Synthesis  and Biochemical  Investigation of

(Thiazin, Oxadiazol, Thiadiazol )- Derivatives

 

Zinah  Hussien Ali

Assistant Lecturer, Department of Pharmaceutical Chemistry, College of Pharmacy,

*Corresponding Author E-mail: zenaa.77 @yahoo.com

The study involved synthesis of six and five- membered rings from hetero cyclic compounds containing sulfur and nitrogen with  oxygen atoms such as (thiazine, oxadiazol, thiadiazol)- derivatives., some of compounds were prepared from condensation reaction and other by chalcone. The synthesized compounds [1-10] were characterized by many methods {FT.IR- spectra, H.NMR- spectra, (C.H.N)- analysis} and tested for their potential antibacterial {Gram(+) positive and Gram(-) negative} and melting points .

 

 

INTRODUCTION:

The oxadiazol, thiazine and  thiadiazole  nucleus are a useful structure for research and development of new pharmaceutical molecules ,it found in several natural and non- natural products., most of sulfur and nitrogen hetero cycles derivatives are marketed as anti-Psychotic drugs, antifungal, anti-thelmintic, antibacterial, anticancer, HIV- Inhibitors, anti- hypertensive, anti- allergic, anticonvulsant, anti-tubercular, anti- inflammatory activity, and some of derivatives have been found to possess some interesting bioactivities such as anti diabetic activity^(1-4) .

 

These derivatives exhibit adverse biological activities possibly due the present of (N-C-S) moiety, which are very interesting compounds for their applications in pharmaceutical and analytical fields^(5-7). In addition, these derivatives have been used for the preparation of structures in polymers .

 

MATERIALS AND METHODS:

Melting points were determined by electro thermal 9300, LTD, FT.IR- Shimadzu 8300, KBr-disc, H.NMR- spectra in DMSO- solvent and (C.H.N)- analysis in  Kashan University  in Iran, biological tests in Bio-Lab, Biology Department  in  College of Education .

 

Synthesis of   Compounds [1 - 3]:

According to procedures^(8,9), a mixture of 2-amino imidazole (0.01mole) and chloro ethyl acetate (0.02mole) was reacted in presence of ethanol with potassium hydroxide under magnetic stirrer., then filtered and recrystallized to produce (84%)  of  compound [1], which (0.01mole) refluxed with (0.02mol) of thiosemicarbazide in presence of absolute ethanol for (3hrs), after filtered and recrystallized to yield (84%) of compound [2], which cyclized by addition (POCl₃) and refluxed in ethanol for (5hrs) to yield (82% )  of compound [3] .

 

Synthesis of  Compounds [4 , 5]:

According to procedure⁽⁹⁾, a mixture of compound [1] (0.01mol) and semicarbazide (0.02mole) was refluxed in present of absolute ethanol for (3hrs) ,then filtered and recrystallized to yield (86%)  of compound [4]., which (0.01mole) cyclized in presence of POCl₃ with ethanol to produce (82%)  of compound [5] .

 

Synthesis of  Compounds [6 , 7] :

According to procedure⁽⁹⁾, a mixture of (0.02 mol) of  2- amino thiazol and (0.01mol) acetyl acetone was refluxed in presence of absolute ethanol and drops of glacial acetic acid for (2hrs) ,then filtered and recrystallized with ethanol to yield (84%)  of compound [6], which (0.01mol) reacted at room temperature with (0.01mole) benzadehyde in presence of (10% NaOH) to yield (82%) of compound [7] .

 

Synthesis of Compounds [8 -10]:

According to procedure⁽⁹⁾ ., a mixture of (0.02mol) P- hydroxyl benzaldehyde  and (0.01mol) chloro acetyl chloride was reacted in presence of  basic medium (KOH)., the solid filtered and dried, recrystallized to yield (82% ) from compound [8], which (0.01mol) reacted with (0.02mol) acetophenone   at room temperature in presence of ethanol with (10% Na OH) to yield (84%)  compound [9], which (0.01mol) refluxed with (0.02mol) of  thiourea in presence  of ethanol with  5ml (HCl), then filtered and dried, recrystallized to yield (84%)  compound [10].

 

 

 

 

RESULTS  AND  DISCUSSIONS:

This study involved, synthesis of heterocyclic compounds (five and six) –membered rings such as  thiadiazol  and  oxadiazol with  thiazin  rings, these compounds [1-10] contain imidazole  and  thiazol in their structures which cause biological activity. All synthesized compounds [1-9] have been characterized by spectrophotometer chemical methods [FT.IR, H.NMR, (C.H.N)- analysis], melting points  and  physical  properties with  biological study :

 

The FT.IR- spectrum : showed an absorption band at 1722 cm^-1 due to carbonyl of ester (-COO-) in compound [1], which disappeared and other bands appeared such as 1690 cm^-1 for carbonyl of amide (CO-NH), bands at (3290 cm^-1, 3310 cm^-1) for amine group (NH₂) in compound [3] ,band at (1686)cm^-1 for carbonyl of amide (CO-NH) in compound [4], bands at (1604, 1618)cm^-1 for (C=N) end o cycle of oxadiazol rings and (3280, 3300) cm^-1 for primary amine group (NH₂) in compound [5] . other bands at 1630 cm^-1 for (C=N) and 782 cm^-1 for (C-S) of thiazol ring in compound [6], band at 3102 cm^-1 for (=CH) alkene in compound [7]., bands at {1710 cm^-1 for carbonyl of aldehyde (CO-H), 1728 cm^-1 for carbonyl of ester, 1230 cm^-1 for (C-O-C) ether in compound [8]., bands at 1728 cm^-1 for carbonyl of ester, 1687 cm^-1 for carbonyl of chalcone, 1235 cm^-1 for (C-O-C) ether, 3110 cm^-1 for (CH=CH) alkene in compound [9], bands at (3280, 3300) cm^-1 for primary amine group (-NH₂), 1725 cm^-1 for carbonyl of ester, 3105 cm^-1 for (=CH) alkene, 1235 cm^-1 for (C-O-C) ether, 795 cm^-1 for (C-S) in thiazine ring in compound [10]., and other bands^(10-13) listed in table (1) .

 

 

Table (1): FT.IR-data (cm^-1) of  Compounds [1-10]

Comp. No.	(C=N) endocycle	NH , NH2	(-COO)	Other groups
[1]	1610	3190	1722	(CH)aliph : 2982
[2]	1608	3205	/	(CH) aliph : 2955., (CO-NH) amide: 1690
[3]	1605, 1618	3290,3310	/	(CH) aliph: 2975
[4]	1610	3220	/	(CH) aliph: 2982., (CO-NH) amide: 1686
[5]	1604, 1618	3280,3300	/	(CH) aliph: 2998
[6]	1612	/	/	(CH) aliph: 2981., (C=N): 1626 (C-S): 782
[7]	1608	/	/	(CH)aliph: 2973., (C=N): 1630., (=CH) alkene: 3102
[8]	/	/	1728	(CO-H) carbonyl of aldehyde: 1710., (C.O.C)ether: 1230., (CH)aliph: 2965., (CH) arom: 3080
[9]	/	/	1720	(CO-CH=CH) chalcone: 1687., (C-O-C)ether: 1235., (CH)aliph: 2990., (CH=CH): 3110
[10]	1614	3280,3300	1725	(=CH)alkene: 3105., (C-O-C)ether: 1242., (CH) aliph: 2982., (CH)arom: 3040., (C-S): 795

 

 

Fig ( 1 ) : FT.IR  of  Compound [ 2 ]

 

Fig ( 2 ) : FT.IR  of  Compound [ 6 ]

 

Fig ( 3 ) : FT.IR  of  Compound [ 7 ]

 

Fig ( 4 ) : FT.IR  of  Compound [ 10 ]

 

 

H.NMR- spectrum: showed signals at δ (3.8-4.30) for (COOC₂H₅) ethyl of  ester in compound [1], which disappeared and other signals appeared at  δ(5.0 , 5.25 , 5.34) for (NH₂ , NH) , δ 10.02 for (NH-CO) amide in compound [2], signals at δ(4.09, 5.20) for (NH₂ , NH) groups in compound [3] ,signals at  δ(5.10, 5.25) for (NH) groups, signals at δ(10.04- 10.28) for amide groups (NH-CO) in compound [4],signals at  δ(5.21, 5.03) for (NH, NH₂) amine groups in compound [5], signals at δ(7.93) for protons of thiazol ring in compound [6], signal at  δ 6.04  for alkene (C=CH), signal at  δ 7.10 for protons of phenyl group., signals at  δ 3.98 for ester (COOCH₂-), signal at δ 11.82 for proton of aldehyde group (CO-H), signals at  δ (6.9- 7.4) for protons of phenyl groups in compound [8]., signals at δ 3.86 for ester (COOCH₂-), signals at δ (6.52- 7.63) for protons of phenyl groups, signals at δ (5.72 , 5.85) for alkene (CH=CH) in compound [9], signals at δ 5.08 for (NH₂), signal at δ 3.94 for ester (COOCH₂-) ,signals at δ(6.76 - 7.54) for protons of phenyl groups., and other signals for functional groups^(14-17) are listed in table (2) .

 

Table (2): ¹H.NMR - data (δ, ppm) of compounds [1-10]

Comp. No.	NH , NH2	(COOCH2-) ester	(CH2), (CH3)	Other groups
[1]	5.02	(3.8- 4.30)	0.95, 1.15	Protons of imidazole ring : 7.8
[2]	5.0 , 5.25 , 5.34	/	1.0 , 1.15	Protons of imidazole ring : 7.86., (CO-NH) amide: 10.02
[3]	5.09, 5.20	/	0.98, 1.18	Protons of imidazole ring : 7.91
[4]	5.10 , 5.25	/	1.0 , 1.20	Protons of imidazole ring : 7.84., (CO-NH) amide and (CO-NH2): (10.04-10.28)
[5]	5.21, 5.03	/	0.96, 1.13	Protons of imidazole ring : 7.81
[6]	/	/	1.04, 1.21	Protons of thiazol ring : 7.93
[7]	/	/	1.03	Protons of thiazol ring : 7.78., (C=CH): 6.04., Phenyl ring: 7.10 .
[8]	/	3.98	/	(HC=O) aldehyde: 11.82., Phenyl rings (6.9- 7.4)
[9]	/	3.86	/	Phenyl rings : 6.52- 7.63., (CH=CH) chalcone: 5.72, 5.85
[10]	5.08	3.94	/	Phenyl rings : 6.76- 7.54 .

 

 

Fig ( 5 ) : H.NMR  of  Compound [ 8 ]

 

Fig ( 6 ) : H.NMR  of  Compound [ 9 ]

 

Fig ( 7 ) : H.NMR  of  Compound [ 10 ]

 

The (C.H.N)- analysis : the microanalytical of carbon, Hydrogen , Nitrogen atoms, melting points, solubility and other physical properties are listed in tables (3) and (4).

 

Table (3): Physical properties and (C.H.N)- analysis of compounds [1-10]

 

 

 

Table (4): Analytical properties of compounds

 

 

 

Biological  Study: ^{(8 , 9)}

Bacteria supplied from bio-Lab in college of Education .,antimicrobial activity was tested by the filtered paper disc diffusion method against gram (+) positive bacteria (Staphylococcus aureus ) and gram (-) negative bacteria (E-coli),  (0.1mol) of the bacterial suspensions was seeded on agar .To determine minimum inhibitory concentration (MIC) for each compounds [1-10] were performed with  two  replicates .

 

Generally, the results showed that the compounds [1-10] have good inhibitory effect against tested bacteria.  Table (5) showed the zone of inhibition of the compounds [1-10] in this study ranged (from 32 to 10) mm . from results , we noted the compounds [3, 5, 7, 10] have higher antibacterial activity against two type of bacteria (G+  and  G-) due to their structures (consist of thiazole and imidazole rings with thiazine rings) consequently ,which it become more effective in precipitating proteins on bacteria.

 

Table (5): Antibacterial Activity of Compounds [1-10]

Compounds	Diameter of zone (MM)
	G+ :  Staphylococcus aureus	G- : E-coil
Compound [1]	16	14
Compound [2]	22	16
Compound [3]	32	28
Compound [4]	18	12
Compound [5]	30	24
Compound [6]	24	16
Compound [7]	26	20
Compound [8]	14	10
Compound [9]	14	8
Compound [10]	28	20

 

REFERENCES:

1.        Tranveer. A and Arvind. K., Int. J. Chem. Sci., 11, 1, 539- 545, 2013 .

2.        Firas. A., Int. J. Res. Pharm. Chem., 2, 1, 58-65, 2012 .

3.        Ibtisam. K., Kerb. J. Pharm. Sci., 2, 196-112, 2011 .

4.        Jitendra. K, Rupesh. D and Sharma. P., Med. Chem. Online., 1, 1001, 1-10, 2010 .

5.        Alaa. H, Jawad .K, Ahmed. A and Mustafa. M., Int. J. Res. Pharm. Chem., 2, 4, 2012 .

6.        Zeki. A, Hanan. A and  Suha. K., Chem. Mat. Res., 7, 6, 50-56, 2015 .

7.        Dangi. R and Chundawat. N., World. J. Pharm. Res., 4, 2, 1292 -1298, 2015 .

8.        Nagham. Aljamali., J. Appl. Phys. Bio Chem. Res., 5, 1, 1-8, 2015 .

9.        Nagham. Aljamali., Res. J. Pharm. Tech., 8, 1, 78-84, 2015 .

10.     Mahgoub. H, Amna. B and Saeed. A., Int. J. Pharm. Sci. Res., 5, 11, 5050- 5056, 2014 .

11.     Navgeet. K, Ajay. K, Neha. S and Balram. C ., Int. J. Pharm. Sci. and Drug Res., 4, 3, 199- 204, 2012 .

12.     Ritabamnela .A and Shrivastava. S., E- Journal Chem., 7, 3, 935- 941, 2010 .

13.     Gupta. J, Sharma .P, Dudhe. R, Chandhary. A and Verma. P., Anal .Uni. din. Buc. Chem., 19, 2, 9-21, 2010 .

14.     Jubie. S, Rajesh Kumar. R, Yellarwddy. B, Siddhartha. G, Sandeep. M, Surndararedy. K, Dushyanth. H and Elango. K., J. Pharm. Sci. and Res., 2, 2, 69-76, 2010 .

15.     Ahlam. M and suroor .A., Bagh. Sci. J., 7, 1, 1-13, 2010 .

16.     Devdatta. V, seema. I and Prafullkumar. A., Int. J. chem. Sci., 12, 4, 1635- 1644, 2014 .

17.     Bhupendra. K, Suresh. C and Vijay. K., Int. J. chem. Sci., 12,4, 1121- 1134, 2014 .

 

 

 

 

 

Received on 14.07.2015         Modified on 20.07.2015

Accepted on 28.07.2015         © AJRC All right reserved

Asian J. Research Chem. 8(7): July- 2015 ; Page 493-500