COMMON METHODS TO SYNTHESIZE BENZOTHIAZOLE DERIVATIVES AND THEIR MEDICINAL SIGNIFICANCE: A REVIEW

COMMON METHODS TO SYNTHESIZE BENZOTHIAZOLE DERIVATIVES AND THEIR MEDICINAL SIGNIFICANCE:  A REVIEW

Sukhbir L. Khokra*¹, Kanika Arora ¹, Heena Mehta¹, Ajay Aggarwal ¹ and Manish Yadav ²

Institute of Pharmaceutical Sciences, Kurukshetra University ¹, Kurukshetra, Haryana, India

Hindu College of Pharmacy ², Sonepat, Haryana, India

ABSTRACT

Recently, heterocyclic compounds analogues and their derivatives have attracted strong interest in medicinal chemistry due to their biological and pharmacological properties. The small and simple benzothiazole nucleus possesses numerous biological properties like - antitumor, antimicrobial, anti-inflammatory, anticonvulsant, and antidiabetic activities. These activities are also possessed by its substituted derivatives as well. The present review focuses on some commonly used easy procedures to synthesize the benzothiazole moiety and its derivatives, which comprise of different biological activities.

Anticonvulsant, Antidiabetic

INTRODUCTION: The chemistry and biological study of heterocyclic compounds has been an interesting field for a long time in medicinal chemistry. A number of heterocyclic derivatives containing nitrogen and sulphur atom serve as a unique and versatile scaffolds for experimental drug design ¹. Benzothiazole is one of the most important heterocycle that has received overwhelming response owing to its diversified molecular design and remarkable optical, liquid and electronic properties ².

Benzothiazole consists of thiazole ring fused with benzene ring and possess multiple applications. In 1950s, a number of 2-aminobenzothiazoles were intensively studied as central muscle relaxants. Since then, biologist’s attention was drawn to this series when pharmacological profile of Riluzole (6-trifluoormethoxy-2-benzothiazolamines, Rilutek), as a Glutamate neurotransmission inhibitor was discovered. After that benzothiazole derivatives have been extensively studied and found to have diverse chemical reactivity and broad spectrum of activity ^3-7.

Due to these biological activities, the synthesis of benzothiazole is a considerable area of current discussion. The classical method involves condensation of o-aminothiophenols with substituted aldehydes ^8-14, acyl chlorides, carboxylic acids ^15-16 or esters, nitriles ¹⁷. Other most commonly used methods include Pd/Cu/Mn/chloranil catalyzed cyclization of o-halothioformanilides ^18-22. The survey of literature related to benzothiazoles reveals the presence of this bicyclic ring system in various amine or terrestrial natural compounds, which have useful biological properties ²³. Benzothiazole derivatives possess a wide spectrum of biological applications such as antitumor ^26-52, antimicrobial ^54-83, schictosomicidal ⁸⁴, anti-inflammatory ^85-93, anticonvulsants ^94-102, antidiabetic ^103-108, antipsychotic ¹⁰⁹ and diuretic ¹¹¹ etc.

Given review is a brief account of some commonly used methods to synthesize benzothiazole derivatives and various structural alterations conducted on benzothiazole ring and preferential specificities imparted in their biological responses.

Some common routes to synthesis of substituted benzothiazole derivatives:

• Condensation of o-aminothiophenol with aldehydes: Treatment of o-aminothiophenols with substituted aldehydes affords the synthesis of 2-substituted benzothiazoles using different catalysts and reaction conditions.

CONDENSATION OF o-AMINOTHIOPHENOL WITH ALDEHYDES

Catalysts (a-f):

1. Montmorillonite,SiO₂/Graphite; Microwave, p-TsOH⁸
2. Diethyl bromophosphonate/tert-Butyl hypochlorite; acetonitrile ⁹
3. Cerium (IV) ammonium nitrate ¹⁰
4. H₂O₂/HCl system in ethanol ¹¹
5. AcOH/Air; Microwave/ Thermal Heating ¹²
6. Baker’s yeast, Dichloro methane ¹³

• Condensation of o-aminothiophenol with acids: Treatment of 2-aminothiophenol and substituted aromatic acids in presence of Polyphosphoric acid provides a good method to synthesize 2-substituted benzothiazoles and gives a good yield ^14-16.

CONDENSATION OF o-AMINOTHIOPHENOL WITH ACIDS

Cyclization of thioformanilides using different reagents: Substituted thioformanilides can be converted to 2-aminobenzothiazoles via intramolecular C-S bond formation/C-H functionalization utilizing various reagents and catalysts.

CYCLIZATION OF THIOFORMANILIDES USING DIFFERENT REAGENTS

Catalysts (a-e):

1. CuI; 1, 10-Phenanthroline, CS₂CO₃, reflux ¹⁸
2. Manganese triacetate ²⁰
3. CS₂CO₃, Dioxane ²¹                                                             
4. Photochemical cyclization induced by chloranil ¹⁹
5. Pd(PPh₃)₄/MnO₂ system under an oxygen atmosphere ²²

• Coupling between thiophenols and aromatic nitriles: Thiophenols when treated with aromatic nitriles to affords a smooth reaction mediated by Ceric ammonium nitrate to give corresponding 2-arylbenzothiazoles in excellent yield ¹⁷.

COUPLING BETWEEN THIOPHENOLS AND AROMATIC NITRILES

• Synthesis using anilines: Different substituted anilines when treated with KSCN in presence of glacial acetic acid to synthesize 2-substituted benzothiazoles ²⁴.

SYNTHESIS USING ANILINES

2-aryl substituted benzothiazoles can be synthesized using reaction of substituted anilines with nitrobenzoyl chloride in pyridine under reflux and further treatment with Lawesson’s reagent and then cyclization of intermediate using Potassium ferricyanide ²⁵.

Biological activities of benzothiazole derivatives:

1. Anticancer Activity: Different substituted benzothiazoles showed antitumor activity. Mainly the 2-(4-aminophenyl) derivatives are especially potent. Stevens et al reported the in-vitro antitumor activity of a new series of alkyl-, halo-, cyano-, alkoxy- and hydroxy- substituted 2-(4-aminophenyl) benzothiazoles (1.1-1.4). Compound (1.1) showed the most potent growth inhibition against the ER+ (MCF-7 and BO) and ER- (MT-1 and MT-3) tumors ^26-28.

Further aryl substituted 2-phenyl benzothiazoles (1.5) and L-lysyl and l-alanyl amide prodrugs of 2-(4-aminophenyl) benzothiazole (1.6) were found to possess exquisitely potent anti-proliferative activity ^29-30.

1.5

1.6

Maria Pelecanou et al., prepared a series of Rhenium (^185/187Re) and Technetium-99m (^99mTc) complexes of 2-(4’-aminophenyl) benzothiazole. The in-vitro evaluation of complexes 1.7 a & 1.7 b, 1.8 a & 1.8 b, and in-vivo application of the ^99mTc complexes (1.7b) and (1.8b) in MCF-7^a tumor bearing SCID mice established the potential of these labeled 2-(4’-aminophenyl) benzothiazole derivatives for radiopharmaceutical applications ³¹.

1.7, 1.8 Structure no. R gp. M 1.7a H Re 1.7b H 99mTc 1.8a CH3 Re 1.8b CH3 99mTc

Antitumor evaluation of some novel cyano and amidino benzothiazole derivatives (1.9) and (1.10)  was described by Kralj et. al. Almost all amidino derivatives showed noticeable anti-proliferative effect on several tumor cell lines while cyano derivatives showed considerably less pronounced activity due to poor solubility in aqueous cell culture^31,32.

1.9

1.10

A series of 2-(4-acylaminophenyl) benzothiazoles (1.11) and polyhydroxylated 2-phenylbenzothiazoles (1.12) were screened for anticancer activity and found to be very active against  breast MCF-7 and MDA 468 cells ^{33, 34}.

1.11

1.12

Devmurari et al., prepared a series of seven substituted 2-phenyl benzothiazoles and substituted 1, 3-benzothiazole-2-yl-4-carbothioate derivatives. All synthesized novel compounds were screened for anticancer activity and compounds (1.13) and (1.14) showed very good anticancer activity ³⁵.

1.13

1.14

Substituted pyrimido (1.15) and cyano, dicyano, amidino and diamidino (1.16) and imidazole (1.17 & 1.18) substituted 2-phenylbenzothiazole derivatives were prepared and evaluated for in-vitro anticancer activity towards 60 human cancer cell lines ^{37, 38, 23}.

2-(4’-aminophenyl) benzothiazoles elicit biphasic growth inhibitory effects against number of human cancer cell lines. A series of 3’-substituted-2-(4’-aminophenyl)-benzothiazoles (1.19) were prepared by Bradshaw et al  and when tested against MCF-7 and MDA 468 cell lines, revealed a unique profile of growth inhibition ^{39, 40}.

1.19

R= H, I, CH_3, Br & Cl

1.20

Benzothiazole linked pyrrolobenzodiazepine (1.20) and 1, 3, 4-oxadiazole-2-thione (1.21 & 1.22) conjugates showed significant effects on leukaemial cell lines ^{41, 42}.

N-(benzothiazol-2-yl) derivatives of 2-benzylthio-4-chloro-5-R¹-benzenesulfonamides were prepared and evaluated for activity and selectivity towards non-small cell lung cancer and melanoma cell lines. Compound (1.23) was found more potent due to high lipophilicity of CH₃ group as compared to CN or CONH₂ group ⁴³.

A new series of 2,6-dichloro-N-[2-(cyclopropanecarbonyl-amino) benzothiazol-6-yl] benzamide (1.24) and fluorinated benzothiazole-substituted- 4- hydroxy cyclohexa- 2, 5- dienones (quinols) (1.25) was synthesized and found to possess good antitumor activity ^{44, 45}.

1.24

1.25

A number of N-bis-(triflouromethyl)-alkyl-N’-benzothiazolyl ureas were prepared and derivatives with an electron withdrawing substituent showed greater activity towards the tumor cell lines. The compounds (1.26) and (1.27) were found to have significant action on prostate, CNS, renal and leukaemial cancer cell lines ⁴⁶.

Several novel 2-carbonitrile (1.28) and 4-thiazolidinone (1.29) benzothiazole derivatives were synthesized and screened for anticancer activity on leukaemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines ^{47, 48}.

Benzothiazole containing phthalimide (1.30) were synthesized and found to exhibit in-vitro cytotoxic potential on human cancer cell lines ⁴⁹.

A new series of benzothiazole substituted Quinol ethers and esters (1.31) were found to be active in-vitro against human colon and breast cancer cell lines ⁵⁰.

The cytotoxicity studies of test compounds 2-(substituted phenyl) benzothiazoles (1.32) was done against human A-549, BFTC-905, RD, MES-SA and HeLa carcinoma cell lines ⁵¹.

A new series of 2-(4-aminophenyl) benzothiazole derivatives with a cyano or alkynyl group at 3’ position was prepared and evaluated for antitumor activity. The 5-flouro derivative (1.33) possessed in-vitro activity against MCF-7 and MDA-468 human cancer cell lines⁵².

1.31

1.32

Kamal and co-workers synthesized benzothiazolo-4β-anilino-podophyllotoxin (1.34) and benzothiazolo -4β- anilino4 -O-demethylepipodophyllotoxin (1.35) cogeners and screened some compounds for cytotoxicity studies against human cancer cell lines and DNA Topoisomerase-II inhibitory activity ⁵³.

1.34

R¹= H, 2’-Cl, 3’-CH₃, 3’-Br

R²=6-OCH₃, 6-F, 4-Cl, 4, 6-dichloro

1.35

R¹= H, 2’-Cl, 3’-CH₃, 3’-Br

R²=6-OCH₃, 6-F, 4-Cl, 4, 6-dichloro

2. Antimicrobiological Activity: Microbes are causative agents for various types of severe diseases and infections like ameobiasis, typhoid, malaria, common cold, cough, tuberculosis, influenza, syphilis, AIDS etc. To verify the role of benzothiazoles as antimicrobial agents, several approaches have been made.

(a) Antibacterial and antifungal activity: Some 2-substituted benzothiazoles (2.1), (2.2) and 4-(2’-substituted benzothiaoles)- 5- mercapto- 3-(substituted)- 1, 2, 4-triazole derivatives (2.3) were examined against E. coli and S. aureus for antibacterial activity and Candida albicins and Aspergillus niger for antifungal activity. Most of the compounds showed promising results for both activities ^{54, 55}.

A series of fluoro, chloro2-(α-subsituted aryl amino acetamido) benzothiazoles (2.4) and 2-[1-aryl azo] methyleneimino- 6- chloro benzothiazole derivatives (2.5) were prepared and showed significant antibacterial activity when examined against B. subtilis, S. typhi, E. coli and S. aureus bacterial strains ^{56, 57}.

2.4

R= p-Bromo/ nitro/ methyl aniline

2.5

Substituted pyrimido [2, 1-b] benzothiazoles (2.6), (2.7) and low molecular weight 2- mercapto benzothiazole derivatives (2.8), (2.9) and fluoro benzothiazole incorporated with 1, 3, 4-thiadiazole were found active against E. coli, B. subtilis, P. typhii and S. aureus, Candida albicans and Aspergillus niger ^58-60.

N-2-Benzothiazolylthiourea derivatives (2.10) and 2-styrylbenzothiazole-N-oxides (2.11)  had been screened and found to have good antimicrobial activities against Gram-positive and Gram-negative bacteria such as S. aureus, P. aeruginosa and E. coli and  a yeast (C. albicans) and a mould (Microsporum gypseum) ^{61, 62}.

R= N, N- dimethyl amine, imidazole, benztriazole

2- (5- substituted- 1, 3, 4- oxadiazole- 2- yl)- 1, 3-benzothiazoles (2.12 a, b, c, d)  were found to have good in-vitro antibacterial activity against Gram positive and Gram negative bacterial strains such as B. subtilis, B. pumilus, E. coli and P. aeruginosa ⁶³.

Alang et al synthesized seven new derivatives of 2-substituted benzothiazole (2.13) and found  them a good antibacterial agent against Gram positive bacteria (S. aureus, S. epidermidis) and Gram negative bacteria (P. aeruginosa and E. coli) ⁶⁴.

A new series of compounds 2-[(6-methyl-1, 3-benzothiazol- 2- yl) amino]- N- [2- (substituted phenyl/ furan- 2- yl)- 4- oxo- 1, 3- thiazolidin- 3-yl] nicotinamides, (2.14 & 2.15) were prepared and examined to possess good in-vitro antimicrobial activity against two Gram positive (S. aureus, S. pyrogens), two Gram negative (E. coli, P. aeruginosa) bacteria and three fungal species (C. albicans, A. niger, A. clvatus) ¹.

Some new 2-amino substituted benzothiazoles (2.16) were synthesized and evaluated for in-vitro antifungal activity against fungal strains such as C. albiacns, A. niger and A. flavus ⁶⁵.

Alkyl derivatives of 3-methoxy benzamide substituted with heterocyclic systems were found to be potent anti-staphylococcal agents with a good to moderate inhibition of essential bacterial cell division protein FtsZ. Agents (2.17) and (2.18) were revealed as most active as antibacterial against S. aureus ⁶⁶. Newer Schiff bases of benzothiazole derivatives (2.19) and thiazolidinones incorporated benzothiazoles (2.20 & 2.21) exhibited moderate antibacterial activity against Gram positive (S. aureus and S. pyrogenus), Gram negative bacteria (E. coli and P. aeruginosa) and Fungi (C. albicans, A. niger and A. clavatus). The results demonstrated that compounds with a 4-hydroxy, 4-dimethylamino and 3, 4-dimethoxy group on the aromatic ring showed good antibacterial activity ^{67, 68}.

Antimicrobial evaluation of some thiourea derivatives (2.22), pyrazole, isoxazole and pyrimidine derivatives of benzothiazole was carried out and 7-amino-n-(benzothaizol-2-yl)- tetrazolo [1, 5-a]pyrimidine- 6-carboxamide (2.23) was found to be most potent against B. subtilis and B. thuringiensis (Gram positive), E. coli and P. aeruginosa (Gram negative) bacteria and Botrytis  fabae and Fusarium oxysporum fungal strains ^{69, 70}.

2-(3, 4-Difluoro-benzylsulfanyl)-4-fluoro benzothiazole (2.24) exhibited most interesting antifungal activities against R. solani, B. cinereapers and D. gregaria among a series of polyfuorinated 2-benzylthiobenzothiazoles ⁷¹.

Further thiazole, thiophene and pyrazole derivatives of benzothiazole were prepared and examined for antibacterial and antifungal. The test compounds (2.25) and (2.26) showed good potency towards S. aureus and S. pyrogenes that was equal to Chloramphenicol ⁷².

Antibacterial and antifungal activity of oxoazetidine derivatives (2.27) and nitrogen mustards of fluoro benzothiazoles was determined against S. aureus, B. subtilis, C. tropicans, A. niger and F. heterosporium. The nitrogen mustards (2.28), (2.29) showed excellent inhibition at a conc. of 50 µg/0.1ml ^{73, 74}.

2-(4-substituted aryl-3-chloro-2-oxo-azetidine)-2-imino benzothiazoles (2.30) were prepared and evaluated for in-vitro antibacterial against B. subtilis, E. coli, S. aureus, K. pneumoniae and antifungal activity against A. niger, A. flavus, F. oxisporium and T. viride ⁷⁵.

(b) Anti-tubercular activity: Some 4-Amino-N-(1,3-benzothiazol-2-yl) benzenesulphonamide derivatives were prepared and found to have good in-vitro Antimycobacterial activity (2.31) against H₃₇Rv strain of mycobacterium tuberculosis and other derivatives (2.32) and (2.33) were also found active as antibacterial and antifungal agents ⁷⁶.

Katz et al synthesized some derivatives of 2-hydrazinobenzothiazole (2.34) and evaluated them for anti-tuberculous activity ⁷⁷.

Triazole anlogs of benzothiazole (2.35) were synthesized and screened for anti-tubercular activity against M. tuberculosis H₃₇Rv strain and antimicrobial activity against some Gram positive and negative bacteria and fungal species. The 4-Cl analogue with MIC 25 µg/ml was revealed better anti-tubercular agent than Rifampicin (MIC 40 µg/ml) ⁷⁸.

(c) Antihelmentic activity: Some fluoro benzothiazole Schiff bases (2.36) and sulfonamido pyrazole derivatives of fluorobenzothiazoles (2.37) were prepared and examined for anthelmintic activity against earthworm Perituma posthuma. Some of the analogs showed significant activity ^{79, 80}.

2.36, R= o, m, p-nitro aniline; o, m, p-chloro aniline

2.37, R= o,m,p-chloro; o,m,p- nitro aniline;  Aniline, PABA; morpholine, piperazine; Dimethylamine, diphenylamine

(d) Antiviral activity: HIV-1 protease inhibition was observed with novel Benzothiazolesulfonamides (2.38) and (2.39) with an IC₅₀ value in 2-3nM range. The carbamate analogues were found to be better antiviral and inhibitors of HIV-1 Protease ⁸¹.

2.38

2.39

R=3-pyridylmethoxy, 5-thiazolylmethoxy and 3-tetrahydrofuranyloxy

(e) Antimalarial activity: Antimalarial activity of 2-substituted-6- nitro and 6-amino benzothiazoles and their anthranilic acids were carried out on W2 and 3D7 strains of P. falciparum. The results revealed the potency of compounds (2.40) and (2.41) as the antimalarial agents of clinical and biological research ⁸².

2.40

2.41

(f) Antileshmanial and Antischistosomicidal activity: Acridone derivatives of benzothiazole were synthesized and evaluated for antileshmanial activity towards Leishmania promastigotes. Two derivatives, 4-(6- nitro- benzothiazol-2- ylamino)- 10H- acridin- 9- one (2.42) and 1-(6-amino-benzothiazol-2-ylamino)-10-H-acridine-9-one (2.43) revealed a selective antileishmanial activity. The prersence of a 6-amino benzothiazole group on position 2-amino chain and a 6-nitro benzothiazole group on position 4 amino chain was found essential for antiamastigote properties ⁸³.

A series of benzothiazol-2-yl-dithiocarbamates (2.44) and their copper complexes was prepared and evaluated for their in-vitro Schistosomicidal activity against Schistosoma mansoni. The copper complexes showed an activity similar to Praziquantel with 100% worm mortality at 10 µg/ml ⁸⁴.

3. Anti-Inflammatory Activity: In the recent years, a large number of benzothiazole based anti-inflammatory agents have been synthesized. Venkatesh et al. synthesized some novel 2-amino benzothiazole derivatives and evaluated them for anti-inflammatory activity. Test compounds (3.1) showed significant anti-inflammatory activity and it was noted that when the 2-amino benzothiazole is substituted at 4 or 5 positions with electron withdrawing groups like Cl, NO₂, OCH₃ increase in anti-inflammatory activity was found ⁸⁵.

3.1

A new series of 2-substituted benzothiazole derivatives was prepared by Shashank and co-workers. All synthesized compounds were evaluated for anti-inflammatory activity and (3.2) and (3.3) were found to be the most active among the series. The maximum activity may be due to presence of –F and –OCH₃ groups. The same series of compounds also showed good anticancer activity ⁸⁶.

Kumar et al prepared 2’-((benzo[d]thiazol-2-ylthio)-methyl)spiro[indoline-3, 5’-thiazolo[4, 3-b][1, 3,4]-oxadiazol]-2-ones and examined them for anti-inflammatory action. (3.4) was the most potent anti-inflammatory agent ⁸⁷.

3.2 (R=Cl), 3.3 (R=OCH₃)

3.4

3.5

R=o/m- toluidine, m-chloroaniline

Various substituted 4-(m-hydroxy-p-methoxy phenyl)-1-[(6’-flouro-7’-substituted (1, 3) - benzothiazol-2’-yl)-amido-2-phenyl]-3-chloro azetidin-2-one were synthesized and evaluated for anti-inflammatory activity. Among tested compounds (3.5) and (3.6) showed significant activity ⁸⁸.

A series of 3-pyridylmethyl-substituted-2-amino-6-hydroxy benzothiazoles (3.7) and 7-chloro-6-flouro-N (substituted hydrazones)-benzothiazoles (3.8) was synthesized and tested for anti-inflammatory activity. Test compound (3.7) imparted a dual inhibitory action against leukotriene B₄ and thromboxane A₂, which was a result of direct action on 5-lipoxygenase and TXA₂ synthetase ^{89, 90}.

Synthesis of N-{6-fluoro-7-(substituted)-amino]-1, 3-benzothiazole-2-yl}-2/3/4-nitrobenzamides derivatives was carried out and screened for anti-inflammatory activity. The compounds (3.9), (3.10) were found to exhibit 70-78% inhibition in carrageenan induced paw oedema model in comparison to the standard Diclofenac (80%) ⁹¹.

2-Amino-heteroaryl-benzothiazole-6-anilides were discovered and evaluated for the anti-inflammatory activity. The 2-aminopyridyl analogue and 2-aminopyrimidinyl analogue (3.11) were identified as potent lck inhibitors with excellent cellular activities against T-cell proliferation ⁹².

Anti-inflammatory activity of O-substituted-4-benzothiazoles (3.12) was determined and most of the derivatives were found potent inhibitors of Bradykinin B₂ receptor. The findings revealed that the 2-methyl group is an essential requirement for highly efficient antagonism of Bk B₂ receptor ⁹³.

5. 
   

   4.1				4.2
   	Structure no.	R1	R2
   	4.1 a	F	CH3
   	b	F	C2H5
   	c	Cl	CH3
   	d	Cl	C2H5
   	e	OCH3	CH3

   Anticonvulsant Activity: For anticonvulsant activity, a large number of benzothiazole derivatives were evaluated and found to possess significant activity against various types of seizures. In search of potent anticonvulsants containing benzothiazole moiety, a series of N-(6-substituted-1, 3-benzothiazol-2-yl)-4-{[(subsituted amino) carbonothioyl] amino} benzene sulfonamides (4.1) and prop-2-eneamido and 1-acetyl-pyrazolin derivatives of aminobenzothiazole (4.2) were synthesized and most of the compounds were active as anticonvulsants in MES and PTZ induced seizures ^{94, 95}.

A series of 1, 3-benzothiazol-2-yl semicarbazones (4.3) and 2-phenyl-3-(substituted benzothiazole-2-yl)-4[3H]- quinazolinone (4.4 & 4.5) was developed and evaluated against (MES)  induced seizures and toxicity studies ^{96, 97}.

4.3

4.4

 Substituted 4-(m-hydroxy-p-methoxy phenyl)-1-[(6’-flouro-7’substituted (1, 3)-benzothiazole-2’-yl) amido-2-phenyl]-3-chloro azetidin-2-ones (4.6) and benzothiazol-2-yl thiadiazole derivatives (4.7) showed significant activity against PTZ and MES induced seizures ^{98, 99}.

4.6, R= o,m,p-nitroaniline; o, m, p-chloroaniline; aniline; o, m, p-anisidine; PABA

 Anticonvulsant activity and toxicity studies of oxazetidin derivatives of benzothiazole (4.8) and isatin (indol-2, 3-dione) Schiff’s bases (4.9) was carried out by Siddqui et al. Both of the compounds were found to exhibit 100% protection against MES induced seizures ^{100, 101}.

A series of 1, 3-benzothiazol-2-yl benzamides (4.10) was prepared by Siddiqui et al and carried out anticonvulsant, neurotoxicity and CNS depressant studies. Most of the compounds were found active in MES and PTZ screen with none of them neurotoxic or hepatotoxic. The compounds bearing the groups like F, CH₃, OCH₃ at the 6-position of benzothiazole ring with H, 2-Cl, 4-Cl substituted distant phenyl ring showed most excellent activity in MES and scPTZ tests ¹⁰².

4.9

R=H, N(CH₃)₂, OCH₃

4.10

R= Br, Cl, F, NO₂, CH₃, OCH₃, R¹= H, 2-Cl, 4-Cl, 4-OCH₃

5. Anti-Diabetic Activity: In order to find potent anti-diabetic agents, several approaches had been made. Some of these approaches also led to synthesis of some benzothiazole based anti-diabetic agents. A series of 2-amino[5’(4-sulphonylbenzylidine)-2, 4-thiazolidinone]-7-chloro-6-flouro benzothiazoles were synthesized and examined for anti-diabetic activity. All the compounds of series (5.1 a-f) showed promising anti-diabetic activity ¹⁰³.

Zandt et al. prepared a novel series of conjugated indole-N-acetic acid with substituted benzothiazoles. All test compounds were evaluated for anti-diabetic activity and (5.2 a-l) were found most active compounds that inhibited aldose reductase with an IC₅₀ of 5-12 nM and (5.2b) was most promising agent with IC₅₀ 5 nM ¹⁰⁴.

A series of dipeptidyl peptidase inhibitors IV for the treatment of type 2 diabetes was synthesized and evaluated. The compound (3R)-3-amino-4- (2, 4, 5-trifluorophenyl)- N- {4- [6- (2- methoxyethoxy)-benzothiazol- 2- yl] tetrahydropyran- 4- yl}butanamide (5.3) was found to reduce the blood glucose level to a significant extent in an oral glucose tolerance test ¹⁰⁵.

Anti-diabetic activity of novel N-(6-substituted-1, 3-benzothiazol-2-yl) benzenesulfonamides derivatives was determined on a NIDDM rat model. The compounds (5.4) and (5.5) were found to be potent inhibitor of 11β-hydroxy steroid dehydrogenase type-1 and showed 38-53% inhibition at 10µM concentration ¹⁰⁶.

5.3

5.4 (R=H), 5.5 (R= NO₂)

Further, Paoli and co-workers prepared a small library of 2-arylsulfonyl aminobenzothiazoles and screened them for protein tyrosine phosphatase 1B inhibition. The most active compounds (5.6), (5.7) were observed rapid reversible inhibitors of PTP-1B and significantly lowered plasma gluose concentration¹⁰⁷.

The novel 2-(5-nitrothiazol-2-ylthio) benzo [d] thiazole derivatives were discovered and screened for their ability to inhibit c-Jun-N-terminal kinase. The compounds (5.8) and (5.9) demonstrated good in-vivo activity in a diabetic model of insulin resistance¹⁰⁸.

6. Miscellaneous Activities: In spite of all these activities, benzothiazoles are also active as antipsychotic agents (6.1), neuroprotective agents (6.2) and (6.3) and diuretic (6.4). Benzothiazole nucleus was found to possess a significant atypical behavior and a good potency to block 5-HT receptors and a good ability of fully antagonizing Glutamate release ^109-111.
7. 

CONCLUSION: This review shows that 2-substituted benzothiazoles own a wide spectrum of biological activities. The benzothiazole substituted quinol ethers and esters, substituted 2-(4-amino phenyl) benzothiazoles and 2-carbonitrile, 4-thiazolidinone and and phthalimide linked benzothizoles are having specifically awesome antitumor activity. Significant antibacterial activity is displayed by some novel triazole, oxadiazole and pyrimidine derivatives of benzothiazoles. Various 2-substituted benzothiazoles are found to have potent anti-inflammatory activity. An interesting anticonvulsant activity is demonstrated by a number of azetidine2-one and semicarbazone analogues of benzothiazole. The 2-hydrazino benzothiazoles are found to be active as antitubercular agents, whereas biphenyl benzothiazole-2-carboxamide is showing carbonic anhydrase inhibitory action.

The biological profiles of this new generation of benzothiazoles represent much progress with regard to older compounds.

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