities and will probably continued to be the necessary factor to prepare new drug molecules. The biological profile of new generation of benzothiazoles represents much progress with regard to the older compounds.

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Received on 30.01.2010 Modified on 29.02.2010

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