Synthesis of Substituted Thienopyrimidines and Their Evaluation as Antibacterial

 

Rahul More1, J. N. Narendra Sharath Chandra1, Shachindra. L. Nargund2 L.V.G. Nargund1*

1Department of Pharmaceutical Chemistry, Nargund College of Pharmacy, Dattatreya Nagar, II main,

100 Ft Ring Road, BSK II Stage, Bangalore- 560085 (India).

2Department of Chemistry, Texas State University, San Marcos, USA

*Corresponding Author E-mail: lvgnargund@gmail.com

 

ABSTRACT:

We have synthesized various substituted thieno(2,3-d)pyrimidines, first by synthesizing ethyl 2-aminothiophene-3-carboxylate (3), by treatment of diethane with ethyl cynoacetate in presence of triethylamine, acetic acid and DMF. Further, the intermediate Ethyl 2-(ethoxycarbonyl)thiophene-3-carboxylate (5) was prepared by  compound (3) refluxed with ethyl chloroformate. The key intermediate 3-(3-chloro-4-fluorophenyl) thieno [2, 3-d]pyrimidine-2, 4(1H, 3H)-dione (7) was  prepared by cyclisation of compound (5)  with 3-chloro-4-fluoro aniline. The nucleophilic substitution of compound 3-(3-chloro-4-fluorophenyl) thieno [2, 3-d]pyrimidine-2, 4(1 H, 3 H)-dione (7) with various aromatic amines(8a-m), aminophenol(8n) gives substituted thienopyrimidines(8a-n). The synthesized new compounds were characterized by MP, TLC, IR and NMR spectra.

 

KEYWORDS: Thienopyrimidine

 


INTRODUCTION:

The known approaches to the synthesis of thienopyrimidines can be divided into two main groups: the construction of the pyrimidine ring by intramolecular cyclization of thiophene derivatives and the thiophene ring closure in pyrimidine derivatives.

 

Synthetic approaches to the construction of thienopyrimidines are sufficiently well developed. Three possible types of annelation of thiophene to the pyrimidine ring and correspondingly, Three isomeric thieno pyrimidines are known: thieno[2,3-d]pyrimidine, thieno[3,2-d]pyrimidine, and thieno[3,4-d]pyrimidine.

 

Condensed thienopyrimidines exhibit interesting biological activity like antibacterial1-6, anticancer 7-10, aldose reductase inhibitor 11, 12, antiviral activity 13-14, anti-inflammatory and analgesic 15-16, anticonvulsant 17, antipsychotic18, DHFR inhibitory19, VEGFR-2 kinase inhibitors 20, tyrosine kinase inhibitors21, adenosine receptor binding properties22.

 

In continuation with our past research on synthesizing a novel class of thienopyrimidines and testing them for appropriate pharmacological activity. Here in, we are presenting synthesis of substituted thieno(2,3-d)pyrimidines  8(a-n) and their antibacterial activities.

 

Bacteria that resist the effects of the most powerful antibiotics are posing a great challenge to the field of medicines. Thus scientists are working to find new ways to defeat bacteria, which are increasingly resistant to the antibiotics already available.

 

To achieve the above mentioned target, scientists have utilized the concept of bioisosterism. It has been defined as group of molecules, which have chemical and physical similarities producing broadly similar biological properties. It is now known that many heterocycles, when appropriately substituted exhibits bioisosterism. Thienopyrimidines occupy a special position among these as these are the structural analogs of biogenic purines. It has been well established, that thienopyrimidines are bioisosteres of quinazolines.

 


 

SCHEME: Synthesis of substituted thienopyrimidines 8(a-n)

 


 

EXPERIMENTAL:

Melting points were determined by Thiel’s melting point tube( capillary tube method). I.R. were recorded on Shimadzu 8700 spectrophotometer using KBr. 1HNMR spectral data of the compound was carried out in Brucker 200 spectrospin NMR using DMSO as internal standard.

 

Synthesis of ethyl 2-aminothiophene-3-carboxylate (3)23:

Dithiane(1)(0.013mol, 2 gm), Ethylcynoacetate(2)(0.038mol, 2.73ml) and DMF (20ml) were taken in RBF. Triethylamine(3.3ml) added dropwise with constant stirring and ice cold condition. Stirring was continued for 2-3 hr. Then acetic acid( 0.4mole,54.4ml) added in solution. The reaction mixture  was extracted with ether  and evaporate  ether. The product was dried and recrystallized from ethanol. Then melting point was determined and found to be 41oc.

 

Synthesis of ethyl 2-(ethoxycarbonyl)thiophene-3-carboxylate (5):[26]

Ethyl 2-aminothiophene-3-carboxylate(3) (0.0158mol, 2.7gm)  and chloroformate(4)  (15 ml) was refluxed for 3 hr. After cooling ,  the reaction mixture was evaporated under reduced pressure.  The residue was in liquid form. 

 

Synthesis of 3-(3-chloro-4-fluorophenyl) thieno [2, 3-d] pyrimidine-2, 4(1h, 3h)-dione (7):[27]

Ethyl 2-(ethoxycarbonyl)thiophene-3-carboxylate(5)(1ml) and  3-chloro 4-fluoro aniline(6)(4.5mol,0.65gm) was heated 120- 130o c for  4 hr. After cooling ,the crude solid was recrystallized from ethanol/ water. The % yield of  product was 60%.  The melting point was determined and found to be 240- 2420c.

 

Synthesis of 3-(3-substituted-4-fluorophenyl) thieno [2, 3-d]pyrimidine-2, 4(1h, 3h)-dione  by using different substituents (8 a-n):

3-(3-chloro-4-fluorophenyl) thieno [2, 3-d]pyrimidine-2, 4(1H, 3H)-dione(7)(0.01mol),  R[8(a-n)](0.01mol), DMF(20ml) and pinch of K2CO3 was added and refluxed for 6-8 hrs. The reaction mixture was cooled and filtered. The filtered compounds (75a-n) was dried and recrystallized using ethanol. Melting point were determined.

 

Antibacterial activity24

Anti-microbial activity is determined based on the in-vitro activity is assayed against Staphylococcus aureus (Gram +ve) and Escherchia coli (Gram –ve). disc were punched from Whatman no 1 filter paper were sterilized at 161 oC for 1 hr.All the glass wares were sterilized at 161 oC for 1 hr. Muller Hindon Agar (M-173), while hot was poured into sterilized Petri dishes (20-25 ml in each Petri dish) and allowed to attain room temperature. The agar plates are inoculated with 18-24 hrs test culture by spreading uniformly  with sterile swabs. The open plates were then allowed to dry in the inverted position in an incubator for 30 minutes. One disc from each sample was placed in Petri dishes with sterile fine pointed forceps. The dishes were incubated for 24 hrs at 37 oC. After 24 hrs the antibacterial activity was found out by the measuring inhibition zones in mm. For all tests the quantity of the test compounds used 100 µg/ml. These values were compared with the values obtained for standard i.e. Ampicillin. All the compounds possessed weak to moderate antibacterial activity.

 

RESULTS AND DISCUSSION:

The synthetic pathway depicited in (scheme)  outlines chemistry of present study. Treatment of diethiane with ethyl cynoacetate in presence of triethylamine, acetic acid and DMF resulted in cyclic compound Ethyl 2-aminothiophene-3-carboxylate (3). The IR spectrum of compound  (3) has shown intense peak at 3412.19 and3304.17 cm-1 for amino(NH2) and 1654.98  cm-1 for carbonyl(c=o) stretching. .

 

Further, the intermediate Ethyl 2-(ethoxycarbonyl)thiophene-3-carboxylate (5) was prepared from  compound 70 by refluxing with ethyl chloroformate. IR spectrum of compound (5) has  shown intense peak at 3296.46 cm-1 for amine, 1730.21  cm-1 for carbonyl (c=o) stretching . 1H NMR spectrum(5) has shown the signal at δ 10.21 for NH, δ 7.152, 6.629  for aromatic proton and δ 4.182-4.3497 for aliphatic proton.

 

The key intermediate 3-(3-chloro-4-fluorophenyl) thieno [2, 3-d]pyrimidine-2, 4(1H, 3H)-dione (7) was  prepared by cyclisation of compound (5)  with 3-chloro 4-fluoro aniline with refluxing 3-5 hr. IR spectrum of compound (7)  has shown  intense signal  at 3321.53  cm-1  for NH stretching  and  at 1658.84   cm-1  for carbonyl (c=o) stretching. 1H NMR spectrum(7) shown the signal at δ 9.5226 for N-H, δ  7.0921 to δ  8.7017 for aromatic proton.

 

To investigate the SAR of synthesized  derivatives  (8a-n),  it has been selected third position, based on the literature support. In this regard we have prepared the same by nucleophilic substitution  with different substituted aromatic primary amines or heterocyclic secondary amines.

Substituted thieno(2,3d)pyrimidines (8a-n) were evaluated for their antibacterial  activity. Antibacterial activity of synthesized compounds was performed by agar diffusion method. The result of it indicates that the test compounds 8b-h and 8k exhibited  for antibacterial activity, in which compound 8b, 8h and 8e showed good antibacterial activity. Compounds 8c, 8d, 8f and 8g shown  moderate activity  whereas compounds 8i, 8j, 8l-n have shown poor antibacterial activity.

 

Table-1: Characterization data of the synthesized compounds

8(a-n)

S.

NO.

C.C.*

R

Molecular Formula

Mol. wt.

%

Yield

m.p.

(°C)

Rf

Value

Solvent

 system

 

1.

 

8a

 

F-Cl aniline

 

C18H10N3O2SF2Cl

 

404

 

62 %

 

235

 

0.55

 

EA:Hex  1:1

2.

8b

4-Cl aniline

C18H11N3O2SFCl

387

55 %

245

0.45

EA:Hex  1:1

3.

8c

2-Cl aniline

C18H11N3O2SFCl

387

71 %

242

0.55

EA:Hex  1:1

4.

8d

3-Cl aniline

C18H11N3O2SFCl

387

63 %

238

0.57

EA:Hex  1:1

5.

8e

Aniline

C18H11N3O2SF

353

52 %

206

0.35

EA:Hex  1:1

6.

8f

n-methyl piperazine

C17H13N4O2SF

360

54 %

203

0.55

EA:Hex  1:1

7.

8g

-Piperidine

C17H11N3O2SF

345

51 %

210

0.55

EA:Hex  1:1

8.

8h

piperazine

C16H11N4O2SF

346

52%

198

0.57

EA:Hex  1:1

9.

8i

Pyrrolidine

C16H11N3O2SF

331

68%

168

0.46

EA:Hex  1:1

10.

11.

12.

13.

14.         

8j

8k

8l

8m

8n

2-nitro aniline

3-nitro aniline

4-nitro aniline

Diethylamine

2-amino phenol

C18H10N3O4SF  C18H10N3O4SF

 C18H10N3O4SF C16H16N3O2SF C18H12N3O3SF

 

362

362

362

333

369

48%

43%

58%

64%

66%

196

185

176

253

173

0.41

0.48

0.67

0.54

0.74

EA:Hex  1:1

EA:Hex  1:1

EA:Hex  1:1

EA:Hex  1:1

EA:Hex  1:1

 

                

                                                


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table-2: Antibacterial evaluation data of the synthesized compounds

Sl. No.

Comp.

Code

Zone of Inhibition (Diameter in mm)

Staphylococcus aureus (+ve)

Bacillus subtillis

(-ve)

100 μg/ml

      100 μg/ml

   1.

       8a

 

   07

 

        08

   2.

       8b

   10

        11

   3.

       8c

   08

        09

   4.

       8d

   09

        08

   5.

       8e

   12

        10

   6.

   7.

   8.

   9.

  10.

  11.

  12.

  13.

  14.

  15.

       8f

       8g

       8h

       8i

       8j

       8k

       8l

       8m

       8n

    control

   10

   11

   12

   08

   08

   10

   07

   06

   06

   NA 

        10

        10

        13

        08

        08

        09

        07

        07

        06

        NA

Standard: Ampicillin = 14mm for gm+ve and 16mm for gm –ve at   100 μg/ml   NA= No Activity

 

 

SPECTRAL DATA OF SOME OF THE SYNTHESIZED COMPOUNDS:

2-aminothiophene-3-carboxylate(3)

IR(KBr) (cm-1): 3412.19 and3304.17 (N-H ) ; 2995.55,2901 (C-H ) ; 1654.98 (C=O);  1325.99 (C-N).s

 

Ethyl 2-(ethoxycarbonyl)thiophene-3-carboxylate(5):

IR(KBr) (cm-1): 3296.46 (N-H ) ; 2962.05 (C-H ) ; 1730.21 (C=O); 1384.94 (C-N).

1H NMR (CDCL3), 200 MHz) δ (ppm): 10.219(N-H); 6.629 and 6.9279(Ar-H); 4.110-4.385 and 1.154-1.409 (Ester proton)

 

3-(3-chloro-4-fluorophenyl) thieno [2, 3-d] pyrimidine-2, 4(1h, 3h)-dione (7):

IR(KBr) (cm-1): 3321.53(N-H ); 2950 (C-H) ; 1658.84 (C=O);  1304.94(C-N); 1220.29(C-F) ; 713.69(C-Cl).

1H NMR (DMSO, 200 MHz) δ (ppm): 8.7(N-H); 7.336-7.898(Ar- H)

 

3-(3-(3-chloro-4-fluorophenylamino)-4-fluorophenyl)thieno[2,3-d]pyrimidine-2,4(1 h,3 h)-dione.(8a)

IR(KBr) (cm-1): 3227.82 (N-H ) ; 3130.36,2979.19(C-H ) ; 1680.06 (C=O) ;  1321(C-N)  ;  1263.42 (C-F) ; 761.91 (C-Cl).

 

3-(3-(4-chlorophenylamino)-4-fluorophenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione .(8b)

IR(KBr) (cm-1): 3439.19  (N-H ) ; 3174.94, 2812.10 (C-H ) ; 1666.91 (C=O) ; 1348.29 (C-N);  1263.42 (C-F); 736.83 (C-Cl).

 

3-(3-(2-chlorophenylamino)-4-fluorophenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione. (8c)

IR(KBr) (cm-1): 3433.41 (N-H ) ; 3140.22, 2926.11 (C-H ) ; 1663.06  (C=O) ; 1366.66 (C-N) ; 1263.42 (C-F); 761.91 (C-Cl) .

 

3-(3-(3-chlorophenylamino)-4-fluorophenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione (8d)

IR(KBr) (cm-1): 3439.19  (N-H ) ; 3174.94, 2812.10 (C-H ) ; 1666.91 (C=O) ; 1348.29 (C-N);  1263.42 (C-F); 736.83 (C-Cl).

 

3-(4-fluoro-3-(phenylamino)phenyl) thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione. (8e)

IR(KBr) (cm-1): 3327.32(N-H ); s3060.05,2950(C-H ) ;1674.27 (C=O); 1304.94(C-N); 1290.60(C-F); 713.69(C-Cl).

 

3-(4-fluoro-3-(4-methyl piperazin-1-yl)phenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione. (8f)

IR(KBr) (cm-1): 3238.89 (N-H ) ; 3147.93, 2850.88 (C-H ) ; 1703.20(C=O); 1301.99(C-N); 1288.85(C-F).

 

3-(4-fluoro-3-(pipridine-1-yl)phenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione (8g)

IR(KBr) (cm-1): 3410.2 (N-H ) ; 3167.22,2965.10 (C-H ) ; 1680.06 (C=O) ; 1383.01(C-N); 1261.19(C-F).

 

3-(4-fluoro-3-(piprazine-1-yl)phenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione. (8h)

IR(KBr) (cm-1): 3238.89 (N-H ) ; 3147.93, 2850.88 (C-H ) ; 1703.20(C=O); 1367.58(C-N); 1242.20(C-F)

 

3-(4-fluoro-3-(pyrrolidine-1-yl)phenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione. (8i)

IR(KBr) (cm-1): 3352.39 (N-H ) ; 3132.50,2936.36 (C-H ) ; 1676.20 (C=O) ; 1236.71(C-N); 1263.42(C-F).

 

3-(3-(2-nitrophenylamino)-4-fluorophenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione.( 8j)

IR(KBr) (cm-1): 3319.40  (O-H) ; 3178.19 (N-H ); 2976.26,2939.61 (C-H  ) ;1651.12(C=O) ; 1366.65 (C-N); 1288.19(C-F).

 

3-(3-(3-nitrophenylamino)-4-fluorophenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione (8k)

IR(KBr) (cm-1): 3448.84  (N-H); 3221.50, 2936.90  (C-H  ); 1 718 (C=O) ; 1360.22 (C-N); 1266.50(C-F).

 

3-(3-(4-nitrophenylamino)-4-fluorophenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione (8l)

IR(KBr) (cm-1): 3412.19  (N-H ); 3173.01, 2901.04 (C-H ); 1654 (C=O); 1311.05 (C-N); 1274.99(C-F).

 

3-(3-(diethylamino)-4-fluorophenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3 H)-dione. (8m)

IR(KBr) (cm-1): 3448.84  (N-H) ; 3221.50, 2936.90  (C-H ); 1718 (C=O) ; 1360.22 (C-N); 1283.87(C-F)

 

3-(4-fluoro-3-(2-hydroxyphenylamino)phenyl)thieno[2,3- d]pyrimidine-2,4(1 H,3H)-dione. (8n)

IR(KBr) (cm-1): 3319.40  (O-H); 3178.19 (N-H ); 2976.26,2939.61 (C-H ) ; 1651.12(C=O) ; 1366.65 (C-N); 1283.19(C-F).

 

CONCLUSION:

Substituted analogues of thieno(2,3-d)pyrimidine served as pharmacologically active lead molecule as supported by previous research work done at our research lab and literature. All compounds were synthesized in good yield and high purity (table-1). All synthesized compounds  characterized by IR and NMR and evaluate the antibacterial activity, compounds 8b, 8h and 8e showed good activity.  Substitution at third position in Thienopyrimidine, it demonstrated good antibacterial activity (table-2). 

 

ACKNOWLEDGEMENT:

Authors want to express their thanks to Shushrutha Educational Trust’s, Nargund College of Pharmacy, Dattatreya Nagar, BSK III Stage, Bangalore-560085, Karnataka, India.

 

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Received on 04.09.2012         Modified on 27.09.2012

Accepted on 24.02.2013         © AJRC All right reserved

Asian J. Research Chem. 6(2):  February 2013; Page 177-181