Post on 06-Jul-2020
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
bjkhairnar@yahoo.com
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
1. Husain Asif and Ahuja Priyanka, Acta Poloniae Pharm., 2008, 65, 527.
2. Franski R, Asian J Chem., 2005, 17, 2063.
3. Narayana B, Vijatraj K K, Ashalatha B V and Kumari N S, Arch Pharm., 2005, 338(8),
373-377.
4. Amir M, Kumar S, Acta Pharm., 2007, 57(1), 31-45.
5. Gaonkar S L and Rai K M, Eur J Med Chem., 2006, 41(7), 841-846.
6. Mishra P, Rajak H and Mehta A, J Gen Appl Microbiol., 2005, 51(2), 133-141.
7. Bezerra N M M, De-oliveria S P, Srivastava R. M and Da Silva, J R Farmaco., 2005,
60(11,12), 955-960.
8. Zareef M, Iqbal R, Rodrigues J and Supuran C T, J Enzyme Inhib Med Chem., 2007,
22(3), 301-308.
9. Tan T M, Chen Y, Kong K H, Bai J, Li Y, Lim S G, Ang T H and Lam Y, Antiviral Res.,
2006, 71, 7.
10. Rasmussen C R, Chem Abstr., 1974, 80, 95987.
11. Cruickshank R, Duguid J P, Marmion B P and Swam H A, The Practice of Medical
Microbiology; 12th
Ed., Churchill Livingstone, London, 1975, 544.
Submit your manuscripts athttp://www.hindawi.com
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation http://www.hindawi.com Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttp://www.hindawi.com
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Journal of
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Organic Chemistry International
Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation http://www.hindawi.com Volume 2014