Synthesis and Biological Activities of Some Benzothiazole Derivatives

 

Hunasnalkar Shivraj G*, Shaikh Gazi, Patil SM and Surwase Ulhas S

ASPM’s, K. T. Patil College of Pharmacy, Osmanabad. (MS) 413501.

*Corresponding Author E-mail: shivaraj2007@rediffmail.com

 

ABSTRACT:

Substituted benzothiazoles have received considerable attention during last two decades as they are endowed with variety of biological activities and have wide range of therapeutic properties. A Literature survey indicates that benzothiazole derivatives possess different pharmacological and biological activities; which of most potent activity are anti-inflammatory and anti-bacterial activity. The starting product is 6-substituted-1, 3-benzothiazol-2-amine was prepared from 4- substituted anilines and potassium thiocyanate in one step. Substituted Benzothiazolyl-2-amines were reacted with chloroacetyl chloride to yield 2-chloro acetyl amino-6-substitued benzothiazoles, which were reacted with 2-mercaptobenzothiazole and 2-hydrazinobenzthiazole gave 2-(1,3-benzothiazol-2-yl thio)-N-(6-substitued-1,3-benzothiazol-2-yl) acetamides and 2-[2-(1,3-benzothiazol-2-yl)hydrazino]-N-(6-methyl-1,3-benzothiazol-2-yl)  acetamides respectively.  The synthesized compounds were characterized by elemental analysis and spectral data.

 

KEYWORDS: Benzothiazoles, Antibacterial, Antifungal.

 


 

INTRODUCTION:

Pharmaceutical chemistry is a science that makes use of the general laws of chemistry to study drugs i.e., their preparation, chemical nature, composition, structure, influences on an organism and studies of the physical and chemical properties of drugs, the methods of quality control, and the conditions of their storage.

 

Pharmaceutical chemistry occupies the most important place among the related science (e.g. drug technology, toxicological chemistry, pharmacognosy, the economy and organization of the pharmacy).

 

At the same time, pharmaceutical chemistry, being a specialized science, depends on other chemical (inorganic, organic, analytical, physical and colloid chemistry) and also on medico biological (Pharmacology, physiology, biological chemistry) disciplines.

 

Knowledge of the biological disciplines is needed to understand the complex physiological processes based on chemical and its physical reactions that occur in an organism.

 

This makes it possible to use drugs more rationally, observe their actions on an organism, and control the molecular structure of the drugs being developed to obtain the desired pharmacological effect. The results of pharmacological tests of drugs determine the possibility of using them is medical practice.

 

“Chemistry must serve the protection of health instead of procuring gold”. Paracelsus proclaimed who introduced the concept of the active principle as a chemical substance.

 

16th century begin pharmaceutical chemistry gave way to Medical Chemistry in the second half of the 17th century, gave new trend in pharmaceutical chemistry. Pharmacists played a major role in the birth and development of Pharmaceutical Chemistry. Medicinal chemistry, according to Burger, “tries to be based on the ever increasing hope that biochemical rationales for drug discovery may be found.

 

The first use of synthetic organic molecules for interference with the life process was probably when chloroform and ether were introduced for anesthesia in the first half of 19th century. Phenacitin probably was the first drug to be designed as a result of knowledge of biochemical transformations.

 

Paul Ehrlich proposed that receptors exits in mammalian cells and that both antigen and chemotherapeutic agents (a term he coined) possess hepatophoric (anchorer) and toxophoric (Poisoner) groups. Chemotherapeutic agent he considered, combine with receptor areas of the cell by ordinary chemical reactions, although modified to include more types of bond formation. Ehrlich concluded that drug resistance developed, when the drug was no longer absorbed by the parasite. His ideas where thus supported by experimental facts.

 

Chemical modifications of drug molecules to locate the number of series having optimal effects and will probably continued to be a factor necessary to drug discovery. To establish the structure of the drug molecule the new inventions in physiochemical directions such as X-ray analysis, UV, IR, NMR, and Mass are immensely helpful for medicinal chemist. In the biochemical view knowledge of drug receptor interactions, Pharmacokinetics, advancements in enzymology, have immensely helped medicinal chemist in hypothesizing the correct mechanism of actions of drug molecules.

 

The approach to practice medicinal chemistry has developed from an empirical one involving organic synthesis of new compounds, based largely on modification of structures of known activity. According to Manfred Wolf present development of medicinal chemistry has renaissance, stating that: “underlying the new age is a foundation that includes explosive development of molecular biology since 1960, the advances in physical chemistry and physical organic chemistry made possible by high speed computers, and new powerful analytical methods….”.

 

In view of the above considerations we have selected Tailor made approach of drug design in search of new potent bioactive drug molecules.

 

THIAZOLE:

A heterocyclic compounds is one that contains a ring made up of more than one kind of atom. In many of the cyclic compounds the rings are made up only of carbon atoms; such compounds are called homocyclic compounds. But there are also rings containing, in addition to carbon, other kinds of atoms, most commonly Nitrogen, Oxygen or Sulphur. Such compounds are called as heterocyclic compounds. For eg; thiazole.

 

Thiazole is a weakly basic liquid (B.P is 117 0C) and is occurs in vitamin B1.  It is very stable compound and is not affected by the usual reducing agents; sodium and ethanol, however open the ring to form thiols (or hydrogen sulphide) and amines. Thiazoles is very resistant to substituted reactions, but if a hydroxyl group (or) an amino group is in position 2 then the molecule is readily attacked by the usual electrophillic reagents to form 5-substitution products, eg., 2-hydroxy-4-methyl thiazole is readily brominated in chloroform solution to give 5-bromo-2-hydroxy-4-methyl-thiazole.

 

BENZOTHIAZOLE:

Benzothiazoles may be prepared by the action of acid anhydrides (or) chlorides on   o-amino thiophenols and formic acid in the presence of acetic anhydride.

 

Benzothiazoles are also formed by the action of phosphorus pentasulphide on o-Acylamidophenols, eg.

 

2- Mercapto benzothiazole is a vulcanization accelerator; it may be prepared as follows:

 

Various derivatives of benzothiazoles have been synthesized by several investigators and have been reported to exhibit a wide range of biological activities like antibacterial, anti-inflammatory, antitubercular, anthelmintic and antiulcer…etc.

 

Benzothiazole derivatives play a vital role in the field of medicinal chemistry. Some of the thiazolotriazoles 1-4 (1) are reported to possess the biological activities like antimicrobial 5 and antitubercular.

 

Mannich bases of Isatins (2) have been reported to show a variety of biological activities like antileishmanial, anthelmintic, antimicrobial and CNS depressant activities.

 

The antitumour 2-(4-aminophenyl) benzothiazole (3) series possess remarkable biological properties. Their activity was first discovered in the early 1990s.

 

MATERIAL AND METHOD:

Preparation of 2-amino-6-substituted-1, 3-benzothiazoles (1a1 - a5):

To glacial acetic acid (20 ml) pre cooled to 5 0C were added 8.0 g (0.08 mole) of potassium thiocyanate and 1.27 g (0.01 mole) of 4-substituted aniline. The reaction mixture was placed in freezing mixture of ice and salt and mechanically stirred, while 1.6 ml of bromine in 6.0 ml of glacial acetic acid was added from a dropping funnel at such a rate that the temperature does not rise beyond 0 0C. After all the bromine has been added   the solution was stirred for an additional two hours at 0 0C and at room temperature for 10 hours. It was then allowed to stand overnight during which period an organic precipitate is settled at the bottom. Water (6.0 ml) was added quickly and slurry was heated to 85 0C on a steam bath and filtered hot. The orange residue was placed in a reaction flask and treated with 10.0 ml glacial acetic acid, heated again to 850C and it was filtered hot. The combined filtrate was cooled and neutralized carefully with ammonia solution to pH 6.0, and then a dark yellow precipitate was separated and was collected. The product was recrystallized twice with benzene by treating with charcoal gave colorless product. The physical characteristics of these compounds are presented in Table-1.

 

Table – 1: Physical data of compounds (1a1 - a5)

 

Sr. No

Product Code

R

Molecular Formula

Melting Point OC

Yield %

1

1a1

H

C7H6N2S

126-129

45

2

1a2

CH3

C8H9N2S

132-134

66

3

1a3

OCH3

C8H9N2SO

158-159

44

4

1a4

F

C7H6N2SF

180-183

50

5

1a5

Cl

C7H6N2SCl

192-195

48

 

Preparation of 2-chloroacetyl amino-6-substituted benzothiazole (2a1 - a5):

To a solution of 2-amino-6-substituted benzothiazole (20gm) dissolved in 150 ml dry benzene was added a solution of 10 ml chloroacetyl chloride in 50 ml of dry benzene. The reaction mixture was then warmed at 70 0C on a water bath for 90 min. The benzene was distilled off and the residue was filtered, washed with sodium bicarbonate solution followed by water and then it was dried .The product was recrystallized from alcohol. The physical characteristic data of these compounds was presented in Table-2.

 

Preparation of 2-hydrazino benzothiazole (4):

A mixture of 2-mercapto benzothiazole 40g (0.4 mole) and hydrazine hydrate 40g (0.4 mole, 80%) was refluxed for 2 hours. On cooling 2-hydrazino benzothiazole precipitated out .It was recrystallized from ethanol.

Melting point: 194 0C, Percentage yield 60%.

 

Preparation of 2-(1,3-benzothiazol-2-ylthio)-N-(6-substituted-1,3-benzothiazol-2-yl) acetamide (5a1 - a5):

A mixture of 2-chloroacetyl amino-6-substituted benzothiazole 10g (0.1 mole) and pyridine was dissolved properly then added to the RB flask containing a solution of 2-mercapto benzothiazole 10g(0.1 mole) in pyridine solution and the reaction mixture was refluxed for 5 hours. After completion of the reaction it was cooled to room temperature and the separated solid was filtered and dried. The product was recrystallized from alcohol. The physical characteristic data of these compounds was presented in Table-3.

 

Preparation of 2-[2-(1,3-benzothiazol-2-yl)hydrazino]-N-(6-substituted-1,3-benzothiazol 2-yl) acetamide (6a1 - a5):

A mixture of 2-chloroacetyl amino-6-substituted benzothiazole 10g (0.1 mole) and pyridine was dissolved properly then added to the RB flask containing a solution of 2-hydrazino benzothiazole 10g (0.1 mole) in pyridine and refluxed for 5 hours. After completion of the reaction, it was cooled to room temperature, filtered and dried. The product was recrystallized from alcohol. The physical characteristic data of these compounds was presented in Table-3.

 

 


Table – 2: Physical data of compounds (2a1 - a5)

 

Sr. No

Product Code

R

Molecular Formula

Melting Point OC

Molecular Weight

Yield %

1

2a1

H

C9H7N2SOCl

163-165

226

56

2

2a2

CH3

C10H10N2SOCl

190-195

241

47

3

2a3

OCH3

C10H10N2SO2Cl

180-184

257

53

4

2a4

F

C9H7N2SOClF

175-180

245

48

5

2a5

Cl

C9H7N2SOCl2

210-215

261

45

 

Table – 3: Physical data of compounds (5a1 - a5) and (6a1 - a5)

Sr. No

Product Code

R

R1

Molecular Formula

Melting Point OC

Molecular Weight

Yield %

1

5a1

H

C16H11N3S3O

245-250

357

44

2

5a2

CH3

C17H13N3S3O

265-270

370

56

3

5a3

OCH3

C17H13N3S2O2

250-252

386

43

4

5a4

F

C16H11N3S3OF

270-275

368

46

5

5a5

Cl

C16H11N3S3OCl

272-275

391

43

6

6a1

H

C16H13N5S2O

240-245

384

50

7

6a2

CH3

C17H15N5S2O

260-265

370

46

8

6a3

OCH3

C17H15N5S2O2

255-260

384

50

9

6a4

F

C16H13N5S2OF

265-268

373

42

10

6a5

Cl

C16H13N5S2OCl

270-272

389

46

 

 

 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RESULTS AND DISCUSSION:

Antibacterial activity:

Preparation of standard solution:

The standard drug used for the testing is ampicillin. It is water-soluble; the concentration of this drug is adjusted so as to contain 50-µg/ ml &100 µg/ ml.

 

The compounds synthesized during the present investigation were screened for their antibacterial activity. The antibacterial tests were conducted on four common microorganisms such as Bacillus subtilis, Bacillus pumilus, Escherichia coli and Pseudomonas aeruginosa that are the

 


 

Table-4. Antibacterial activity of benzothiazole derivatives


 

Sample Code

*Inhibition zone diameter in mm

B.subtilis

B.pumillis

E.coli

P.aeruginosa

50mg

100mg

50mg

100mg

50mg

100mg

50mg

100mg

5a1

13

13

14

19

13

13

14

21

5a2

15

15

14

13

13

15

15

14

5a3

13

13

15

13

14

18

19

18

5a4

12

12

16

16

15

13

20

14

5a5

15

15

15

20

12

15

15

21

6a1

12

12

16

19

14

22

12

19

6a2

13

13

15

16

14

15

15

16

6a3

12

12

14

20

13

13

17

13

6a4

13

13

15

13

12

15

20

21

6a5

13

13

13

19

13

15

15

16

Ampicillin

22

22

21

24

22

24

21

25

DMSO

-

-

-

-

-

-

-

-

*Each value is an average of three independent determination ± Standard deviation Note: ‘-‘denotes no activity, 8-12 mm poor activity, 13-17 mm moderate activity, 18-20 and above good activity.

 

Table-5. Data showing anti-inflammatory activity of benzothiazole derivatives in Carageenan induced acute rat paw oedema model

Group

Treatment

Dose

mg/kg

Paw oedema volume

After 1st hr

After 2nd hr

After 3rd hr

After 4th hr

Mean

%

ROV

 

Mean

%

ROV

 

Mean

%

ROV

 

Mean

%
ROV

1

Control

0.5 ml

0.393

-

0.516

-

0.583

-

0.55

-

2

Standard

50

0.168

57.25

0.166

67.75

0.166

71.43

0.050

90.90

3

5a1

200

0.212

46.05

0.26

49.67

0.187

67.94

0.087

84.18

4

5a2

200

0.325

17.30

0.362

29.92

0.275

52.85

0.162

70.54

5

5a3

200

0.337

14.24

0.387

25.08

0.237

59.36

0.10

81.81

6

5a4

200

0.225

42.74

0.287

44.44

0.175

69.99

0.075

86.36

7

5a5

200

0.375

04.58

0.412

20.24

0.337

42.22

0.25

54.54

8

6a1

200

0.301

23.40

0.340

34.18

0.255

56.28

0.170

69.09

9

6a2

200

0.355

09.66

0.392

34.11

0.317

45.65

0.24

56.36

10

6a3

200

0.202

48.60

0.25

50.32

0.177

66.65

0.088

84.00

11

6a4

200

0.221

48.60

0.278

46.18

0171

70.68

0.092

83.27

12

6a5

200

0.325

17.30

0.362

29.92

0.275

52.85

0.162

70.54

Animals: Albino rat, Route: P.O, Standard: Diclofenac, ROV- Reduction in paw oedema volume.

 

 


representative types of gram positive and gram-negative organisms respectively. The antibacterial activity of the compounds was assessed by disc-diffusion method.

 

All the synthesized compounds were screened for antibacterial activity studies at a concentration of 50 µg /ml & 100 µg /ml using DMSO as a control against B.substilis, B.pumillus, Escherchia coli and P.aeruginosa by disc-diffusion method on nutrient agar media, Ampicillin 50 µg /ml & 100 µg /ml used as standard against Gram positive and Gram negative bacteria.

 

The data in the Table 4 indicate that 5a1, 5a5 and 6a4 compounds was found to possess a broad spectrum activity. While compounds 5a2, 5a3, 5a4, 6a1, 6a2, 6a3 and 6a5 were found to exhibit moderate activities. Among the synthesized compounds the compounds 5a1, 5a5 and 6a4 showed good activities.

 

Anti-inflammatory activity:(557/02/c/CPCSEA[)

Inflammation is a normal protective response to tissue injury caused by physical trauma, noxious chemicals or microbiologic agents. Inflammation is body’s response for tissue repair 69. Inflammation is triggered by the release of chemical mediators from the injured tissues and migrating cells. The specific chemical mediators vary with the type of inflammatory process and include amines such as histamine, serotonin, and lipids such as prostaglandins and small peptides such as kinins 70. The acute inflammatory response has 3 main functions.

 

1.A transient material called the acute inflammatory exudates occupies the affected area. The exudate carries proteins, fluid and cells from local blood vessels into the damaged area to mediate local defenses.

 

2. If an infective causative agent (e.g. bacteria) is present in the damaged area, it can be destroyed and eliminated by components of the exudates.

 

3. The damaged tissue can be broken down and partially liquefied, and the debris removed from the site of damage.

 

Mechanism of inflammation:

In and around the inflamed tissue, there is an accumulation of oedema fluid in the interstitial compartment which comes from blood plasma by its escape through the endothelial wall of peripheral vascular bed. In initial stage the escape of fluid i.e. due to vasodilatation and consequent elevation in hydrostatic pressure, the characteristic inflammatory oedema, and exudates appear by increased vascular permeability of microcirculation. Inflammatory diseases including different types of rheumatic diseases are a major cause of morbidity of the working force throughout the world. Many drugs produced a dramatic symptomatic improvement in rheumatic processes, but all of them shared the common undesirable effect i.e., gastrointestinal irritation71.

 

Procedure: 72 ,73

Carrageenan induced rat paw oedema model:

Albino rats of either sex weighing 150 – 200gms were selected. They were maintained on standard pellet diet and free access to water.

 

The animals were divided into 6 groups each having six animals. The various groups were treated as follows:

Group   1       -      Normal Control   (treated with 0.2 ml of 5% gum acacia p.o.)

Group   2    -      Diclofenac (20 mg / kg, p.o.)

Group   3    -      Compound 5a1 (200 mg/ kg, p.o.)

Group   4    -      Compound 5a2 (200 mg/ kg, p.o.)

Group   5    -      Compound 5a3 (200 mg/ kg, p.o.)

Group   6    -      Compound 5a4 (200 mg/ kg, p.o.)

Group   7    -      Compound 5a5 (200 mg/ kg, p.o.)

Group   8    -      Compound 6a1(200 mg/ kg, p.o.)

Group   9    -      Compound 6a2 (200 mg/ kg, p.o.)

Group   10  -      Compound 6a3 (200 mg/ kg, p.o.)

Group   11  -      Compound 6a4 (200 mg/ kg, p.o.)

Group   12  -      Compound 6a5 (200 mg/ kg, p.o.)

 

The normal control, diclofenac and test compounds were administered to the rats 30 minutes before the injection of 0.1ml of 1% carrageenan suspension in normal saline. Carrageenan suspension was injected into the sub-planar region of the left hind paw, and the right hind paw served as reference. Immediately thereafter the oedema volume of the injected paws were measured plethysmographically by mercury displacement method 74.

For comparison purpose, the volume of oedema at various prefixed time intervals was measured. The difference between paw  volume of the treated animals was measured and the mean oedema volume was calculated.

 

Percentage reduction in oedema volume was calculated by using the formula,

                                                Vo - Vt

Percentage reduction =                              x 100

                                                   vo

Where, Vo = Volume of the paw of control at time ‘t’.

Vt  = Volume of the paw of drug treated at time ‘t’.

From the data obtained, the mean oedema volume with standard error (SEM), standard deviation (S.D.), percentage reduction in oedema was calculated. The anti-inflammatory activity of synthesized compound is given in the Table No-5.

 

All the ten compounds 5a1, 5a2, 5a3, 5a4, 5a5, 6a1, 6a2, 6a3, 6a4 and 6a5 at dose of 200mg/ kg exhibited significant anti-inflammatory activity in acute inflammatory models in rats. Results are tabulated in Table 5. Compounds 5a1, 5a2, 5a3, 5a4, 5a5, 6a1, 6a2, 6a3, 6a4 and  6a5 exhibited maximum inhibition of 84.18 %, 70.54 %, 81.81 %,86.36 %, 54.54 %,69.09 %, 56.36 %,84.00 %,83.27 %,70.54 % respectively where as standard Diclofenac sodium showed reduction in oedema volume by 90.90 % in carrageenan induced rat hind paw oedema model.

 

CONCLUSION:

From the antibacterial and anti-inflammatory screening it was found that the compounds showed significant activity and were found to be good with respect to the standard at the given concentration levels. Hence these compounds appear to be promising antibacterial, anti-inflammatory agents. Perhaps the substituent at 2nd position of benzothiazole ring and which contains substituted 2-mercapto benzothiazole and 2-hydrazino benzothiazole ring may be largely responsible for the marked bactericidal and anti-inflammatory activity. The above results establish the fact that substituted benzothiazoles can be studied further to search for new anti-inflammatory and   anti-microbial compounds.

 

The two moieties, i.e., 2-subtituted benzothiazoles and 2-chloroacetamido -6-substitued benzothiazole moieties independently are showing antibacterial activity. Here when the two moieties are fused and screened for antibacterial studies they showed a broad spectrum of antibacterial activity. They showed good activity against Gram positive and Gram negative bacteria. 2-subtituted benzothiazoles and 2-chloroacetamido -6-substitued benzothiazole are responsible for antibacterial activity, but it is interesting to note that benzothiazole moieties when fused with other moieties showed a broad spectrum antibacterial activity. Hence in search of new generation of antibiotics it may be worthwhile to explore the possibility in this area by fusing different moieties and increase potency.

 

ACKNOWLEDGEMENT:

The authors are thankful to Dr. S.M. Shantakumar for providing necessary infrastructural facilities and also to management of ASPM’s K.T. Patil college of Pharmacy for constant encouragement and support.

 

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Received on 14.10.2009        Modified on 29.11.2009

Accepted on 28.12.2010        © AJRC All right reserved

Asian J. Research Chem. 3(2): April- June 2010; Page 421-427