Benzothiazole. Biologically useful and important scaffold

Table of Contents

1. Introduction

2. About Benzothiazole
Synthesis from arylthioureas
Synthesis from p-toluidine

3. Reported literature of benzothiazole

4. References

Acknowledgement

In the name of Allah – The almighty, the most beneficent and the most merciful who bestows blessings to everyone without any discrimination of colour, race, age, sex, time, country or language.

With deep gratitude, I would like to thank my research supervisor , Prof. (Dr.) N. B. Patel, (Professor & Head, Department of Chemistry, Veer Narmad South Gujarat University, Surat) for his constant advice, guidance, enduring support, patience, criticism, insight, encouragement and for sharing his extensive knowledge of chemistry during my research study which enables me to write this book.

I would like to thank all of my family and friends who have provided me endless support over the years as a student and now as a teacher.

Finally, I would like to thank C.B. Patel Computer College & J. N. M. Patel Science College, Bharthana (Vesu), Surat and its management for providing me necessary infrastructure and other facilities for this project.

Thanking You,

Dr. Faiyazalam M. Shaikh

M.Sc., M.Phil., Ph.D.

Head, Department of Chemistry,

C.B. Patel Computer College & J. N. M. Patel Science College,

Bharthana (Vesu),

Surat (Gujarat),

India.

1. Introduction

A large number of drugs and biologically relevant molecules contain heterocyclic systems. Often the presence of hetero atoms or groupings imparts preferential specificities in their biological responses. Amongst the heterocyclic systems; compounds containing hetero atoms such as nitrogen and/or sulfur e.g., thiazolidinones, benzothiazoles, triazines, etc. have great importance due to their diverse biological activity. Finding numerous biological importances of these ring systems, it is worth to study such building blocks for better understanding of medicinal chemistry as well as synthetic organic chemistry involving the synthesis of such different biologically active nitrogen and/or sulfur containing heterocyclic moieties like substituted benzothiazoles, triazines, pyrrolidine, azetidinones, pyridines, oxazoles, thiazoles, Schiff bases, etc. In view of such facts, present book deals with the review of biologically important heterocyclic moiety benzothiazole.

2. About Benzothiazole

A broad spectrum of pharmacological properties has been demonstrated by the benzothiazole nucleus. Benzothiazole derivatives have attracted a great deal of interest due to their anti-inflammatory, antitumor, antiglutamate and anticancer activity. Benzothiazole is a privileged bicyclic ring system. Due to its 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 involving research aimed at evaluating new products that possess interesting biological activities. 2-Substitued benzothiazole has emerged in its usage as a core structure in the diversified therapeutic applications.

Many polycyclic and fused ring systems containing the thiazole nucleus are important in which the second ring is fused to the 4,5 position of the thiazole ring. Benzothiazole I and its many derivatives are particularly important. The three naphthothiazoles II, III and IV are known and are treated as derivatives of benzothiazole [1].

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I

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II

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III

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IV

There are several reported methods for the synthesis of benzothiazole derivatives [2] likewise;

Synthesis from:

1. o -Aminothiophenols, aldehydes and carboxylic acid

2. N -Arylthioamides or thioanilides, arylthioureas, arylisothiocynates, arylmonothiocarbamates or arylthiourethanes and aryldithiocarbamates

3. o -Nitroarylthiocynates, S-acyl- o -aminothiophenols, o -nitroarylthio ethers

4. p -Benzoquinone

5. Benzanilide and N, N -dimethylaniline

6. p -Toluidine

Out of these methods, we have mentioned some of the important synthetic routs as follows:

Synthesis from arylthioureas

Mono-, di- and tri- substituted arylthioureas are very easily cyclized to 2-amino benzothiazoles by the action of bromine in a solvent such as CHCl3, CCl4, CS2, S2Cl2 (Hugershoff’s method) followed by a treatment with SO2 and with a base.

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Synthesis from p-toluidine

An industrial process for the preparation of 2- p -aminophenyl-6-methylbenzothiazole is based on the high temperature reaction of sulfur with p -toluidine. Benzothiazole-2-thione is synthesized industrially by reaction of aniline with sulfur and carbon disulfide. In this synthesis, sulfur plays the role of a dehydrogenating reagent and may be replaced by nitrobenzene (Scheme-I & II).

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Scheme-I

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Scheme-II

3. Reported literature of benzothiazole

Following is some of the examples quoted from literature about synthesis of different benzothiazole derivatives having diverse biological activities which makes benzothiazole as one of the most diversified heterocyclic molecule containing nitrogen and sulfur as hetero atoms.

Siddiqui et al have synthesized a new series of 1-(6-substituted-1,3-benzothiazol-2-yl)-3-(substitutedphenyl)hexahydro-2,4,6-pyrimidine triones V and 1,3-benzothiazol-2-yl-semicarbazones VI and evaluated for their anticonvulsant, neurotoxicity and other toxicity studies [3,4].

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V

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VI

A new series of 3-(6-substituted-benzothiazol-2-yl)-6-phenyl-[1,3]-oxazinane-2-thiones VII has been synthesized by Chopade and co-workers and evaluated as anticonvulsant agents [5].

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VII

A series of 6-substituted-[3-substituted-prop-2-eneamido] benzothiazoles VIII and 6-substituted-2-[(1-acetyl-5-substituted)-2-pyrazolin-3-yl]aminobenzothiazoles IX have been synthesized and evaluated for anticonvulsant activity and 3D-QSAR study by Amnerkar and Bhusari [6].

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VIII

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IX

Amir and co-workers have synthesized a new series of N -(6-chloro benzothiazol-2-yl)-2-substituted-acetamides X and N -(6-chlorobenzo thiazol-2-yl)-2-(substituted-benzylidene)hydrazinecarbothioamides XI and screened their in vivo anticonvulsant and acute toxicity [7].

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X

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XI

A series of 2-[2-(substituted)hydrazinyl]-1,3-benzothiazoles XII and 2-(1,3-benzothiazol-2-ylsulfanyl)- N’ -(substituted)acetohydrazides XIII have been designed and synthesized by Kumar et al as anticonvulsant agents [8].

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XII

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XIII

Kok and co-workers have synthesized benzothiazole containing phthalimides XIV by one pot condensation reaction and evaluated their anticancer activity by exhibiting in vitro cytotoxic potential on human cancer cell lines [9].

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XIV

Synthesis, DNA-binding ability and anticancer activity of benzothiazole/benzoxazole-pyrrolo[2,1-c][1,4]benzodiazepine conjugates were studied by Kamal et al [10].

Bhuva and co-workers have synthesized some novel substituted 2-phenyl-1,3- benzothiazoles XV and tested for their anticancer activity against breast cancer cell line MCF-7 by MTT assay. Most of the compounds showed moderate to good anti-breast cancer activity [11].

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XV

Saeed and co-workers have synthesized new thiourea derivatives bearing benzothiazole moiety XVI and evaluated as potential antimicrobial and anticancer agents [12].

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XVI

Jin et al have synthesized some new α-aminophosphonates containing benzothiazoles XVII and evaluated for their anticancer activities against PC3, A431, A375, and Bcap37 cells in vitro by the MTT method [13].

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XVII

Some new benzothiazole derivatives have been synthesized and evaluated for anticancer activity by Huang et al [14].

Kamal and co-workers have carried out an efficient one-pot synthesis of benzothiazolo-4β-anilino-podophyllotoxin congeners XVIII, XIX and evaluated their DNA topoisomerase-II inhibition and anticancer activity [15].

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XVIII XIX

Caputo et al have synthesized some new benzothiazole derivatives XX, XXI and evaluated as anticancer agents [16].

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XX XXI

Solomon and co-workers have used a hybrid pharmacophore approach to design and synthesize isatin-benzothiazole analogs XXII to examine their anti-breast cancer activity and also concluded that the isatin-linked benzothiazole analog can serve as a prototype molecule for further development of a new class of anti-breast cancer agents [17].

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XXII

Wells et al have synthesized benzothiazole substituted quinol ethers and esters XXIII, XXIV, XXV as antitumor agents and found them to be active in vitro against human colon and breast cancer cell lines [18].

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XXIII XXIV

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XXV

A series of amide and urea derivatives of benzothiazole XXVI, XXVII have been synthesized and evaluated for their antiproliferative profile in human SK-Hep-1 (liver), MDA-MB-231 (breast), and NUGC-3 (gastric) cell lines by Song et al. Some of the compounds showed potent to moderate inhibitory activities and were further investigated for their ability to inhibit Raf-1 activity [19].

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XXVI XXVII

Al-Soud et al have synthesized a series of benzothiazole bearing piperazino-arylsulfonamides XXVIII and arylthiol XXIX, XXX analogues as well as substituted benzothiazoles having sulfonamides and evaluated their in vitro antiproliferative activity against a large panel of human tumor-derived cell lines [20].

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XXVIII XXIX

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XXX

Racane and co-workers have synthesized new bis-substituted nitro-amidino, amino-amidino and diamidino 2-phenyl-benzothiazoles and evaluated their in vitro antiproliferative and in vivo acute toxicity [21, 22].

A new series of benzothiazole Schiff bases XXXI has been synthesized and tested in vitro for antiviral and antimicrobial activities by Vicini et al [23].

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XXXI

Hameed et al have synthesized new benzothiazole derivatives XXXII and evaluated their in vitro antitumor and antiviral activity [24].

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XXXII

Navarrete-Vazquez et al have synthesized 2-arylsulfonylaminobenzothiazoles XXXIII and evaluated their in vitro inhibitory activity against protein tyrosine phosphatase 1B (PTP-1B) and antihyperglycemic activity [25].

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XXXIII

A new series of 2-thioether-benzothiazoles XXXIV has been synthesized and evaluated as novel c-Jun N -terminal kinase inhibitor by De et al [26].

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XXXIV

Tasler et al have carried out a systematic optimization program based on an (aminoaryl)benzothiazole quinazoline XXXV hit structure and N -substituted 2’-(aminoaryl)benzothiazoles XXXVI for kinase inhibition which resulted in a lead structure allowing for inhibitory activities in cellular phosphorylation assays in the low nanomolar range [27,28].

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XXXV

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XXXVI

A series of novel 4-benzothiazole amino quinazolines Dasatinib derivatives XXXVII has been designed and synthesized by Cai et al. The entire target compounds were investigated for their in vitro cytotoxic activity by the MTT-based assay against 6 human cancer cell lines and were also screened for Src and Abl kinase inhibitory activity [29].

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XXXVII

A series of novel 4-(difluoromethyl)-1-(6-halo-2-substituted-benzothiazol-5-yl)-3-methyl-1 H -1,2,4-triazol-5(4 H)-ones XXXVIII has been designed and synthesized via the ring-closure of two ortho-substituents by Yang et al as protoporphyrinogen oxidase inhibitors [30].

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XXXVIII

Jeon et al have synthesized new benzothiazole derivatives of thiazolidinediones (TZD) XXXIX using a modified Mitsunobu reaction of 2-(benzothiazol-2-ylmethylamino)ethanol with 5-(4-hydroxybenzyl)-3-triphenylmethyl thiazolidine-2,4-dione and assayed for activity on peroxisome proliferator-activated receptor (PPAR) subtypes and inhibitory activity of NO production in lipopolysaccharide activated macrophages. Most of the tested compounds were identified as potent PPARγ agonists, indicating their potential as drug candidates for diabetes [31].

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XXXIX