Synthesis, Characterization and CNS Depressant Activity of Some Schiff Bases of 2-Amino-4-(4-Chlorophenyl)Thiophene-3carboxamide

 

Shivaji Bhattacharjee*, J. Saravanan and S. Mohan

Department of Pharmaceutical Chemistry, PES College of Pharmacy, Bangalore-50, Karnataka, India.

*Corresponding Author E-mail: bhattacharjee.shivaji@gmail.com

ABSTRACT:

2-amino-4-(4-chlorophenyl)thiophene-3carboxamide was synthesized using versatile Gewald reaction conditions started with the preparation of acetamide, which was carried out by cold condensation of aniline and ethylcynoacetate, which was then reacted with p-chloro acetophenone, sulphur, diethyl amine to give 2-amino-4-(4-chlorophenyl)thiophene-3carboxamide. Later the compound was treated with twelve different substituted aryl aldehydes to yield twelve new Schiff bases (SBJ-Ia-l). The compounds were characterized by IR, 1H NMR and Mass spectral data and screened for CNS depressant activity.

 

 

 

INTRODUCTION:

Heterocyclic compounds containing sulphur have a number of pharmacological activities. Thiophene, is a sulphur containing heterocyclic moiety which has essential role in drug development in pharmaceutical industry¹. Thiophene containing molecules have several pharmacological activities such as antimicrobial², anti-inflammatory³, antioxidant⁴, antitumor⁵, analgesic⁶ and so on. On the other hand Schiff base derivatives also have been reported to possess an array of biological activities^7-8. The above reports encouraged us to synthesis novel benzo(b)thiophene and their Schiff base derivatives, characterize the compounds by IR,NMR and Mass spectroscopic techniques,  and evaluate them for CNS depressant activity.

 

MATERIALS AND METHOD:

Chemicals:

Aniline, ethylcyanoacetate, p-chloro acetophenone, sulphur, 4’-di methyl amino benzaldehyde, 4’-hydroxy benzaldehyde, 2’-nitro benzaldehyde, 3’-nitro benzaldehyde, 3’,4’,5’-trimethoxy benzaldehyde, 2’-hydroxy benzaldehyde, 4’-hydroxy 3’-methoxy benzaldehyde, 2’-chloro benzaldehyde, 4’-methoxy benzaldehyde, 3’,4’-dimethoxy, 4’-chloro benzaldehyde, 4’-methyl benzaldehyde were obtained from local dealer. All other chemicals used where of laboratory grade.

 

Preparation of 3-(4-Chlorophenyl)-2-cyanobut-2-enamide:

Cyanoacetamide was prepared by cold condensation of aniline and ethylcyanoacetate (1:1), which was then refluxed with equimolar p-chloro acetophenon, ammonium acetate (1gm) and glacial acetic acid (2 ml) in benzene (100 ml) for 12 hours in Dean Stark apparatus with continuous separation of water. After 12 hours the reaction mixture was cooled. On cooling the mixture turned to fine crystalline solid, which was used for the next step directly.

 

Preparation of  2-amino-4-(4-chlorophenyl)thiophene-3carboxamide SBJ-I:

To a mixture of 3-(4-Chlorophenyl)-2-cyanobut-2-enamide in alcohol (40 ml) and sulphur (1.28 gm) at 45º-50ºC, diethyl amine (4.0 ml) was added drop wise with stirring. The reaction was stirred for further 3 hr at same temperature. The reaction mixture was chilled over night and poured on crushed ice, the solid obtained was filtered, washed with ethanol and crystallized from 2-propanol. 40% M.P- 131ºC.

 

Preparation of 2-[(substituted benzylidene) amino]-4-(4- chloro phenyl) thiophene SBJ-Ia-l:

A mixture of equimolar amount (0.01) of 2-amino thiophene, benzaldehyde derivatives (a-l) in ethanol (40 ml) and glacial acetic acid (0.3 ml) was refluxed for 2 hrs on water bath. The reaction mixture was concentrated, cooled, the solid obtained was filtered and recrystallised from ethanol to give Schiff base (SBJ-Ia-l). It was obtained in 60-65% yield.

 

 

 

CNS Depressant activity:

The CNS depressant activity of the compounds was studied on mice using pentobarbitone induced sleep method. In this method, mice of either sex weighing 25-30 gm were randomly taken and divided into control, standard and different test groups, each group contain six animals. Group I served as control and treated with normal saline (10 ml/kg, i.p.), group II (standard) treated with standard drug chlorpromazine hydrochloride (1mg/kg, i.m.) 15 min before the administration of pentobarbitone (40mg/kg, i.p.). Test groups III-VIII were treated with (100 mg/kg, i.p). Pentobarbitone (40mg/kg, i.p.) was administered 30 min later. Onset of sleep and duration of sleep measured for the entire group. Onset of action was recorded by noting the time of loss of reflex for three consecutive trials, duration of sleep recorded by time difference between loss of righting reflex and recovery time.

 

Scheme

 

Table-1 Physical data of 2-amino-4-(4-chlorophenyl)thiophene-3carboxamide SBJ-I

Comp. Code	Molecular Formula	M.W(g)	Recrystalization Solvent	M.P(0C)	%Yield	T.L.C Solvent	Rf Value
SBJ-I	C11H9ClN2OS	252	2-propanol	172	40	Methanol: Chloroform(9:1)	0.69

 

 

Table-2 Physical data of 2-[(substituted benzylidene)amino]-4-(4-chlorophenyl) thiophene SBJ-Ia-l

Comp Code	X	Molecular Formula	M.W(g)	M.P (0C)	%Yield	T.L.C Solvent	Rf Value
SBJ-Ia	4’-di methyl amino benzaldehyde	C20H18 ClN3OS	383	203	54	Methanol: Chloroform(9:1)	0.45
SBJ-Ib	4’-hydroxy benzaldehyde	C18H13 ClN2O2S	356	223	57	Methanol: Chloroform(9:1)	0.63
SBJ-Ic	2’-nitro benzaldehyde	C18H12 ClN3O3S	275	205	54	Methanol: Chloroform(9:1)	0.32
SBJ-Id	3’-nitro benzaldehyde	C18H12 ClN3O3S	275	212	58	Methanol: Chloroform(9:1)	0.46
SBJ-Ie	3’,4’,5’-trimethoxy benzaldehyde	C21H19 ClN2O4S	430	205	50	Methanol: Chloroform(9:1)	0.72
SBJ-If	2’-hydroxy benzaldehyde	C18H13ClN2O2S	356	172	57	Methanol: Chloroform(9:1)	0.69
SBJ-Ig	4’-hydroxy 3’-methoxy benzaldehyde	C18H15ClN2O3S	386	185	51	Methanol: Chloroform(9:1)	0.45
SBJ-Ih	2’-chloro benzaldehyde	C18H12Cl2N2OS	374	191	70	Methanol: Chloroform(9:1)	0.64
SBJ-IIIi	4’-methoxy benzaldehyde	C19H15ClN2O2S	370	189	71	Methanol: Chloroform(9:1)	0.62
SBJ-Ij	3’,4’-dimethoxy	C20H17ClN2O3S	400	180	77	Methanol: Chloroform(9:1)	0.72
SBJ-Ik	4’-chloro benzaldehyde	C18H12Cl2N2O2S	374	173	50	Methanol: Chloroform(9:1)	0.68
SBJ-Il	4’-methyl benzaldehyde	C19H15ClN2O2S	370	167	70	Methanol: Chloroform(9:1)	0.69

 

Table-3 Spectral data of 2-amino-4-(4-chlorophenyl)thiophene-3carboxamide SBJ-I

Comp Code	λ max. (nm)	IR	1 H NMR
SBJ-I	143	3298(NH);1652(C=O);752(C-Cl).3050(ArCH);1559 cm-1(Ar-C=C) 778.75 (C-S)	7.4-7.6(2H,m.aromatic H)7.3-7.4(2H,m.aromaticH)7.4 (2H,s,NH2of amide)6.9(1H,s H of thiophene)5.5(2H,s,of NH2) 775.75 (C-S)

 

Table-4 Spectral data of Physical data of 2-[(substituted benzylidene) amino]-4-(4-chlorophenyl) thiophene SBJ-Ia-l

X	λmax. (nm)	IR	1 H NMR	Mass
4’-di methyl amino benzaldehyde	211	3736cm-1(NH);1667cm-1(C=O); 1610 cm-1,1526 cm-1(Ar-C=C) ; 1605 cm-1(-N=CH); 1188 cm-1(C=N) 778.75 (C-S)		383
4’-hydroxy benzaldehyde	245	3245 cm-1(OH);  3261 cm-1(NH); 1647 cm-1(C=O);1605 cm-1(-N=CH); 1614 cm-1,1559 cm-1(Ar-C=C); 1227 cm-1(C-N) 778.56 (C-S)
2’-nitro benzaldehyde	218	3271.70 cm-1(NH); 1683.91 cm-1(C=O); 1624 cm-1(-N=CH);1485 cm-1(Ar-C=C); 1315 cm-1(NO2). 777 (C-S)
3’-nitro benzaldehyde	254	2929 cm-1(NH); 1664 cm-1(C=O);1646.08 cm-1(-N=CH); 1351 cm-1(Ar-C=C) ;1540 cm-1(m)(C-N);1348 cm-1, 1348 cm-1(NO2) 778 (C-S)		275
3’,4’,5’-trimethoxy benzaldehyde	235	3226 cm-1(NH); 1669 cm-1(C=O); 1614 cm-1,1508 cm-1(ArC=C); 1665 cm-1(-N=CH); 1302 cm-1(CN);1099 cm-1(-C-0-C) 772.75 (C-S)	8.5(1H, s,of N=CH),7.3-7.5(2H,m.aromatic H)7.4-7.5(4H,m.aromaticH)7.4 (2H,s,NH2of amide)6.9(1H,s H of thiophene)3.8(9H,s,of OCH3)
2’-hydroxy benzaldehyde	251	3400 cm-1(s)(OH);  3064 cm-1(NH); 1669.93 cm-1(C=O); 1676 cm-1(-N=CH); 1614 cm-1,1522 cm-1(Ar-C=C);1319 cm-1(C-N) 778.67 (C-S)
4’-hydroxy 3’-methoxy benzaldehyde	267	3249 cm-1(NH); 1650 cm-1(C=O); 1600 cm-1,1558 cm-1(Ar-C=C); 1654 cm-1(-N=CH); 1294 cm-1(C-N) 1200 cm-1(C-F);1035 cm-1(-C-0-C) 778.75 (C-S)	8.5(1H, s,of N=CH),7.5-7.7(8H,m.aromatic H)7.4(2H,s,NH2of amide)6.7(1H,s,of OH) 6.9(1H,s H of thiophene)3.8(3H,s,of OCH3 )
2’-chloro benzaldehyde	283	332 cm-1(NH); 1669 cm-1(C=O); 1639(N=CH);1610 cm-1,1550 cm-1(Ar-C=C);1319 cm-1(C-N) ;742 cm-1(C-Cl) 778.53 (C-S)	8.8(1H, s,of N=CH),7.7-7.6(2H,m.aromatic H)7.6-7.5(2H,m.aromaticH)7.4 (2H,s,NH2of amide)7.35-7(4H,m.aromatic H) 6.9(1H,s H of thiophene)
4’-methoxy benzaldehyde	265	3070 cm-1(NH); 1672cm-1(C=O); 1648(N=CH)1581 cm-1,1454 cm-1(Ar-C=C); 1251 cm-1(C-N) ,2929 cm-1 (Ali-CH) 779.62 (C-S)
3’,4’-dimethoxy	250	3232(NH);1667(C=O);1638(N=C H);1208(C-F);3018(Ar-CH);2929(Ali-CH) 771.75 (C-S)	8.45(1H, s,of N=CH),7.3-7.5(2H,m.aromatic H)7.5-7.6(4H,m.aromaticH)7.4 (2H,s,NH2of,amide)6.7(1H,s H of thiophene)3.5(6H,s,of OCH3)	400
4’-chloro benzaldehyde	223	3232(NH);1597(C=O);1640(N=CH);1019(C-N);100(Ar-CH);2929(Ali-CH) 770.75 (C-S)
4’-methyl benzaldehyde	214	3232(NH);1667(C=O);1638(N=C H);3018(Ar-CH);2929(Ali-CH) 778.43 (C-S)

 

Table 5  Prolongation of pentobarbital-induced sleeping time by the compound SBJ-Ia-l

Comp Code	Dose (mg/kg)	Onset of sleep(min)	Duration of Sleep (min)
SBJ-Ia	100	5.75±0.25	71.00±1.87
SBJ-Ib	100	7.50±0.29	69.50±2.06*
SBJ-Ic	100	5.00±0.205*	101.75±2.135*
SBJ-Id	100	7.75±0.79	70.25±2.625
SBJ-Ie	100	7.25±0.855	75.25±1.03
SBJ-If	100	8.75±0.48	74.75±1.88
SBJ-Ig	100	6.00±0.41	63.50±1.89
SBJ-Ih	100	8.25±0.48	74.25±2.17
SBJ-IIIi	100	8.25±0.25*	100.5±3.07*
SBJ-Ij	100	7.75±0.25	66.75±2.84
SBJ-Ik	100	6.75±0.48	79.00±1.58
SBJ-Il	100	3.50±0.29*	106.25±0.95*
Chlorpromazine	1	4.75±0.48*	128.25±1.89*
Pentobarbitone	40	7.75±0.63	56.25±1.04

Values are expressed in Mean±SEM, n = 6, ^*Indicates significant difference at p<0.001 when compared to control

 

 

RESULT:

The result of pentobarbitone induced sleeping time test showed that the newly synthesized derivatives SBJ-Ia-l have moderate to good CNS depressant activity. Table 5 showed that compounds SBJ-Ib, SBJ-Ic, SBJ-Ii and SBJ-Il at dose 100mg/kg produced significant reduction in the onset and prolongation of sleep duration induced by pentobarbitone. The other derivatives also showed comparable result to that of the standard drug chlorpromazine.

 

DISCUSSION:

From the IR, 1H NMR and Mass spectra obtained, characterization of data has been done and given in table 1,2, 3 and 4. The IR spectrum of 2-amino-4-(4-chlorophenyl) thiophene-3carboxamide (SBJ-I) shows the –NH2 peak at 3298 cm-1. The NMR spectrum shows a broad peak at δ = 5.5 of –NH2.

 

The IR spectra of all the Schiff bases show the disappearance of –NH2 peak and the appearance of –N=CH (Imine) peak at a range of 1690-1640 cm-1, which clearly suggest the formation of the expected compounds. The NMR spectra of the compounds SBJ-Ie, SBJ-Ig, SBJ-Ih and SBJ-Ij show sharp singlet peak at the range of δ = 8.4- 8.8 of –N=CH (Imine-H) which also further confirm the formation of the compounds of the series. The compounds SBJ-Ia, SBJ-id and SBJ-Ij were also confirmed by Mass spectrum.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Management, PES College of Pharmacy for providing necessary facilities.

 

REFERENCE:

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Received on 18.07.2011        Modified on 02.08.2011

Accepted on 14.08.2011        © AJRC All right reserved