synthesis and antimicrobial activity of some new 1, 4...

ISSN: 0973-4945; CODEN ECJHAO

E-Journal of Chemistry

http://www.e-journals.net 2012, 9(1), 318-322

Synthesis and Antimicrobial Activity of

Some New 1, 4-Benzothiazine Containing

Thiosemicarbazides and 1, 3, 4-Oxadiazole Derivatives

BHIKAN J KHAIRNAR, RAHUL S SALUNKE,

PREMCHAND B PATIL, SANJAY A PATIL, RAJESHWAR J KAPADE,

PRAVIN S GIRASE and BHATA R CHAUDHARI*

Department of Chemistry

JET’s Z.B. Patil College, Dhule-424 002, India

[email protected]

Received 24 May 2011; Accepted 31 July 2011

Abstract: A series of novel 3- methyl-7-substituted-4H-1,4-benzothiazine-2-

carbohydrazide (3a-e) and corresponding thiosemicarbazides (4-a-q); 2-[3-methyl-7-

substituted- 4H -1, 4-benzothiazine-2-yl]-N-(aryl) hydrazine carbothiamide have

been synthesized. The thiosemicarbazide when cyclized with iodine via

intramolecular cyclisation gave benzothiazonyl oxadiazoles (5-a-q); 5-(3-methyl

-7-substitued-4H- 1,4-benzothiazin-2-yl)- N –aryl- 1,3,4- oxadiazol -2-amine and

the compounds were tested for antibacterial and antifungal activities against

different microorganisms.

Keywords: 2-Aminothiophenol, 1, 4-Benzothiazine, 1, 3, 4-Oxadiazole, Thiosemicarbazide, Intramolecular

cyclisation, Antimicrobial activity

Introduction

The chemistry of heterocyclic compounds has been an interesting field of study for a long

time. The synthesis of novel oxadiazole derivatives and investigation of their chemical and

biological behaviour have gained more importance in recent decades for medicinal and

agricultural reasons. Different classes of oxadiazole compounds possess an extensive

spectrum of pharmacological activities, particularly in compounds bearing 1, 3, 4- oxadiazole

nucleus which are known to exhibit unique antiedema and anti-inflammatory activity1,2

.

Substituted oxadiazole moiety has been found to have important activities such as analgesic3,4

,

antimicrobial5,6

, antitumor7, antimalerial

8 and antihepatities

9. In some cases 1,4-benzothiaazine

are also known for their utility as dyes, photographic developers, ultraviolet light absorbers

and antioxidants10

.

Synthesis and Antimicrobial Activity 319

The multifarious applications of 1, 4-benzothiazine have directed organic chemists to

synthesize new 1, 4- benzothiazine bearing heteryl pharmacophores. In view of this, we are

working on the synthesis of new 1, 4, benzothiazine containing 1, 3, 4- oxadiazole derivatives,

because it is common observation that combination of two or more biologically active

heterocyclic rings in some compounds results in enhancement of biological profiles of such

compounds by many folds.

NH2

SHR

+O

CH3

OEtO

H2N-NH

2 .H

2O

Ethanol

NH

S

CH3

O

OEt

R

H2N-NH

2 .H

2O

Reflux

NH

S

CH3

RNH

NH2

O

NCS

R'

NH

S

CH3

RNH

O

NH

S

NH

R'

I2

4N. NaOHEthanol

NH

S

R

CH3

O

N N

NH

R'

(1a-e)

(2a-e)

(4a-q)(3a-e)

(5a-q)

R=H, Cl, Br, Me, OEt

R'=H, Cl, Br, Me, OMe

Reaction scheme

Experimental

Melting points were determined in open capillaries in a liquid paraffin bath and are

uncorrected. The purity of compounds was checked by TLC. IR spectra were recorded in

Nujol on a Perkin-Elmer FT-IR spectrophotometer and 1HNMR spectra in DMSO-d6 using

TMS as internal standard.

Step I: Preparation of 2-carboethoxy-3-methyl-7-substituted-1,4-benzothiazine (2a-e)

A mixture of 2-amino-5-substituted-thiophenol (1a-e) (0.1 mol) and hydrazine hydrate

(0.01 mol) was heated at 100 0C for 2-3 minutes before introducing the ethyl acetoacetate

(0.1 mol) and warming the reaction mixture to 100 0C for further 10 minutes. After cooling

to room temperature, 4-5 mL of ethyl alcohol was added. The solid that separated was

filtered and recrystallised from ethyl alcohol. The compounds (2a-e) were prepared in same

fashion and their physical constants are given in Table 1.

Step II: Preparation of 3-methyl-7-substituted-4H-1, 4- benzothiazine-2-carbohydrazide

(3a-e)

To 0.1 mole of (2a-e) in ethanol (20 mL), hydrazine hydrate (0.1 moles, 99%) was added,

followed by the addition of a catalytic amount of conc.H2SO4 (2-3drops). The mixture was

320 BHATA R CHAUDHARI et al.

refluxed for two hours. Excess solvent was removed and on cooling a solid was formed. The

solid was crystallized from ethanol. The compounds (3a-e) were prepared in the same

method and their physical constants are given in the Table 1.

Table 1. Characterization data of synthesized compounds (2a-e) and (3a-e)

Compound 2 Compound 3 Compound

No. R Yield,

%

M.P., 0C

Yield,

%

M.P., 0C

a H 92 145 60 92

b Cl 88 166 72 190

c Br 84 160 65 198

d CH3 90 174 70 217

e OC2H5 86 196 56 240

Step III: Preparation of 2-[3-methyl-7-substituted- 4H -1, 4-benzothiazine-2-yl]-N-

(aryl) hydrazine carbothiamide (4a-q)

Above acid hydrazide (3a-e) (0.1 mole) was treated with 4-substitued phenyl isothiocyanate

(0.2 mole) in the presence of ethyl alcohol. The reaction mixture was refluxed for 2 h,

cooled, solid obtained was filtered, wash with aq.ethanol and crystallized from ethyl alcohol.

The compounds (4a-q) were prepared in the same fashion and their physical constants are

given in Table 2.

Table 2. Characterization data for the synthesized compounds (4a-q)

Compound R R’ Yield, % M.P., 0C

4a H H 56 138

4b H Cl 66 216

4c H Br 62 232

4d H CH3 67 170

4e H OCH3 54 210

4f Cl H 58 173

4g Cl Cl 64 225

4h Cl Br 68 177

4i Cl CH3 63 221

4j Cl OCH3 58 232

4k CH3 H 56 198

4l CH3 Cl 61 187

4m CH3 Br 64 176

4n CH3 CH3 65 153

4o CH3 OCH3 62 194

4p Br Cl 56 102

4q OCH3 Cl 54 272

Step IV: Preparation of “5-(3-methyl-7-substitued-4H- 1,4-benzothiazin-2-yl)- N-

aryl- 1,3,4- oxadiazol-2-amine” (5a-q)

A mixture of thiosemicarbazide (4a-q) (0.1 mol) and 4 N NaOH (4-5 mL) was refluxed in

ethanol (25 mL) & iodine added to it, till the colour of iodine persisted. Cooled, poured into

water and filtered. The filtered solid was recrystalised from ethanol. The compounds (5a-q)

were prepared by the same method and their physical constants are given in Table 3.

Synthesis and Antimicrobial Activity 321

Table 3. Characterization data for the synthesized compounds (5a-q)

Compound R R’ Yield, % M.P., 0C

5a H H 64 107

5b H Cl 68 234

5c H Br 62 224

5d H CH3 66 190

5e H O CH3 60 168

5f Cl H 66 215

5g Cl Cl 62 174

5h Cl Br 68 255

5i Cl CH3 58 235

5j Cl O CH3 56 248

5k CH3 H 68 249

5l CH3 Cl 64 222

5m CH3 Br 62 242

5n CH3 CH3 60 170

5o CH3 O CH3 62 228

5p Br Cl 60 82

5q OC2H5 Cl 58 104

Antimicrobial screening

All the newly synthesized compounds (5a-q) were evaluated for in vitro antibacterial

activity against gram positive and gram negative bacterial strains such as Bacillus subtilis,

Bacillus pumilus, Escherichia coli and pseudomonas aureginosa at concentration 100 µg/mL

by disc diffusion method11

by using DMSO as solvent control and nutrient agar was

employed as culture media. After 24 hours of incubation at 37 0C, the zone of inhibition

were measured in mm. The activity was compared with known antibiotic ciprofloxacin. All

these compounds were also screened (doses of 100 µg) for their antifungal activity against

Aspergillus niger using Greseofulvin as a standard. The results of antibacterial to antifungal

screening studies are reported in Table 4.

Table 4. Antimicrobial activity of compounds (5a-q)

Inhibition of zone diameter in mm

B. subtilis B.Pulmilis E. coli P.aeruginosa A.niger

Sample

code

100 µg 100 µg 100 µg 100 µg 100 µg

5a 12 14 14 13 04

5b 16 17 17 15 07

5c 17 18 17 16 07

5d 14 15 15 13 06

5e 15 16 18 16 07

5f 16 18 17 16 07

5g 18 18 17 16 09

5h 18 17 18 16 09

5i 16 17 17 15 07

5j 18 18 17 16 08

5k 15 14 15 13 06

5l 16 16 16 15 07 Contd...

322 BHATA R CHAUDHARI et al.

5m 16 17 17 14 07

5n 15 15 16 14 06

5o 16 15 15 14 06

5p 18 17 18 16 09

5q 18 16 17 16 08

Ciprofloxacin 22 23 20 22 NT

Greseofulvin NT NT NT NT 14

DMSO 0 0 0 0 0

Note: NT- Not tested

Conclusion

All the 17 newly synthesized compounds were screened for antibacterial and antifungal

studies. The data in the table indicates that among the synthesized compounds 5c, 5f, 5g, 5h,

5j, 5p and 5q has found to broad spectrum of activity. However, the activities of tested

compounds are much less than those of standard antibacterial and antifungal agents used.

Acknowledgment

The Authors are thankful to the Management, Principal & Head (Dept. of Chemistry), JET’s

Z.B. Patil College, Dhule for providing the lab facilities and constant encouragement.

References

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